Takayuki Ise, 内藤 紘一, 佐藤 聡見, 小野 慎太郎, 石井 亜由美, 西川 幸治, Muneyuki Kadota, Shusuke Yagi and Masataka Sata : ウェアラブルデバイスとコミュニケーションアプリを用いた遠隔伴走型心リハシステムの開発, Jul. 2023.
7.
田中 君枝 and Masataka Sata : 心臓周囲脂肪/内臓脂肪, Apr. 2023.
8.
田中 君枝 and Masataka Sata : EPAをめぐるコントロバーシー, Mar. 2023.
9.
Shusuke Yagi, Takayuki Ise, Muneyuki Kadota, Tserensonom Munkhtsetseg, 石井 亜由美, 西川 幸治 and Masataka Sata : 冠動脈疾患の一次予防に関する身体活動指導, Oct. 2022.
10.
Masataka Sata : 各都道府県における循環器病対策推進協議会の活動報告, Sep. 2022.
11.
Masataka Sata : 選択的心筋ミオシン活性化薬であるomecamtiv mecarbil, Jun. 2022.
12.
Koji Yamaguchi and Masataka Sata : 血管機能不全の診断, Jan. 2022.
13.
Koji Yamaguchi and Masataka Sata : 生活習慣病から起こる心臓病について, Tokushima Medical Association, Dec. 2021.
(Summary)
Formerly, we used to call the disease caused by hypertension, diabetes, hyperlipidemia, or history of smoking etc ``Adult Disease''. Recently, that is called ``Lifestyle Disease''. Lifestyle disease is associated with ischemic heart disease. Percutaneous coronary intervention using durable polymer(DP)drug-eluting stents(DESs)has been the most common strategy to treat patients with symptomatic coronary artery disease. Use of first-generation DESs reduced in-stent restenosis rates compared with bare metal stents(BMSs); however, their use was associated with late stent thrombosis due to delayed arterial healing. Therefore, the patients with DESs need to continue antiplatelet therapy for more than one month. On the other hand, in several situations where foreign body reaction may occur, stent materials should not be left in the patient. Recently, several clinical trials have supported the efficacy of drugcoated balloons(DCBs)in the treatment of stent restenosis and small vessel de novo lesions. Finally, we propose the following, ① It is possible to prevent the arterioscrelosis and reduce the onset probability of heart disease(ischemic heart disease)by improving lifestyle habit. ② The therapy of ischemic heart disease progresses recently, and we get several new devices for restenosis lesions and severe calcified lesions. ③ It is important for the patients who undergo the catheter therapy to control the status of lifestyle disease. The good relationship between the patient and the doctor is sure to lead the patient to longevity in the future.
Akira Takashima and Masataka Sata : Ⅴ心臓疾患 心臓膿瘍(心嚢内膿瘍), Sep. 2019.
24.
田中 君枝 and Masataka Sata : 動脈硬化の基礎, Nankodo, Jan. 2018.
25.
Akira Takashima and Masataka Sata : ω系不飽和脂肪酸の心血管イベントリスク低減作用, YODOSHA CO., LTD., 2018.
26.
Masataka Sata : 6., 朝倉書店, Mar. 2017.
27.
Koji Yamaguchi and Masataka Sata : 2. 冠動脈疾患, Iyaku Journal Co., Ltd., Mar. 2017.
28.
Akira Takashima and Masataka Sata : Omega-3 polyunsaturated fatty acids reduce the risk of cardiovascular events in the patients with ischemic heart disease and heart failure, The Vitamin Society of Japan, 2017.
Masataka Sata, K Tanaka and Daiju Fukuda : Wire-mediated endovascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia., Springer Japan, Tokyo, Mar. 2016.
Masataka Sata, Tanaka Kimie and Daiju Fukuda : Wire-Mediated Eendovascular Injury That Induces Rapid Onset of Medical Cell Apoptosis Followed by Reproducible Neointimal Hyperplasia., Springer Japan, 2016.
34.
Masataka Sata and しらいし やすこ : 医学監修, 辰巳出版, Tokyo, Dec. 2015.
35.
高島 啓, Takayuki Ise and Masataka Sata : 心不全治療に魚油が効く!?-ω-3不飽和脂肪酸慢性心不全治療へ- (第4章 慢性心不全の治療 1. 内服治療 ), Medicus SHUPPAN, Osaka, Oct. 2014.
36.
Shusuke Yagi and Masataka Sata : 甲状腺疾患と心臓, Nankodo, Tokyo, Jan. 2014.
37.
Masataka Sata : 第Ⅱ章 冠動脈イベントの機序を知る 1 冠動脈イベントのプロセスを理解しよう(TOPICS 心臓周囲脂肪組織とその意義), Nankodo, Tokyo, Oct. 2013.
38.
田中 君枝 and Masataka Sata : 第Ⅱ章 冠動脈イベントの機序を知る 1 冠動脈イベントのプロセスを理解しよう (1 血管内皮機能とその異常 2 単球とリンパ球 3 動脈硬化プラークの進展 4 動脈硬化プラークの破裂 5 血栓形成を促進させるもの) 冠動脈疾患のパーフェクトマネジメント, Nankodo, Tokyo, Oct. 2013.
39.
Takeshi Soeki and Masataka Sata : 循環器領域における新たな検査法の導入, Nankodo, Tokyo, Jun. 2013.
40.
Michio Shimabukuro, M Dagvasumberel, Masayoshi Ishida, Sachiko Matsumoto, 小塚 智沙代, 平良 伸一, 屋比久 浩市, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Seiichi Oyadomari, 益埼 裕章 and Masataka Sata : Ectopic fat deposition, type 2 diabetes mellitus and cardiovascular diseases, Tokushima Medical Association, Tokushima, Apr. 2013.
(Summary)
There is evidence supporting the notion that excess abdominal fat is predictive of insulin resistance and the presence of related metabolic abnormalities currently referred to as the metabolic syndrome (MetS). Despite the fact that abdominal obesity is a highly prevalent feature of MetS, the mechanisms by which abdominal obesity is causally related to MetS are not fully elucidated. Besides visceral fat accumulation, ectopic lipid deposition, especially in the liver and skeletal muscle, has been implicated in the pathophysiology of diabetes, insulin resistance and obesity-related disorders. In addition, ectopic fat deposition play a critical role in the heart components such as (1) circulatory and locally recruited fat, (2) intra-and extra-myocellular fat, (3) perivascular fat, and (4) pericardial fat. In this review, the contribution of ectopic lipid deposition to global cardiometabolic risk is discussed via possible mechanisms including adipocytokine, insulin resistance and lipotoxicity.
沖 美環 and Masataka Sata : 動脈硬化を改善する効果があります, 文光堂, Tokyo, Feb. 2013.
42.
原 知也 and Masataka Sata : 血管機能を改善する効果があります, 文光堂, Tokyo, Feb. 2013.
43.
田中 君枝 and Masataka Sata : 5. 動脈硬化とアレルギー・炎症, 株式会社 中外医学社, Tokyo, Jan. 2013.
44.
Yoshio Taketani and Masataka Sata : 4. 治療薬総論 硝酸薬, IGAKU-SHOIN Ltd.Tokyo,Japan, Jan. 2013.
45.
Takeshi Soeki and Masataka Sata : 第2章 7. むずかしくてイヤになる動脈硬化のサイエンス, YODOSHA CO., LTD., Tokyo, Nov. 2012.
46.
田中 君枝 and Masataka Sata : 第2章 糖代謝関連 2．PPARγ, Medical Review Co.,Ltd, Osaka, Jul. 2012.
47.
田中 君枝 and Masataka Sata : 第II章 8 トランスレーショナルリサーチに期待する予防医学, NANZANDO Co.,Ltd., Tokyo, Mar. 2012.
48.
Koji Yamaguchi and Masataka Sata : 6. 不安定プラーク破裂に関与する因子は何か?, 株式会社 中外医学社, Tokyo, Mar. 2012.
49.
Michio Shimabukuro and Masataka Sata : 心臓病と肥満-メタボリックシンドロームを中心に-, Nankodo, Tokyo, Mar. 2012.
50.
Hirotsugu Kurobe and Masataka Sata : 第6章 病態・治療 Tissue Engineering技術による血管の再生, 朝倉書店, Tokyo, Dec. 2011.
51.
田中 君枝 and Masataka Sata : 第1章 血管構築 間葉系細胞, 朝倉書店, Tokyo, Dec. 2011.
52.
Michio Shimabukuro, 山川 研, 益崎 裕章 and Masataka Sata : 【Ⅰ.基礎・成因】 2. 血管内皮障害の病態, フジメディカル出版, Osaka, May 2011.
53.
Masataka Sata : 2010年の総括, フジメディカル出版, Osaka, May 2011.
54.
Michio Shimabukuro, 山川 研, 益崎 裕章 and Masataka Sata : 血管内皮機能障害の病態, フジメディカル出版, Osaka, Mar. 2011.
55.
平田 陽一郎, 高岡 稔, Masataka Sata and 他 : 異所性脂肪-メタボリックシンドロームの新常識, Japan Medkal Journal, Dec. 2010.
56.
田中 君枝, Masataka Sata and 他 : 疾患モデルの作製と利用-循環器疾患, LIFE-SCIENCE INFORMATION CENTER, Aug. 2010.
57.
Toshiyuki Niki, Masataka Sata and 他 : Ⅶ.心膜疾患，腫瘍 4.心内血栓, Nankodo, Feb. 2010.
58.
Masataka Sata and K Walsh : Contribution of circulating progenitor cells to vascular repair and lesion formation, Humana Press Inc, Totowa,NJ., Aug. 2007.
Masataka Sata and R Nagai : Vascular regeneration and remodeling by circulating progenitor cells, Springer-Verlag, Tokyo, 2005.
60.
K Walsh and Masataka Sata : Regulation of inflammation by Fas ligand expression on the vascular endothelium, Kluwer Academic Publishers, Boston, 1999.
61.
S Sugiura, H Yamashita, Masataka Sata, H Fujita, S Momomura, T Serizawa and H Sugi : Kinetic property of cardiac myosin in vitro, Kluwer Academic Publishers, Boston, 1995.
Academic Paper (Judged Full Paper):
1.
Kenya Kusunose, T Imai, A Tanaka, M Doi, Y Koide, K Fukumoto, T Kadokami, M Ohishi, H Teragawa, N Ohte, Hirotsugu Yamada, Masataka Sata and K Node : Effects of ipragliflozin on left ventricular diastolic function in patients with type 2 diabetes: A sub-analysis of the PROTECT trial, Journal of Cardiology, Vol.84, No.4, 246-252, 2024.
(Summary)
We hypothesized that the beneficial effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on diastolic function might depend on baseline left ventricular (LV) systolic function. To investigate the effects of SGLT2 inhibitors on LV diastolic function in patients with type 2 diabetes mellitus (T2DM), we conducted a post-hoc sub-study of the PROTECT trial, stratifying the data according to LV ejection fraction (LVEF) at baseline. After excluding patients without echocardiographic data at baseline or 24 months into the PROTECT trial, 31 and 38 patients with T2DM from the full analysis dataset of the PROTECT trial who received ipragliflozin or no SGLT2 inhibitor (control), respectively, were included. The primary endpoint was a comparison of the changes in echocardiographic parameters and N-terminal pro-brain natriuretic peptide levels from baseline to 24 months between the two groups stratified according to baseline LVEF. Differences in diastolic functional parameters (e' and E/e') were noted between the two groups. Among the subgroups defined according to median LVEF values, those with higher LVEF (≥60 %) who received ipragliflozin appeared to have a higher e' and lower E/e' than did those who received the standard of care with no SGLT2 inhibitor, indicating longitudinal improvements between baseline and follow up (p = 0.001 and 0.016, respectively). Ipragliflozin generally improved LV diastolic function in patients with type 2 diabetes, the extent of this improvement might appear to vary with LV systolic function.
Shusuke Yagi, Ryosuke Miyamoto, Masayoshi Tasaki, Hiroyuki Morino, Ryuji Otani, Muneyuki Kadota, Takayuki Ise, Hiroki Yamazaki, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Daiju Fukuda, Mitsuharu Ueda and Masataka Sata : The APOA1 p.Leu202Arg variant potentially causes autosomal recessive cardiac amyloidosis., Human Genome Variation, Vol.11, No.1, 2024.
(Summary)
ApoA-I amyloidosis is an extremely rare form of systemic amyloidosis that commonly involves the heart, kidneys, and liver. ApoA-I amyloidosis is caused by amyloidogenic variants of APOA1 that are inherited in an autosomal dominant manner. Here, we report a 69-year-old man with sporadic cardiac amyloidosis who was born to consanguineous parents and carried a homozygous variant of p.Leu202Arg in APOA1.
Bollos Christine Anne Leah Locsin, Ryosuke Kasai, Hideki Otsuka, Youichi Otomi, Koji Yamaguchi, Tomomi Matsuura, Tamaki Otani, Takanori Bandoh, Yuya Ueki, Noritake Matsuda, Satoru Takashi, Shota Azane, Yamato Kunikane, Shoichiro Takao, Shusuke Yagi, Masataka Sata, Hitoshi Ikushima and Masafumi Harada : Ventilation/Perfusion Mismatch in Pulmonary Vein Stenosis Secondary to Atrial Fibrillation Ablation, Asia Oceania Journal of Nuclear Medicine & Biology, 2024.
(Summary)
We present two patients with a history of paroxysmal atrial fibrillation who developed pulmonary vein stenosis (PVS) following atrial fibrillation (AF) ablation. Case 1 involved a female patient in her 50s who was asymptomatic for pulmonary symptoms but was found to have a high degree of left superior PVS 15 months after AF ablation. This was demonstrated using contrast-enhanced computed tomography (CE-CT) and supported by findings of perfusion defects on ventilation-perfusion (V/Q) scan. Case 2 was a male patient in his 60s who developed progressive left superior PVS nine months after AF ablation, evidenced by serial CE-CT and V/Q scans. PVS is a rare but well-known complication of pulmonary vein ablation for the treatment of AF that can lead to severe complications if left untreated. V/Q scans effectively assess the functional significance of PVS by detecting abnormal blood flow segments. Although a V/Q mismatch characterized by reduced perfusion defects is more commonly used in evaluating pulmonary embolism, PVS should not be disregarded as a differential diagnosis. Few studies emphasize the utility of V/Q scans in managing PVS and highlight V/Q mismatch as a notable finding. This case report aimed to highlight their significance.
Shusuke Yagi, Muneyuki Kadota, Ryo Bando, Ryosuke Miyamoto, Hiroyuki Morino, Akiyoshi Kakutani, Yoshiaki Kubo, Takayuki Ise, Rie Ueno, Tomoya Hara, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Daiju Fukuda and Masataka Sata : Pulmonary Arterial Hypertension in Neurofibromatosis Type 1: A Case with a Novel NF1 Gene Mutation, Internal Medicine, 2024.
(Summary)
Neurofibromatosis type 1 (NF1) is an autosomal dominant multi-organ disease. The clinical manifestations include not only skin lesions and malignant tumors but also lung complications, including pulmonary arterial hypertension (PAH). However, the association between gene mutations in NF1 and the occurrence of PAH has not yet been elucidated. We herein report a case of isolated PAH in a 67-year-old woman with NF1, presumably caused by a novel heterozygous mutation, c.4485_4486delinsAT (p.Lys1496Ter), in the NF1 gene.
TOMONORI Takahashi, Tetsuzo Wakatsuki, Takayuki Ise and Masataka Sata : Spontaneous thrombosis of a giant aneurysm complicated with the coronary-to-pulmonary artery fistula: a case report, European Heart Journal. Case Reports, Vol.8, 2024.
(Summary)
Background A coronary-to-pulmonary artery fistula (CPAF) with a giant aneurysm is a rare clinical occurrence. The rupture of an aneurysm leads to a fatal outcome, thus prompting the incorporation of prophylactic measures, which have encompassed surgical resections or endovascular embolization procedures. The indications for these treatment strategies are controversial, and little has been elucidated regarding the salient characteristics underpinning the selection of a therapeutic strategy. We report a case of a giant aneurysm associated with CPAFs that was thrombosed before interventional treatment. Case summary A 43-year-old woman, who had previously undergone a right adrenalectomy for primary aldosteronism, was referred for an abnormal heart silhouette on a chest X-ray, which had not been seen three years earlier. Contrast-enhanced computed tomography and coronary angiography (CAG) revealed a giant aneurysm on the anterior aspect of the heart associated with two CPAFs. Because of the risk of rupture of the aneurysm, surgical resection was recommended; however, the patient requested endovascular therapy. On the day of intervention, CAG showed spontaneous occlusion of the feeding vessel to the aneurysm, and the aneurysm showed minimal contrast agent, suggesting spontaneous thrombosis. Because of possible recanalization of the aneurysm, coil embolization was performed, without complications. The patient remained asymptomatic, and the aneurysm was completely embolized at the one-year follow-up. Discussion The case shows that minimally invasive endovascular treatment is feasible instead of surgical resection for giant aneurysms associated with CPAFs, depending on their morphological characteristics. This perspective may offer novel insights into treatment strategies for CPAF.
A Fujiyoshi, S Kohsaka, J Hata, M Hara, H Kai, D Masuda, N Miyamatsu, Y Nishio, M Ogura, Masataka Sata, K Sekiguchi, Y Takeya, K Tamura, A Wakatsuki, H Yoshida, Y Fujioka, R Fukazawa, O Hamada, A Higashiyama, M Kabayama, K Kanaoka, K Kawaguchi, S Kosaka, A Kunimura, A Miyazaki, M Nii, M Sawano, M Terauchi, Shusuke Yagi, T Akasaka, T Minamino, K Miura and K Node : JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease, Circulation Journal, Vol.88, No.5, 763-842, 2024.
(Keyword)
Humans / Coronary Artery Disease / Primary Prevention / Japan
Uugantsetseg Munkhjargal, Daiju Fukuda, J Maeda, Tomoya Hara, S Okamoto, O Bavuu, Takayuki Yamamoto and Masataka Sata : LCZ696, an Angiotensin Receptor-Neprilysin Inhibitor, Ameliorates, Journal of Atherosclerosis and Thrombosis, Vol.31, No.9, 1333-1340, 2024.
Motoki Sugasaki, S Nakamura, K Teramoto, M Urushihara, Y Inoue, T Nakao, Yasuhiko Nishioka and Masataka Sata : Lupus anticoagulant hypoprothrombinemia syndrome with multiple and high-titer antiphospholipid antibodies strongly interfered with coagulation assays, Blood Coagulation & Fibrinolysis, Vol.35, No.3, 149-153, 2024.
Yoshihito Saijyo, Kenya Kusunose, TOMONORI Takahashi, Hirotsugu Yamada, Masataka Sata, Kimi Sato, Noor Albakaa, Tomoko Ishizu, Yoshihiro Seo and JSE TAVI investigators : Impact of Transcatheter Aortic Valve Replacement on Cardiac Reverse Remodeling and Prognosis in Mixed Aortic Valve Disease, Journal of the American Heart Association, Vol.13, No.4, e033289, 2024.
(Summary)
The management of mixed aortic valve disease (MAVD), defined as the concomitant presence of aortic stenosis (AS) and aortic regurgitation, remains a clinical challenging. The present study assessed the impact of transcatheter aortic valve replacement (TAVR) on cardiac geometry and prognosis in patients with MAVD. A retrospective multicenter TAVR registry was conducted, including patients who underwent TAVR for severe symptomatic AS between January 2015 and March 2019. Patients were subdivided into 2 groups according to concomitant presence of moderate or more severe aortic regurgitation as the MAVD group, and with mild or less severe aortic regurgitation as the isolated AS group. The primary outcome was a composite of cardiovascular death and rehospitalization due to cardiovascular causes. A total of 1742 patients (isolated AS, 1522 patients; MAVD, 220 patients) were included (84.0±5.2 years). Although MAVD exhibited significantly larger left ventricular volumes and higher left ventricular mass index at the TAVR procedure than isolated AS (respectively, <0.001), MAVD showed a greater improvement of left ventricular volumes and left ventricular mass index after TAVR (respectively, ≤0.001). During a median follow-up of 747 days, 301 patients achieved the primary event. The prognosis post-TAVR was comparable between the 2 groups (log-rank =0.65). Even after adjustment using propensity score matching to reduce the potential bias between the 2 groups, similar results were obtained for the entire cohort. Despite more advanced cardiac remodeling in MAVD at the time of TAVR compared with isolated AS, a greater improvement of cardiac reverse remodeling was found in MAVD, and the prognosis following TAVR was comparable between the 2 groups.
Yukina Hirata, Yuka Nomura, Yoshihito Saijyo, Masataka Sata and Kenya Kusunose : Reducing echocardiographic examination time through routine use of fully automated software: a comparative study of measurement and report creation time, Journal of Echocardiography, 2024.
(Summary)
Manual interpretation of echocardiographic data is time-consuming and operator-dependent. With the advent of artificial intelligence (AI), there is a growing interest in its potential to streamline echocardiographic interpretation and reduce variability. This study aimed to compare the time taken for measurements by AI to that by human experts after converting the acquired dynamic images into DICOM data. Twenty-three consecutive patients were examined by a single operator, with varying image quality and different medical conditions. Echocardiographic parameters were independently evaluated by human expert using the manual method and the fully automated US2.ai software. The automated processes facilitated by the US2.ai software encompass real-time processing of 2D and Doppler data, measurement of clinically important variables (such as LV function and geometry), automated parameter assessment, and report generation with findings and comments aligned with guidelines. We assessed the duration required for echocardiographic measurements and report creation. The AI significantly reduced the measurement time compared to the manual method (159 ± 66 vs. 325 ± 94 s, p < 0.01). In the report creation step, AI was also significantly faster compared to the manual method (71 ± 39 vs. 429 ± 128 s, p < 0.01). The incorporation of AI into echocardiographic analysis led to a 70% reduction in measurement and report creation time compared to manual methods. In cases with fair or poor image quality, AI required more corrections and extended measurement time than in cases of good image quality. Report creation time was longer in cases with increased report complexity due to human confirmation of AI-generated findings. This fully automated software has the potential to serve as an efficient tool for echocardiographic analysis, offering results that enhance clinical workflow by providing rapid, zero-click reports, thereby adding significant value.
Yukina Hirata, Takumasa Tsuji, Jun'ichi Kotoku, Masataka Sata and Kenya Kusunose : Echocardiographic artificial intelligence for pulmonary hypertension classification, Heart, Vol.110, No.8, 586-593, 2024.
(Summary)
The classification of pulmonary hypertension (PH) is crucial for determining the appropriate therapeutic strategy. We investigated whether machine learning (ML) algorithms may assist in echocardiographic PH prediction, where current guidelines recommend integrating several different parameters. We obtained physical and echocardiographic data from 885 patients who underwent right heart catheterisation (RHC). Patients were classified into three groups: non-PH, precapillary PH and postcapillary PH, based on values obtained from RHC. Using 24 parameters, we created predictive models employing four different classifiers and selected the one with the highest area under the curve. We then calculated the macro-average classification accuracy for PH on the derivation cohort (n=720) and prospective validation data set (n=165), comparing the results with guideline-based echocardiographic assessment obtained from each cohort. Logistic regression with elastic net regularisation had the highest classification accuracy, with areas under the curves of 0.789, 0.766 and 0.742 for normal, precapillary PH and postcapillary PH, respectively. The ML model demonstrated significantly better predictive accuracy than the guideline-based echocardiographic assessment in the derivation cohort (59.4% vs 51.6%, p<0.01). In the independent validation data set, the ML model's accuracy was comparable to the guideline-based PH classification (59.4% vs 57.8%, p=0.638). This preliminary study suggests promising potential for our ML model in predicting echocardiographic PH. Further research and validation are needed to fully assess its clinical utility in PH diagnosis and treatment decision-making.
N Yamaguchi, Yukina Hirata, Susumu Nishio, TOMONORI Takahashi, Yoshihito Saijo, Muneyuki Kadota, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata and Kenya Kusunose : Pulmonary Pressure-flow responses to exercise in heart failure treated with angiotensin receptor neprilysin inhibitor., International Journal of Cardiology, Vol.400, 131789, 2024.
(Summary)
The role of the angiotensin receptor neprilysin inhibitor (ARNI) in cardiac function, particularly its impact on pulmonary circulation, remains underexplored. Recent studies have described abnormal mean pulmonary artery pressure (mPAP)-cardiac output (CO) responses as having the potential to assess the disease state. The aim of this study was to assess the effects of ARNI on pulmonary circulation in heart failure. We measured echocardiographic parameters post 6-min walk (6 MW) and compared the changes with baseline and follow-up. Our hypothesis was that pulmonary pressure-flow relationship of the pulmonary circulation obtained by 6 MW stress echocardiography would be improved with treatment. We prospectively enrolled 39 heart failure patients and conducted the 6 MW test indoors. Post-6 MW echocardiography measured echocardiographic variables, and CO was derived from electric cardiometry. Individualized ARNI doses were optimized, with follow-up echocardiographic evaluations after 1 year. Left ventricular (LV) volume were significantly reduced (160.7 ± 49.6 ml vs 136.0 ± 54.3 ml, P < 0.001), and LV ejection fraction was significantly improved (37.6 ± 11.3% vs 44.9 ± 11.5%, P < 0.001). Among the 31 patients who underwent 6 MW stress echocardiographic study at baseline and 1 year later, 6 MW distance increased after treatment (380 m vs 430 m, P = 0.003). The ΔmPAP/ΔCO by 6 MW stress decreased with treatment (6.9 mmHg/L/min vs 2.8 mmHg/L/min, P = 0.002). The left atrial volume index was associated with the response group receiving ARNI treatment for pulmonary circulation. Initiation of ARNI was associated with improvement of left ventricular size and LVEF. Additionally, the 6 MW distance increased and the ΔmPAP/ΔCO was improved to within normal range with treatment.
S Yamaguchi, M Maeda, K Oba, G Maimaituxun, O Arasaki, Shusuke Yagi, Kenya Kusunose, Takeshi Soeki, Hirotsugu Yamada, Daiju Fukuda, H Masuzaki, Masataka Sata and Michio Shimabukuro : Sex differences in the association between epicardial adipose tissue volume and left atrial volume index, BMC Cardiovascular Disorders, Vol.24, No.1, 46, 2024.
(Summary)
Sex disparities in the association between epicardial adipose tissue volume (EATV) and cardiovascular disease have been reported. The sex-dependent effects of EATV on left atrial (LA) size have not been elucidated. Consecutive 247 subjects (median 65 [interquartile range 57, 75] years; 67% of men) who underwent multi-detector computed tomography without significant coronary artery disease or moderate to severe valvular disease were divided into two groups: patients with sinus rhythm (SR) or atrial fibrillation (AF). Sex differences in the association between the EATV index (EATVI) (mL/m) and LA volume index (LAVI) in 63 SR (28 men and 35 women) and 184 AF (137 men and 47 women) patients were evaluated using univariate and multivariate regression analyses. In overall that includes both men and women, the relationship between EATVI and LAVI was not significantly correlated for patients with SR and AF. The relationship between EATVI and LAVI differed between men and women in both SR and AF groups. In SR patients, there was a positive relationship between EATVI and LAVI in men, but not in women. In contrast, in patients with AF, a negative relationship was found between EATVI and LAVI in women, whereas no association was found in men. We evaluated sex differences in the association between EATVI and LAVI in patients with either SR or AF, and found a positive relationship in men with SR and a negative relationship in women with AF. This is the first report to evaluate sex differences in the relationship between EATVI and LAVI, suggesting that EAT may play a role, at least in part, in sex differences in the etiology of AF.
Y Higashikuni, W Liu and Masataka Sata : Nocturnal blood pressure and left ventricular hypertrophy in patients with diabetes mellitus, Hypertension Research, Vol.47, No.3, 819-822, 2023.
Kenya Kusunose, T Tsuji, Yukina Hirata, TOMONORI Takahashi, Masataka Sata, K Sato, N Albakaa, T Ishizu, J Kotoku and Y Seo : Unsupervised cluster analysis reveals different phenotypes in patients after transcatheter aortic valve replacement, European Heart Journal Open, Vol.4, No.1, oead136, 2023.
(Summary)
The aim of this study was to identify phenotypes with potential prognostic significance in aortic stenosis (AS) patients after transcatheter aortic valve replacement (TAVR) through a clustering approach. This multi-centre retrospective study included 1365 patients with severe AS who underwent TAVR between January 2015 and March 2019. Among demographics, laboratory, and echocardiography parameters, 20 variables were selected through dimension reduction and used for unsupervised clustering. Phenotypes and outcomes were compared between clusters. Patients were randomly divided into a derivation cohort ( = 1092: 80%) and a validation cohort ( = 273: 20%). Three clusters with markedly different features were identified. Cluster 1 was associated predominantly with elderly age, a high aortic valve gradient, and left ventricular (LV) hypertrophy; Cluster 2 consisted of preserved LV ejection fraction, larger aortic valve area, and high blood pressure; and Cluster 3 demonstrated tachycardia and low flow/low gradient AS. Adverse outcomes differed significantly among clusters during a median of 2.2 years of follow-up ( < 0.001). After adjustment for clinical and echocardiographic data in a Cox proportional hazards model, Cluster 3 (hazard ratio, 4.18; 95% confidence interval, 1.76-9.94; = 0.001) was associated with increased risk of adverse outcomes. In sequential Cox models, a model based on clinical data and echocardiographic variables ( = 18.4) was improved by Cluster 3 ( = 31.5; = 0.001) in the validation cohort. Unsupervised cluster analysis of patients after TAVR revealed three different groups for assessment of prognosis. This provides a new perspective in the categorization of patients after TAVR that considers comorbidities and extravalvular cardiac dysfunction.
Munkhtsetseg Tserensonom, Shusuke Yagi, Takayuki Ise, Yutaka Kawabata, Muneyuki Kadota, Tomoya Hara, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis, The Journal of Medical Investigation : JMI, Vol.70, No.3.4, 450-456, 2023.
(Summary)
Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.
PT Pham, Oyunbileg Bavuu, JR Kim-Kaneyama, XF Lei, T Yamamoto, K Otsuka, Kumiko Suto, Kenya Kusunose, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Michio Shimabukuro, GN Barber, Masataka Sata and Daiju Fukuda : Innate Immune System Regulated by Stimulator of Interferon Genes, a Cytosolic DNA Sensor, Regulates Endothelial Function, Journal of the American Heart Association, Vol.12, No.22, e030084, 2023.
(Summary)
Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin-induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild-type mice. Streptozotocin elevated blood glucose and lipid levels in both wild-type and STING-deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (<0.05) in STZ-injected mice. Endothelium-independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP-AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, and ) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP-AMP significantly impaired endothelial function of aortic segments obtained from wild-type mice, which was ameliorated in the presence of C-176, a STING inhibitor, or a neutralizing interferon-β antibody. Furthermore, the administration of C-176 ameliorated endothelial dysfunction in STZ-induced diabetic mice (<0.01). Conclusions The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.
T Yamaji, T Harada, M Kajikawa, T Maruhashi, S Kishimoto, FM Yusoff, K Chayama, C Goto, A Nakashima, H Tomiyama, B Takase, T Kohro, T Suzuki, T Ishizu, S Ueda, T Yamazaki, T Furumoto, K Kario, T Inoue, K Watanabe, Y Takemoto, T Hano, Masataka Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito, A Yamashina, S Koba and Y Higashi : Role of Small Dense Low-density Lipoprotein Cholesterol in Cardiovascular Events in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus Receiving Statin Treatment, Journal of Atherosclerosis and Thrombosis, Vol.31, No.4, 478-500, 2023.
(Summary)
There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of <40.0 mg/dL and TG of <150 mg/dL, sdLDL-C of 40.0 mg/dL and TG of <150 mg/dL, sdLDL-C of <40.0 mg/dL and TG of 150 mg/dL, and sdLDL-C of 40.0 mg/dL and TG of 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of 40.0 mg/dL and TG of <150 mg/dL and in patients with sdLDL-C of 40.0 mg/dL and TG of 150 mg/dL, but not in patients with sdLDL-C of <40.0 mg/dL and TG of 150 mg/dL, than in patients with sdLDL-C of <40.0 mg/dL and TG of <150 mg/dL. Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at <150 mg/dL.
(Keyword)
Small dense low-density lipoprotein cholesterol / Triglycerides / Type 2 diabetes mellitus / Statin / Cardiovascular events
TOMONORI Takahashi, H Iwano, K Shibayama, T Kitai, H Tanaka, Hirotsugu Yamada, Masataka Sata and Kenya Kusunose : The Clinical Utility of Noninvasive Forrester Classification in Acute Heart Failure from PREDICT Study, The American Journal of Cardiology, Vol.207, 75-81, 2023.
(Summary)
The Forrester classification plays a crucial role in comprehending the underlying pathophysiology of heart failure (HF) and is employed to categorize the severity and predict the outcomes of patients with acute HF. Our objective was to assess the predictive value of the Forrester classification, based on noninvasive hemodynamic measurements obtained through Doppler echocardiography at admission, in forecasting the short-term prognosis posthospitalization of patients with acute HF. Patients were recruited for the Prospect trial to elucidate the utility of EchocarDIography-based Cardiac ouTput in acute heart failure (PREDICT) study, a multicenter, prospective study conducted in Japan. Participants were stratified into 4 profiles using cardiac index (CI) and early mitral filling velocity (E)/early-diastolic mitral annular velocity (e') ratio obtained from Doppler echocardiography upon admission (profile I: CI >2.2, E/e' ≤15, profile II: CI >2.2, E/e' >15, profile III: CI ≤2.2, E/e' ≤15, profile IV: CI ≤2.2, E/e' >15). The primary composite outcome of the study was all-cause mortality or worsening HF during the 14 days of hospitalization. Cox proportional hazards model analysis was employed to identify prognostic factors during the observation period. A total of 270 subjects, with a mean age of 74 ± 14 years and a male proportion of 60%, were enrolled in the study. During the 14-day period of hospitalization, 58 participants (22%) had a composite outcome. Patients with low CI (i.e., profiles III and IV) demonstrated an elevated risk of composite outcome after adjusting for confounding variables, as evidenced by the adjusted hazard ratios of 5.85 (95% confidence interval 1.17 to 29.09, p <0.01, vs profile III) and 6.50 (95% confidence interval 1.53 to 27.68, p <0.01, vs profile IV) in comparison with profile I, respectively. In conclusion, the Forrester classification, derived from noninvasive Doppler echocardiography at admission, may predict early deterioration in patients hospitalized with acute HF.
Sanae Morita, Yukina Hirata, Susumu Nishio, TOMONORI Takahashi, Yoshihito Saijo, Hirotsugu Yamada, Masataka Sata and Kenya Kusunose : Correlation between energy loss index and B-type natriuretic peptide: a vector flow mapping study, Journal of Echocardiography, Vol.22, No.1, 25-33, 2023.
(Summary)
Vector Flow Mapping (VFM) and Energy Loss (EL) evaluation are emerging echocardiographic techniques that offer detailed insights into cardiac function. This study aimed to explore the relationship between EL parameters and B-type natriuretic peptide (BNP) levels, a well-established marker of heart failure severity. Our study prospectively enrolled 62 patients experiencing shortness of breath and suspected heart failure, who underwent echocardiography and had BNP levels measured between January 2018 and August 2020. Patients were stratified based on BNP levels, and their clinical and echocardiographic characteristics were evaluated. Univariate and multivariate regression analyses were performed to assess the correlation between BNP levels and various echocardiographic variables, including VFM parameters. Patients were stratified into two groups based on their BNP levels: BNP < 200 pg/ml (n = 53) and BNP 200 pg/ml (n = 9). Patients with BNP 200 pg/ml presented significantly different clinical and echocardiographic characteristics, such as older age, larger left ventricular mass and volume indices, higher pulmonary artery systolic pressure, higher E/e' ratio, and larger EL parameters. Multivariate regression analysis demonstrated the E/e' ratio and ELA (EL during Atrial contraction phase/A wave ratio as significant determinants of logBNP. Receiver operating characteristic curve analysis showed ELA/A > 36.0 J/m as a significant predictor of high BNP with 89% sensitivity and 85% specificity. ELA/A demonstrated an incremental diagnostic value over elevated left atrial pressure for predicting high BNP (C statistic = 0.98 vs 0.74, P = 0.006). This study provides novel insights into the potential utility of EL parameters as auxiliary indicators of cardiac load, thereby enhancing our understanding of heart failure.
N Masaki, T Adachi, H Tomiyama, T Kohro, T Suzuki, T Ishizu, S Ueda, T Yamazaki, T Furumoto, K Kario, T Inoue, S Koba, Y Takemoto, T Hano, Masataka Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito, Y Higashi, A Yamashina and B Takase : Reduced reactive hyperemia of the brachial artery in diabetic patients assessed by repeated measurements: The FMD-J B study, Physiological Reports, Vol.11, No.16, e15786, 2023.
(Summary)
Type 2 diabetes mellitus (T2DM) is a major cause of microvascular dysfunction. However, its effect on blood flow patterns during ischemic demand has not been adequately elucidated. In this study, we investigated the hypothesis that microvascular dysfunction in patients with T2DM manifests as brachial reactive hyperemia (BRH), defined as the ratio of peak blood flow velocities in a brachial artery before and after forearm cuff occlusion. The study enrolled 943 subjects (men, n = 152 [T2DM] and n = 371 [non-T2DM]; women, n = 107 [T2DM] and n = 313 [non-T2DM], respectively) with no history of cardiovascular disease. Semiautomatic measurements were obtained three times at 1.5-year intervals to confirm the reproducibility of factors involved in BRH for each sex. An age-adjusted mixed model demonstrated attenuated BRH in the presence of T2DM in both men (p = 0.022) and women (p = 0.031) throughout the study period. Post hoc analysis showed that the estimated BRH was significantly attenuated in patients with T2DM regardless of sex, except at baseline in women. In multivariate regression analysis, T2DM was a negative predictor of BRH at every measurement in men. For women, BRH was more strongly associated with alcohol consumption. Repeated measurements analysis revealed that T2DM was associated with attenuated postocclusion reactive hyperemia.
(Keyword)
Male / Humans / Female / Brachial Artery / Diabetes Mellitus, Type 2 / Hyperemia / Reproducibility of Results / Forearm
Yasutomi Higashikuni, Wenhao Liu and Masataka Sata : Not a small frog in a big pond: targeting bradykinin receptor B2 signaling in vascular smooth muscle cells for treatment of hypertension, Hypertension Research, Vol.46, No.10, 2415-2418, 2023.
Yuichiro Okushi, Yoshihito Saijyo, Hirotsugu Yamada, Hiroaki Toba, Robert Zheng, Hiromitsu Seno, TOMONORI Takahashi, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata and Kenya Kusunose : Effectiveness of surveillance by echocardiography for Cancer therapeutics-related cardiac dysfunction of patients with breast Cancer, Journal of Cardiology, Vol.82, No.6, 467-472, 2023.
(Summary)
Cancer therapeutics-related cardiac dysfunction (CTRCD) affect the prognosis of patients with breast cancer. Echocardiographic surveillance of patients treated with anti-human epidermal growth factor receptor type 2 (HER2) antibodies has been recommended, but few reports have provided evidence on patients with breast cancer only. We aimed to evaluate the effectiveness of echocardiographic surveillance for breast cancer patients. We identified 250 patients with breast cancer who were treated with anti-HER2 antibodies from July 2007 to September 2021. We divided 48 patients with echocardiographic surveillance every 3 months into the surveillance group and 202 patients without echocardiographic surveillance into the non-surveillance group. In the surveillance group, patients with a considerable reduction in global longitudinal strain of 15 % were considered for the initiation of cardioprotective drugs. The composite outcome of CTRCD and acute heart failure was the study endpoint. The mean age was 59 ± 12 years. During the follow-up period of 15 months (12-17 months), 12 patients reached the endpoint. The surveillance group had significantly lower incidence of the composite outcome (2.1 % vs. 5.5 %, adjusted odds ratio: 0.28, 95 % confidential intervals: 0.09-0.94; p = 0.039) and higher rates of prescriptions of cardioprotective drugs than the non-surveillance group. The incidence of cardiac complications was significantly lower in the surveillance group than the non-surveillance group, which supports the effectiveness of echocardiographic surveillance in patients with breast cancer.
Tomoya Hara, Daiju Fukuda, Byambasuren Ganbaatar, Phuong Tran Pham, Kunduziayi Aini, Arief Rahadian, Kumiko Suto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Olive mill wastewater and hydroxytyrosol inhibits atherogenesis in apolipoprotein E-deficient mice, Heart and Vessels, Vol.38, No.11, 1386-1394, 2023.
(Summary)
The Mediterranean diet, which is characterized by high consumption of olive oil, prevents cardiovascular disease. Meanwhile, olive mill wastewater (OMWW), which is obtained as a byproduct during olive oil production, contains various promising bioactive components such as water-soluble polyphenols. Hydroxytyrosol (HT), the major polyphenol in OMWW, has anti-oxidative and anti-inflammatory properties; however, the atheroprotective effects of OMWW and HT remain to be fully understood. Here, we investigated the effect of OMWW and HT on atherogenesis. Male 8-week-old apolipoprotein E-deficient mice were fed a western-type diet supplemented with OMWW (0.30%w/w) or HT (0.02%w/w) for 20 weeks. The control group was fed a non-supplemented diet. OMWW and HT attenuated the development of atherosclerosis in the aortic arch as determined by Sudan IV staining (P < 0.01, respectively) without alteration of body weight, plasma lipid levels, and blood pressure. OMWW and HT also decreased the production of oxidative stress (P < 0.01, respectively) and the expression of NADPH oxidase subunits (e.g., NOX2 and p22phox) and inflammatory molecules (e.g. IL-1β and MCP-1) in the aorta. The results of in vitro experiments demonstrated that HT inhibited the expression of these molecules that were stimulated with LPS in RAW264.7 cells, murine macrophage-like cells. OMWW and HT similarly attenuated atherogenesis. HT is a major component of water-soluble polyphenols in OMWW, and it inhibited inflammatory activation of macrophages. Therefore, our results suggest that the atheroprotective effects of OMWW are at least partially attributable to the anti-inflammatory effects of HT.
A Tanaka, I Taguchi, I Hisauchi, H Yoshida, Michio Shimabukuro, H Hongo, T Ishikawa, T Kadokami, Shusuke Yagi, Masataka Sata and K Node : Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA), European Journal of Medical Research, Vol.28, No.1, 238, 2023.
(Summary)
Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was - 35.8% (95% confidence interval [CI] - 39.7% to - 32.0%, P < 0.001), with approximately three quarters of patients achieving an SUA level of ≤ 6.0 mg/dL at week 24. The proportional changes from baseline in the geometric mean of CAVI and d-ROMs at week 24 were 0.96 (95% CI 0.92 to 1.00, P = 0.044) and 0.96 (95% CI 0.92 to 1.00, P = 0.044), respectively. In addition to meaningful SUA-lowering effects, 24 weeks of dotinurad therapy may favorably affect arterial stiffness and oxidative stress markers, suggesting off-target vascular protection of dotinurad. Further research is expected to verify our findings and elucidate the entire off-target effects of dotinurad. Trial registration jRCTs021210013, registration date June 24, 2021.
(Keyword)
Male / Humans / Middle Aged / Aged / Aged, 80 and over / Female / Hyperuricemia / Uric Acid / Prospective Studies / Uricosuric Agents / Hypertension
Kenya Kusunose, Shuichiro Kashima and Masataka Sata : Evaluation of the Accuracy of ChatGPT in Answering Clinical Questions on the Japanese Society of Hypertension Guidelines, Circulation Journal, Vol.87, No.7, 1030-1033, 2023.
(Summary)
To assist healthcare providers in interpreting guidelines, clinical questions (CQ) are often included, but not always, which can make interpretation difficult for non-expert clinicians. We evaluated the ability of ChatGPT to accurately answer CQs on the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019).Methods and Results: We conducted an observational study using data from JSH 2019. The accuracy rate for CQs and limited evidence-based questions of the guidelines (Qs) were evaluated. ChatGPT demonstrated a higher accuracy rate for CQs than for Qs (80% vs. 36%, P value: 0.005). ChatGPT has the potential to be a valuable tool for clinicians in the management of hypertension.
Natsumi Yamaguchi, Yoshitaka Kosaka, Akihiro Haga, Masataka Sata and Kenya Kusunose : Artificial intelligence-assisted interpretation of systolic function by echocardiogram, Open Heart, Vol.10, No.2, e002287., 2023.
(Summary)
Precise and reliable echocardiographic assessment of left ventricular ejection fraction (LVEF) is needed for clinical decision-making. Recently, artificial intelligence (AI) models have been developed to estimate LVEF accurately. The aim of this study was to evaluate whether an AI model could estimate an expert read of LVEF and reduce the interinstitutional variability of level 1 readers with the AI-LVEF displayed on the echocardiographic screen. This prospective, multicentre echocardiographic study was conducted by five cardiologists of level 1 echocardiographic skill (minimum level of competency to interpret images) from different hospitals. Protocol 1: Visual LVEFs for the 48 cases were measured without input from the AI-LVEF. Protocol 2: the 48 cases were again shown to all readers with inclusion of AI-LVEF data. To assess the concordance and accuracy with or without AI-LVEF, each visual LVEF measurement was compared with an average of the estimates by five expert readers as a reference. A good correlation was found between AI-LVEF and reference LVEF (r=0.90, p<0.001) from the expert readers. For the classification LVEF, the area under the curve was 0.95 on heart failure with preserved EF and 0.96 on heart failure reduced EF. For the precision, the SD was reduced from 6.1±2.3 to 2.5±0.9 (p<0.001) with AI-LVEF. For the accuracy, the root-mean squared error was improved from 7.5±3.1 to 5.6±3.2 (p=0.004) with AI-LVEF. AI can assist with the interpretation of systolic function on an echocardiogram for level 1 readers from different institutions.
Shusuke Yagi, Tomoya Hara, Hirotsugu Yamada, Kenya Kusunose, Takayuki Ise and Masataka Sata : Intimal Sarcoma of the Pulmonary Artery as an Embolic Cause of Sudden Death, Circulation Journal, Vol.87, No.7, 1036, 2023.
Kenya Kusunose, Yukina Hirata, Natsumi Yamaguchi, Y Kosaka, T Tsuji, J Kotoku and Masataka Sata : Deep learning approach for analyzing chest x-rays to predict cardiac events in heart failure, Frontiers in Cardiovascular Medicine, Vol.10, 1081628, 2023.
(Summary)
A deep learning (DL) model based on a chest x-ray was reported to predict elevated pulmonary artery wedge pressure (PAWP) as heart failure (HF). The aim of this study was to (1) investigate the role of probability of elevated PAWP for the prediction of clinical outcomes in association with other parameters, and (2) to evaluate whether probability of elevated PAWP based on DL added prognostic information to other conventional clinical prognostic factors in HF. We evaluated 192 patients hospitalized with HF. We used a previously developed AI model to predict HF and calculated probability of elevated PAWP. Readmission following HF and cardiac mortality were the primary endpoints. Probability of elevated PAWP was associated with diastolic function by echocardiography. During a median follow-up period of 58 months, 57 individuals either died or were readmitted. Probability of elevated PAWP appeared to be associated with worse clinical outcomes. After adjustment for readmission score and laboratory data in a Cox proportional-hazards model, probability of elevated PAWP at pre-discharge was associated with event free survival, independent of elevated left atrial pressure (LAP) based on echocardiographic guidelines ( < 0.001). In sequential Cox models, a model based on clinical data was improved by elevated LAP (= 0.005), and increased further by probability of elevated PAWP (< 0.001). In contrast, the addition of pulmonary congestion interpreted by a doctor did not statistically improve the ability of a model containing clinical variables (compared = 0.086). This study showed the potential of using a DL model on a chest x-ray to predict PAWP and its ability to add prognostic information to other conventional clinical prognostic factors in HF. The results may help to enhance the accuracy of prediction models used to evaluate the risk of clinical outcomes in HF, potentially resulting in more informed clinical decision-making and better care for patients.
T Tsuji, Yukina Hirata, Kenya Kusunose, Masataka Sata, S Kumagai, K Shiraishi and J Kotoku : Classification of chest X-ray images by incorporation of medical domain knowledge into operation branch networks., BMC Medical Imaging, Vol.23, No.1, 62, 2023.
(Summary)
This study was conducted to alleviate a common difficulty in chest X-ray image diagnosis: The attention region in a convolutional neural network (CNN) does not often match the doctor's point of focus. The method presented herein, which guides the area of attention in CNN to a medically plausible region, can thereby improve diagnostic capabilities. The model is based on an attention branch network, which has excellent interpretability of the classification model. This model has an additional new operation branch that guides the attention region to the lung field and heart in chest X-ray images. We also used three chest X-ray image datasets (Teikyo, Tokushima, and ChestX-ray14) to evaluate the CNN attention area of interest in these fields. Additionally, after devising a quantitative method of evaluating improvement of a CNN's region of interest, we applied it to evaluation of the proposed model. Operation branch networks maintain or improve the area under the curve to a greater degree than conventional CNNs do. Furthermore, the network better emphasizes reasonable anatomical parts in chest X-ray images. The proposed network better emphasizes the reasonable anatomical parts in chest X-ray images. This method can enhance capabilities for image interpretation based on judgment.
U Munkhjargal, Daiju Fukuda, B Ganbaatar, Kumiko Suto, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : A Selective Mineralocorticoid Receptor Blocker, Esaxerenone, Attenuates Vascular Dysfunction in Diabetic C57BL/6 Mice, Journal of Atherosclerosis and Thrombosis, Vol.30, No.4, 326-334, 2023.
(Summary)
Pharmacological blockade of mineralocorticoid receptors (MRs) is a potential therapeutic approach to reduce cardiovascular complications since MRs play a crucial role in cardiovascular regulation. Recent studies suggest that MR antagonists affect several extrarenal tissues, including vessel function. We investigated the effect of a novel nonsteroidal selective MR blocker, esaxerenone, on diabetes-induced vascular dysfunction. Diabetes was induced by a single dose of streptozotocin in 8-week-old male C57BL/6 mice. Esaxerenone (3 mg/kg/day) or a vehicle was administered by gavage to diabetic mice for 3 weeks. Metabolic parameters, plasma aldosterone levels, and parameters related to renal function were measured. Endothelium-dependent or -independent vascular responses of the aortic segments were analyzed with acetylcholine or sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro study. Induction of diabetes elevated plasma aldosterone level (P<0.05) and impaired endothelium-dependent vascular relaxation (P<0.05). The administration of esaxerenone ameliorated the endothelial dysfunction (P<0.01) without the alteration of metabolic parameters, blood pressure, and renal function. Esaxerenone improved the eNOS phosphorylation in the aorta obtained from diabetic mice (P<0.05) compared with that in the vehicle-treated group. Furthermore, a major MR agonist, aldosterone, decreased eNOS phosphorylation and increased eNOS phosphorylation in HUVECs, which recovered with esaxerenone. Esaxerenone ameliorated the endothelium-dependent vascular relaxation caused by aldosterone in the aortic segments obtained from C57BL/6 mice (P<0.001). Esaxerenone attenuates the development of diabetes-induced endothelial dysfunction in mice. These results suggest that esaxerenone has potential vascular protective effects in individuals with diabetes.
A Kudo, N Machii, T Ono, H Saito, Y Oshiro, R Takahashi, K Oshiro, Y Taneda, M Higa, K Nakachi, Shusuke Yagi, H Masuzaki, Masataka Sata and Michio Shimabukuro : Effect of dapagliflozin on 24-hour glycemic variables in Japanese patients with type 2 diabetes mellitus receiving basal insulin supported oral therapy (DBOT): a multicenter, randomized, open-label, parallel-group study, BMJ Open Diabetes Research & Care, Vol.11, No.2, e003302, 2023.
(Summary)
This study aimed to evaluate the impacts of dapagliflozin on 24-hour glucose variability and diabetes-related biochemical variables in Japanese patients with type 2 diabetes who had received basal insulin supported oral therapy (BOT). Changes in mean daily blood glucose level before and after 48-72 hours of add-on or no add-on of dapagliflozin (primary end point) and diabetes-related biochemical variables and major safety variables during the 12 weeks (secondary end point) were evaluated in the multicenter, randomized, two-arm, open-label, parallel-group comparison study. Among 36 participants, 18 were included in the no add-on group and 18 were included in the dapagliflozin add-on group. Age, gender, and body mass index were comparable between the groups. There were no changes in continuous glucose monitoring metrics in the no add-on group. In the dapagliflozin add-on group, mean glucose (183-156 mg/dL, p=0.001), maximum glucose (300-253, p<0.01), and SD glucose (57-45, p<0.05) decreased. Time in range increased (p<0.05), while time above the range decreased in the dapagliflozin add-on group but not in the no add-on group. After 12-week treatment with dapagliflozin add-on, 8-hydroxy-2'-deoxyguanosine (8OHdG), as well as hemoglobin A1c (HbA1c), decreased. This study showed that the mean daily blood glucose and other daily glucose profiles were amended after 48-72 hours of dapagliflozin add-on in Japanese patients with type 2 diabetes who received BOT. The diabetes-related biochemical variables such as HbA1c and urinary 8OHdG were also obtained during the 12 weeks of dapagliflozin add-on without major adverse events. A preferable 24-hour glucose profile in 'time in ranges' and an improvement in reactive oxygen species by dapagliflozin warrant us to evaluate these benefits in larger clinical studies. UMIN000019457.
(Keyword)
Humans / Diabetes Mellitus, Type 2 / Blood Glucose / Hypoglycemic Agents / Glycated Hemoglobin / Blood Glucose Self-Monitoring / 8-Hydroxy-2'-Deoxyguanosine / East Asian People / Treatment Outcome / Insulins
Noritake Matsuda, Hideki Otsuka, Tamaki Otani, Shota Azane, Yamato Kunikane, Yoichi Otomi, Yuya Ueki, Masahiro Kubota, Masafumi Amano, Shusuke Yagi, Masataka Sata and Masafumi Harada : New quantitative indices of cardiac amyloidosis with 99mTc-pyrophosphate scintigraphy, Japanese Journal of Radiology, Vol.41, No.4, 428-436, 2023.
(Summary)
Amyloid light chain (AL) and transthyretin (ATTR) are the major subtypes of cardiac amyloidosis (CA). Tc-pyrophosphate (PYP) scintigraphy is used to differentiate ATTR from other CA subtypes. We adapted the standardized uptake value (SUV) for Tc-PYP and proposed two quantitative indices, amyloid deposition volume (AmyDV) and total amyloid uptake (TAU). This study aimed to evaluate the utility of these quantitative indices in differentiating ATTR from non-ATTRs. Before the SUV measurement, the Becquerel calibration factor (BCF) of Tc was obtained by a phantom experiment. Thirty-two patients who had undergone hybrid SPECT/CT imaging 3 h after injection of Tc-PYP (370 MBq) were studied. CT attenuation correction for image reconstruction was applied in all. We calculated SUV, AmyDV, and TAU using a quantitative analysis software program for bone SPECT (GI-BONE) and analyzed AmyDV using two methods: threshold method (set 40%); and constant value method (average SUV of ribs). We assessed the diagnostic ability of heart-to-contralateral lung (H/CL) ratio, SUV, AmyDV, and TAU to differentiate ATTR from non-ATTR using receiver operating characteristic (ROC) analysis. Statistically significant differences in all quantitative indices were observed between ATTR and non-ATTR. The area under the curve of each quantitative index for discriminating between ATTR and non-ATTR were as follows: H/CL, 0.997; SUV, 0.953; SUV (M1), 0.964; SUV (M2), 0.969; AmyDV (M1), 0.875; AmyDV (M2), 0.974; and TAU, 0.974. The AmyDV (M2) had higher diagnostic ability than AmyDV (M1). Thus, TAU was calculated as AmyDV (M2) × SUV (M2). In the ROC curve, SUV, AmyDV, and TAU had almost the same diagnostic ability as H/CL in distinguishing ATTR from non-ATTRs. We propose two novel 3D-based quantitative parameters (AmyDV and TAU) that have almost equal ability to discriminate ATTR from non-ATTR.
Tomoya Hara, Masataka Sata and Daiju Fukuda : Emerging roles of Protease-Activated Receptors in Cardiometabolic Disorders, Journal of Cardiology, Vol.81, No.4, 337-346, 2023.
(Summary)
Cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis, share sterile chronic inflammation as a major cause; however, the precise underlying mechanisms of chronic inflammation in cardiometabolic disorders are not fully understood. Accumulating evidence suggests that several coagulation proteases, including thrombin and activated factor X (FXa), play an important role not only in the coagulation cascade but also in the proinflammatory responses through protease-activated receptors (PARs) in many cell types. Four members of the PAR family have been cloned (PAR 1-4). For instance, thrombin activates PAR-1, PAR-3, and PAR-4. FXa activates both PAR-1 and PAR-2, while it has no effect on PAR-3 or PAR-4. Previous studies demonstrated that PAR-1 and PAR-2 activated by thrombin or FXa promote gene expression of inflammatory molecules mainly via the NF-κB and ERK1/2 pathways. In obese adipose tissue and atherosclerotic vascular tissue, various stresses increase the expression of tissue factor and procoagulant activity. Recent studies indicated that the activation of PARs in adipocytes and vascular cells by coagulation proteases promotes inflammation in these tissues, which leads to the development of cardiometabolic diseases. This review briefly summarizes the role of PARs and coagulation proteases in the pathogenesis of inflammatory diseases and describes recent findings (including ours) on the potential participation of this system in the development of cardiometabolic disorders. New insights into PARs may ensure a better understanding of cardiometabolic disorders and suggest new therapeutic options for these major health threats.
Ryota Miyamoto, Takayuki Ise, Tomoya Yoshida and Masataka Sata : Endomyocardial biopsy-proven fulminant lymphocytic myocarditis presenting with mid-apical ballooning, European Heart Journal. Case Reports, Vol.7, No.3, ytad123, 2023.
TOMONORI Takahashi, Kenya Kusunose, S Hayashi, Robert Zheng, Natsumi Yamaguchi, Sae Morita, Yukina Hirata, Susumu Nishio, Yoshihito Saijyo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Isoproterenol loading transesophageal echocardiography in atrial fibrillation, The International Journal of Cardiovascular Imaging, Vol.39, No.3, 511-518, 2023.
(Summary)
In patients with sludge or severe spontaneous echo contrast (SEC) in the left atrial appendage (LAA), cases with isoproterenol loading transesophageal echocardiography (ISP-TEE) have been reported to identify the presence of thrombus in the LAA. This study aimed to assess the validity and hemodynamic changes of ISP-TEE in the LAA. We prospectively enrolled patients with atrial fibrillation (AF) who underwent ISP-TEE. The degree of sludge/SEC was categorized as being either absent (grade 0), mild SEC (grade 1), moderate SEC (grade 2), severe SEC or sludge (grade 3). The hemodynamic evaluation was performed by measuring LAA flow velocity, LAA tissue Doppler imaging (LAA-TDI) velocity, and pulmonary vein systolic forward flow velocity (PVS). In total, 35 patients (mean age 71 ± 7 years; 71% male) underwent ISP-TEE. Among 35 patients, 30 patients had grade 3 or 2 SEC, 5 patients had grade 1 SEC. After ISP loading, 23 patients (66% of all patients) showed improved sludge/SEC and one patient was diagnosed with thrombus in the LAA. There were 25 patients with grade 1 SEC, or no SEC (classified as Group1), 10 patients had residual sludge or grade 2 to 3 SEC (classified as Group2) after ISP administration. LAA flow, LAA-TDI, and PVS velocities were significantly higher in group 1 than in group 2 after ISP administration. There was no complication during the examination and after 24 h and 3 months. ISP infusion may be a potential tool to recognize LAA thrombus under the sludge/SEC during TEE in AF.
(Keyword)
Humans / Male / Middle Aged / Aged / Female / Atrial Fibrillation / Echocardiography, Transesophageal / Isoproterenol / Sewage / Atrial Appendage / Predictive Value of Tests / Thrombosis
A Tanaka, Masataka Sata, Y Okada, H Teragawa, K Eguchi, Michio Shimabukuro, I Taguchi, K Matsunaga, Y Kanzaki, H Yoshida, T Ishizu, S Ueda, M Kitakaze, T Murohara and K Node : Effect of ipragliflozin on carotid intima-media thickness in patients with type 2 diabetes: a multicenter, randomized, controlled trial, European Heart Journal. Cardiovascular Pharmacotherapy, Vol.9, No.2, 165-172, 2023.
(Summary)
To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0-10.0% (42-86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), -0.0155-0.0182] mm and 0.0015 (95% CI, -0.0155-0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191-0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [-0.1% (95% CI, -0.2-0.1); P = 0.359]. Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.
Kenya Kusunose, Yuichiro Okushi, Y Okayama, Robert Zheng, M Nakai, Y Sumita, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Benefits of guideline-directed medical therapy to loop diuretics in management of heart failure, The Journal of Medical Investigation : JMI, Vol.70, No.1.2, 41-53, 2023.
Y Higashikuni, W Liu, G Numata, K Tanaka, Daiju Fukuda, Y Tanaka, Y Hirata, T Imamura, E Takimoto, I Komuro and Masataka Sata : NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload, Circulation, Vol.147, No.4, 338-355, 2023.
(Summary)
Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart. C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')--(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1β antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1β and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. Genetic disruption of NLRP3 resulted in significant loss of IL-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1β production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1β-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β production, and adaptive cardiac hypertrophy during pressure overload. Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.
Yutaka Kawabata, Tetsuzo Wakatsuki, Koji Yamaguchi, Daiju Fukuda, Hiroyuki Ito, Tomomi Matsuura, Kenya Kusunose, Takayuki Ise, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Y Tsuruo and Masataka Sata : Association of Microluminal Structures Assessed by Optical Coherence Tomography With Local Inflammation in Adjacent Epicardial Adipose Tissue and Coronary Plaque Characteristics in Fresh Cadavers, Circulation Journal, Vol.87, No.2, 329-335, 2023.
(Summary)
Coronary intraplaque microluminal structures (MS) are associated with plaque vulnerability, and the inward progression of vascular inflammation from the adventitia towards the media and intima has also been demonstrated. Therefore, in the present study we investigated the relationships among MS, local inflammation in adjacent epicardial adipose tissue (EAT), and coronary plaque characteristics.Methods and Results: Optical coherence tomography (OCT) revealed MS in the left anterior descending coronary artery in 10 fresh cadaveric hearts. We sampled 30 lesions and subdivided them based on the presence of MS: MS (+) group (n=19) and MS (-) group (n=11). We measured inflammatory molecule levels in the adjacent EAT and percentage lipid volume assessed by integrated backscatter intravascular ultrasound in each lesion. The expression levels of vascular endothelial growth factor B and C-C motif chemokine ligand 2 were significantly higher in the MS (+) group than in the MS (-) group (0.9±0.7 vs. 0.2±0.2 arbitrary units (AU), P=0.04 and 1.5±0.5 vs. 0.6±0.7 AU, P=0.02, respectively). Percentage lipid volume was significantly higher in the MS (+) group than in the MS (-) group (38.7±16.5 vs. 23.7±10.9%, P=0.03). Intraplaque MS observed on OCT were associated with lipid-rich plaques and local inflammation in the adjacent EAT. Collectively, these results suggest that local inflammation in the EAT is associated with coronary plaque vulnerability via MS.
石井 亜由美, Takayuki Ise, 西川 孝治, Hirokazu Ohminami, Muneyuki Kadota, Shusuke Yagi, Tetsuya Matsuura and Masataka Sata : TAVI後の認知機能低下に関わる因子の検討, 心臓リハビリテーション(JJCR), Vol.29, No.3,4, 242-208, 2023.
42.
Tomonori Takahashi, Kenya Kusunose, Robert Zheng, Natsumi Yamaguchi, Yukina Hirata, Susumu Nishio, Yoshihito Saijyo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Association between cardiovascular risk factors and left ventricular strain distribution in patients without previous cardiovascular disease, Journal of Echocardiography, Vol.20, No.4, 208-215, 2022.
(Summary)
Some cardiovascular (CV) risk factors, such as hypertension and diabetes mellitus, have been reported to reduce left ventricular (LV) longitudinal strain (LS) even in patients with preserved LV ejection fraction. We hypothesized that multiple CV risk factors might cause changes in myocardial strain. Our study aimed to assess the association between multiple CV risk factors and strain in patients without previous CV disease (CVD). We retrospectively evaluated 137 patients without CVD, who underwent echocardiography at our institution between May 2017 and February 2020. They were divided into four groups based on the number of risk factors (group 0: no risk factor, group 1: one risk factor, group 2: two risk factors, and groups 3: three or four risk factors). Risk factors were hypertension, dyslipidemia, diabetes mellitus, and chronic kidney disease. Absolute values of global LS (GLS) and relative apical LS ratio (RALSR) defined using the equation: average apical LS/(average basal LS + average mid LS) and was used as a marker of strain distribution. Out of 137 patients, group 0 had 35 patients, group 1 had 35 patients, group 2 had 32 patients, and group 3 had 35 patients. GLS was 22.4 ± 2.0%, 21.7 ± 2.1%, 21.3 ± 1.8%, 20.7 ± 2.2%, and RALSR was 0.64 ± 0.06, 0.66 ± 0.06, 0.68 ± 0.08, 0.69 ± 0.07 in groups 0-3, respectively. The one-way ANOVA detected significant differences between groups in GLS (p = 0.005) and RALSR (p = 0.037), respectively. Group 3 had a significantly lower GLS and higher RALSR than group 0 (p < 0.05). In patients without previous CVD, LS decreased especially from the basal segment as the number of cardiovascular risks increased. The segmental LS may be markers of occult LV dysfunction in patients with CV risk factors.
Atsushi Tanaka, Takumi Imai, Michio Shimabukuro, Ikuko Nakamura, Kazuo Matsunaga, Yukio Ozaki, Tohru Minamino, Masataka Sata and Koichi Node : Effect of canagliflozin on white blood cell counts in patients with type 2 diabetes and heart failure: A subanalysis of the randomized CANDLE trial, Journal of Diabetes Investigation, Vol.13, No.12, 1990-1999, 2022.
(Summary)
Clinical evidence is lacking about the influence of sodium-glucose cotransporter 2 inhibitors on white blood cell (WBC) counts, a commonly used and widely available marker of inflammation. The aim of the present analysis was to assess the effect of canagliflozin relative to glimepiride on WBC counts. This was a post-hoc subanalysis of the CANDLE trial (Effects of Canagliflozin in Patients with Type 2 Diabetes and Chronic Heart Failure: A Randomized Trial; UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. A total of 233 patients with type 2 diabetes and concomitant heart failure were randomly assigned to either canagliflozin (n = 113) or glimepiride (n = 120) treatment for 24 weeks. Overall, patient baseline characteristics were as follows: mean ± standard deviation age, 68.6 ± 10.1 years; hemoglobin A1c, 7.0 ± 0.9%; left ventricular ejection fraction, 56.7 ± 14.4%; and median N-terminal pro-brain natriuretic peptide, 252 pg/mL (interquartile range 96-563 pg/mL). The mean baseline WBC counts were 6704 cells/μL (95% confidence interval 6,362-7,047) in the canagliflozin group and 6322 cells/μL (95% confidence interval 5,991-6,654) in the glimepiride group. There were no significant differences between treatment groups in terms of changes in WBC counts from baseline to weeks 4 and 12. In contrast, a group difference (canagliflozin minus glimepiride) from baseline to week 24 was significant (mean difference - 456 cells/μL [95% confidence interval -774 to -139, P = 0.005]). Our findings suggest that 24 weeks of treatment with canagliflozin, relative to glimepiride, reduced WBC counts in patients with type 2 diabetes and heart failure.
O Bavuu, Daiju Fukuda, B Ganbaatar, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet., European Journal of Pharmacology, 175190, 2022.
(Summary)
Esaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (Csige et al.) blocker. MR activation plays a crucial role in the development of cardiovascular and metabolic diseases. In this study, we investigated the effects of esaxerenone on various metabolic parameters in mice. Esaxerenone (3 mg/kg/day) was orally administered to high-fat diet (HFD)-fed male C57BL/6 mice. Mice fed a normal diet (ND) served as controls. Glucose and insulin tolerance, plasma lipid levels, and transaminase levels were assessed as metabolic parameters. Macrophage accumulation in the adipose tissue was evaluated using histological analysis. 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes were used for in vitro experiments. Gene expression and insulin signaling were examined using quantitative RT-PCR and western blotting, respectively. HFD successfully induced insulin resistance compared with that in ND. Esaxerenone ameliorated insulin resistance (P < 0.05) without altering other metabolic parameters, such as the lipid profile. Esaxerenone administration tended to decrease plasma transaminase levels compared with those in the non-treated group. In the adipose tissue, esaxerenone decreased macrophage accumulation (P < 0.05) and increased the expression levels of adiponectin and PPARγ. Aldosterone significantly decreased the expression levels of PPARγ and adiponectin in 3T3-L1 adipocytes. Furthermore, aldosterone attenuated insulin-induced Akt phosphorylation in 3T3-L1 adipocytes, HepG2 cells, and C2C12 myotubes in a dose-dependent manner (P < 0.01). These effects were ameliorated by pretreatment with esaxerenone. Esaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.
Sachiko Nishimoto, Masataka Sata and Daiju Fukuda : Expanding role of deoxyribonucleic acid-sensing mechanism in the development of lifestyle-related diseases, Frontiers in Cardiovascular Medicine, Vol.9, 881181, 2022.
(Summary)
In lifestyle-related diseases, such as cardiovascular, metabolic, respiratory, and kidney diseases, chronic inflammation plays a causal role in their pathogenesis; however, underlying mechanisms of sterile chronic inflammation are not well-understood. Previous studies have confirmed the damage of cells in these organs in the presence of various risk factors such as diabetes, dyslipidemia, and cigarette smoking, releasing various endogenous ligands for pattern recognition receptors. These studies suggested that nucleic acids released from damaged tissues accumulate in these tissues, acting as an endogenous ligand. Undamaged DNA is an integral factor for the sustenance of life, whereas, DNA fragments, especially those from pathogens, are potent activators of the inflammatory response. Recent studies have indicated that inflammatory responses such as the production of type I interferon (IFN) induced by DNA-sensing mechanisms which contributes to self-defense system in innate immunity participates in the progression of inflammatory diseases by the recognition of nucleic acids derived from the host, including mitochondrial DNA (mtDNA). The body possesses several types of DNA sensors. Toll-like receptor 9 (TLR9) recognizes DNA fragments in the endosomes. In addition, the binding of DNA fragments in the cytosol activates cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS), resulting in the synthesis of the second messenger cyclic GMP-AMP (cGAMP). The binding of cGAMP to stimulator of interferon genes (STING) activates NF-κB and TBK-1 signaling and consequently the production of many inflammatory cytokines including IFNs. Numerous previous studies have demonstrated the role of DNA sensors in self-defense through the recognition of DNA fragments derived from pathogens. Beyond the canonical role of TLR9 and cGAS-STING, this review describes the role of these DNA-sensing mechanism in the inflammatory responses caused by endogenous DNA fragments, and in the pathogenesis of lifestyle-related diseases.
Kenya Kusunose, Hirotsugu Yamada, Y Saijo, Susumu Nishio, Yukina Hirata, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Clinical course and decision-making in heart failure by preload stress echocardiography: a preliminary study, ESC Heart Failure, Vol.9, No.6, 4020-4029, 2022.
(Summary)
Abnormal left ventricular diastolic response to preload stress can be an early marker of heart failure (HF). The aim of this study was to assess clinical course in patients with HF with preserved ejection fraction (HFpEF) who underwent preload stress echocardiography. In the subgroup analysis, we assessed the prognosis of patients with unstable signs during preload stress classified by treatment strategies. We prospectively conducted preload stress echocardiographic studies between January 2006 and December 2013 in 211 patients with HFpEF. Fifty-eight patients had abnormal diastolic reserve during preload stress (unstable impaired relaxation: unstable IR). Of 58 patients with unstable IR, 19 patients were assigned to additional therapy by increased or additional therapy and 39 patients were assigned to standard therapy. Composite outcomes were prespecified as the primary endpoint of death and hospitalization for deteriorating HF. During a median period of 6.9 years, 19 patients (33%) reached the composite outcome. Unstable group with standard therapy had significantly shorter event-free survival than stable group. Patients with uptitration of therapy had longer event-free survival than those with standard therapy group after adjustment of laboratory data (hazard ratio, 0.20, 95% confidence interval, 0.05-0.90; P = 0.036); the 10 year event-free survival in patients with and without uptitration of therapy was 93% and 51%, respectively (P = 0.023). Patients with unstable sign had significantly shorter event-free survival than patients with stable sign. After additional therapy, the prognosis of patients with unstable signs improved. This technique may impact decision-making for improving their prognosis.
S Abe, Y Haruyama, G Kobashi, S Toyoda, T Inoue, H Tomiyama, T Ishizu, T Kohro, Y Higashi, B Takase, T Suzuki, S Ueda, T Yamazaki, T Furumoto, K Kario, S Koba, Y Takemoto, T Hano, Masataka Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito and A Yamashina : Effect of Novel Stratified Lipid Risk by "LDL-Window" and Flow-Mediated Dilation on the Prognosis of Coronary Artery Disease Using the FMD-J Study A Data, Circulation Journal, Vol.86, No.9, 1444-1454, 2022.
(Summary)
Elevated levels of triglyceride (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) are regarded as a residual lipid risk in low-density lipoprotein cholesterol (LDL-C)-lowering therapy. This study investigated the association between lipid risk stratified by TG and non-HDL-C and the prognosis of patients with coronary artery disease (CAD), and the association between stratified lipid risk and flow-mediated dilatation (FMD) index.Methods and Results: The 624 CAD patients enrolled in flow-mediated dilation (FMD)-J study A were divided into 4 groups: low-risk group (n=413) with TG <150 mg/dL and non-HDL-C <170 mg/dL; hyper-TG group (n=180) with TG 150 mg/dL and non-HDL-C <170 mg/dL; hyper-non-HDL group (n=12) with TG <150 mg/dL and non-HDL-C 170 mg/dL; and high-risk group (n=19) with TG 150 mg/dL and non-HDL-C 170 mg/dL. Comparison of the groups showed the cumulative incidence of a 3-point major adverse cardiovascular event (MACE) was different and highest in the high-risk group in all the patients (P=0.009), and in patients with a FMD index 7.0% (P=0.021), but not in those with a FMD index <7.0%. Multivariable regression analysis showed that high lipid risk (P=0.019) and FMD <7.0% (P=0.040) were independently correlated with the incidence of a 3-point MACE. Novel stratification of lipid risk, simply using TG and non-HDL-C levels, combined with FMD measurement, is useful for predicting cardiovascular outcomes in patients with CAD.
A Sezai, A Tanaka, T Imai, K Kida, H Sekino, T Murohara, Masataka Sata, N Suzuki and K Node : Comparing the Effects of Canagliflozin vs. Glimepiride by Body Mass Index in Patients with Type 2 Diabetes and Chronic Heart Failure: A Subanalysis of the CANDLE Trial, Biomedicines, Vol.10, No.7, 1656, 2022.
(Summary)
We present results of a 24-week comparative study of the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin vs. the sulfonylurea glimepiride, by baseline body mass index (BMI), in patients with type 2 diabetes and chronic heart failure. We conducted a post hoc analysis of the CANDLE trial. This subanalysis evaluated NT-proBNP, BMI, and other laboratory parameters, according to the subgroups stratified by BMI ≥ 25 kg/m vs. BMI < 25 kg/m. A group ratio of proportional changes in the geometric means of NT-proBNP was 0.99 ( = 0.940) for the subgroup with BMI ≥ 25 kg/m and 0.85 ( = 0.075) for the subgroup with BMI < 25 kg/m, respectively. When baseline BMI was modeled as a continuous variable, results for patients with BMI < 30 kg/m showed a slightly smaller increase in NT-proBNP in the canagliflozin group vs. the glimepiride group ( = 0.295); that difference was not seen among patients with BMI ≥30 kg/m ( = 0.948). Irrespective of obesity, the canagliflozin group was associated with significant reduction in BMI compared to the glimepiride group. There was no significant difference in the effects of canagliflozin, relative to glimepiride, on NT-proBNP concentrations irrespective of baseline obesity. UMIN clinical trial registration number: UMIN000017669.
Y Higashikuni, W Liu and Masataka Sata : Give a Leg Up: Screening for Peripheral Artery Disease after Acute Myocardial Infarction, Journal of Atherosclerosis and Thrombosis, Vol.29, No.7, 989-991, 2022.
Koji Yamaguchi, Tetsuzo Wakatsuki, Tomomi Matsuura, Kazuhisa Matsumoto, Yutaka Kawabata, Muneyuki Kadota, Kenya Kusunose, Takayuki Ise, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Drug-coated balloon angioplasty for severe pulmonary vein stenosis resulting from cryoballoon ablation for atrial fibrillation, Journal of Cardiology Cases, Vol.26, 35-38, 2022.
Y Okushi, Kenya Kusunose, M Nakai, Y Sumita, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Comparison of Direct Oral Anticoagulants for Acute Hospital Mortality in Venous Thromboembolism, American Journal of Cardiovascular Drugs, Vol.22, No.4, 407-416, 2022.
(Summary)
The choice of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) is at the physician's discretion; however, it is useful to know the differences in the clinical data of DOACs to help physicians choose. We aimed to compare the mortality associated with the use of rivaroxaban, edoxaban, and apixaban in clinical practice. We identified 38,245 patients with first hospitalization for VTE from the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). We classified patients into three groups by DOAC (rivaroxaban and edoxaban group, rivaroxaban and apixaban group, and edoxaban and apixaban group) and compared the in-hospital mortality and bleeding risk by propensity score (PS) matching in each group. After PS matching, patients with rivaroxaban use had significantly lower total in-hospital mortality (1.2% vs. 2.1%; odds ratio [OR] 0.55, p = 0.012) and in-hospital mortality within 21 days (0.4% vs. 1.0%; OR 0.41, p = 0.020) and 28 days (0.7% vs. 1.3%; OR 0.53, p = 0.042) than patients with apixaban use. In the subanalysis, significant differences were only observed in patients younger than 80 years of age, patients with pulmonary embolism, and patients without heart failure. There was no significant difference in in-hospital mortality in the other groups and in the rate of bleeding events among the three groups. On PS-matched analysis, there was a difference in in-hospital mortality, especially in the rivaroxaban and apixaban group. Identifying the clinical characteristics of patients associated with each DOAC, as well as prognosis, will be useful in determining treatment strategies for VTE.
Kenya Kusunose, Yukina Hirata, Natsumi Yamaguchi, Y Kosaka, T Tsuji, J Kotoku and Masataka Sata : Deep Learning for Detection of Exercise-Induced Pulmonary Hypertension Using Chest X-Ray Images, Frontiers in Cardiovascular Medicine, Vol.9, 891703, 2022.
(Summary)
Stress echocardiography is an emerging tool used to detect exercise-induced pulmonary hypertension (EIPH). However, facilities that can perform stress echocardiography are limited by issues such as cost and equipment. We evaluated the usefulness of a deep learning (DL) approach based on a chest X-ray (CXR) to predict EIPH in 6-min walk stress echocardiography. The study enrolled 142 patients with scleroderma or mixed connective tissue disease with scleroderma features who performed a 6-min walk stress echocardiographic test. EIPH was defined by abnormal cardiac output (CO) responses that involved an increase in mean pulmonary artery pressure (mPAP). We used the previously developed AI model to predict PH and calculated PH probability in this cohort. EIPH defined as ΔmPAP/ΔCO >3.3 and exercise mPAP >25 mmHg was observed in 52 patients, while non-EIPH was observed in 90 patients. The patients with EIPH had a higher mPAP at rest than those without EIPH. The probability of PH based on the DL model was significantly higher in patients with EIPH than in those without EIPH. Multivariate analysis showed that gender, mean PAP at rest, and the probability of PH based on the DL model were independent predictors of EIPH. A model based on baseline parameters (age, gender, and mPAP at rest) was improved by adding the probability of PH predicted by the DL model (AUC: from 0.65 to 0.74; = 0.046). Applying the DL model based on a CXR may have a potential for detection of EIPH in the clinical setting.
W Liu, Y Higashikuni and Masataka Sata : Linking RNA dynamics to heart disease: the lncRNA/miRNA/mRNA axis in myocardial ischemia-reperfusion injury, Hypertension Research, Vol.45, No.6, 1067-1069, 2022.
A Mizuno, Kenya Kusunose, T Kishi, J Rewley, C Matsumoto, Y Sahashi, M Ishida, S Sanada, M Fukuda, T Sugimoto, M Hirano, D Yoneoka, Masataka Sata, T Anzai and K Node : Impact of Tweeting Summaries by the Japanese Circulation Society Official Account on Article Viewership - Pilot Trial, Circulation Journal, Vol.86, No.4, 715-720, 2022.
(Summary)
The impact of promotional tweets from the official journal account (forCirculation JournalandCirculation Reports) on article viewership has not been thoroughly evaluated.Methods and Results:We retrospectively collected journal viewership data forCirculation JournalandCirculation Reportsfrom March 2021 to August 2021. We compared viewership between articles with (n=15) and without (n=250) tweets. After 1 : 4 propensity score matching (15 tweeted articles and 60 non-tweeted matched controls), journal viewership metrics within 7 days of the tweeting date (and the hypothetical tweeting date), was larger in tweeted articles than non-tweeted articles (median [interquartile range] Abstract page views 89 [60-104] vs. 18 [8-41]). This pilot study suggests a positive relationship between journal-posted promotional tweets and article viewership.
(Keyword)
Benchmarking / Humans / Japan / Pilot Projects / Retrospective Studies / Social Media
Daiju Fukuda, PT Pham and Masataka Sata : Emerging Roles of the Innate Immune System Regulated by DNA Sensors in the Development of Vascular and Metabolic Diseases, Journal of Atherosclerosis and Thrombosis, Vol.29, No.3, 297-307, 2022.
(Summary)
Sterile chronic inflammation causes cardiometabolic disorders; however, the mechanisms are not fully understood. Previous studies have demonstrated the degradation of cells/tissues in the vasculature and metabolic organs in lifestyle-associated diseases, such as diabetes and hyperlipidemia, suggesting the release and/or accumulation of nucleic acids from damaged cells. DNA is indispensable for life; however, DNA fragments, especially those from pathogens, strongly induce inflammation by the activation of DNA sensors. Growing evidence suggests that DNA-sensing mechanisms, which are normally involved in self-defense against pathogens as the innate immune system, are associated with the progression of inflammatory diseases in response to endogenous DNA fragments. There are several types of DNA sensors in our bodies. Toll-like receptor 9 (TLR9)-one of the most studied DNA sensors-recognizes DNA fragments in endosome. In addition, stimulator of interferon genes (STING), which has recently been extensively investigated, recognizes cyclic GMP-AMP (cGAMP) generated from DNA fragments in the cytosol. Both TLR9 and STING are known to play pivotal roles in host defense as the innate immune system. However, recent studies have indicated that the activation of these DNA sensors in immune cells, such as macrophages, promotes inflammation leading to the development of vascular and metabolic diseases associated with lifestyle. In this review, we discuss recent advances in determining the roles of DNA sensors in these disease contexts. Revealing a novel mechanism of sterile chronic inflammation regulated by DNA sensors might facilitate clinical interventions for these health conditions.
(Keyword)
Animals / DNA / Humans / Immunity, Innate / Metabolic Diseases / Signal Transduction / Vascular Diseases
Kazuhisa Matsumoto, Takeshi Tobiume, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Tetsuzo Wakatsuki, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Evaluation of the input site and characteristics of the antegrade fast pathway based on three-dimensional bi-atrial stimulus-ventricle mapping, Journal of Interventional Cardiac Electrophysiology, Vol.63, No.2, 417-424, 2022.
(Summary)
Previous studies examined the right atrial (RA) input site of the antegrade fast pathway (AFp) (AFpI). However, the left atrial (LA) input to the atrioventricular (AV) node has not been extensively evaluated. In this study, we created three-dimensional (3-D) bi-atrial stimulus-ventricle (St-V) maps and analyzed the input site and characteristics of the AFp in both the RA and LA. Forty-four patients diagnosed with atrial fibrillation or WPW syndrome were included in this study. Three-dimensional bi-atrial St-V mapping was performed using an electroanatomical mapping system. Sites exhibiting the minimal St-V interval (MinSt-V) were defined as AFpIs and were classified into seven segments, four in the RA (F, S, M, and I) and three in the LA (M1, M2, and M3). By combining the MinSt-V in the RA and LA, the AFpIs were classified into three types: RA, LA, and bi-atrial (BA) types. The clinical and electrophysiological characteristics were compared. AFpIs were most frequently observed at site S in the RA (34%) and M2 in the LA (50%), and the BA type was the most common (57%). AFpIs in the LA were recognized in 75% of the patients. There were no clinical or electrophysiological indicators for predicting AFpI sites. Three-dimensional bi-atrial St-V maps could classify AFpIs in both the RA and LA. AFpIs in the LA were frequently recognized. There were no significant clinical or electrophysiological indicators for predicting AFpI sites, and 3-D bi-atrial St-V mapping was the only method to reveal the precise AFp input site.
Kenya Kusunose, Robert Zheng, Hirotsugu Yamada and Masataka Sata : How to standardize the measurement of left ventricular ejection fraction, Journal of Medical Ultrasonics, Vol.49, No.1, 35-43, 2022.
Shusuke Yagi, Daiju Fukuda, Takayuki Ise, Koji Yamaguchi, Kenya Kusunose, Muneyuki Kadota, Yutaka Kawabata, Tomomi Matsuura, Tomohiro Soga, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Shinji Kawahito and Masataka Sata : Clinical clerkship students' preferences and satisfaction regarding online lectures during the COVID-19 pandemic, BMC Medical Education, Vol.22, No.1, 43, 2022.
(Summary)
The COVID-19 pandemic has caused an unprecedented disruption in medical education. Students and lecturers had to adapt to online education. The current study aimed to investigate the level of satisfaction and future preference for online lectures among clinical clerkship students and elucidated the factors that affect these outcomes. We selected a sample of 114 medical students undergoing clinical clerkship during the COVID-19 pandemic. We conducted onsite lectures before the pandemic and online lectures after the outbreak. A survey was conducted, and the sample included students and 17 lecturers. The average scores of total satisfaction and future preference related to online lectures were computed. Students' scores on total satisfaction with online lectures and their future preference were higher than those for onsite lectures. Scores on the ease of debating dimension were low and those on accessibility of lectures in online lectures were higher than those in onsite lectures. There was no difference between the two groups in the scores on the comprehensibility and ease of asking questions dimensions. Results of the multiple regression analysis revealed that accessibility determined total satisfaction, and future preference was determined by comprehensibility as well as accessibility. Contrary to students' future preferences, lecturers favored onsite lectures to online ones. Online lectures are an acceptable mode of teaching during the COVID-19 pandemic for students undergoing clinical clerkship. Online lectures are expected to become more pervasive to avoid the spread of COVID-19.
(Keyword)
COVID-19 / Clinical Clerkship / Humans / Pandemics / Personal Satisfaction / SARS-CoV-2 / Students, Medical
Nao Ishii, Kenya Kusunose, A Shono, K Matsumoto, Susumu Nishio, Natsumi Yamaguchi, Yukina Hirata, Tomomi Matsuura, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Effects of Radiofrequency Catheter Ablation on Cardiac Reserve Using Preload Stress Echocardiography in Paroxysmal and Persistent Atrial Fibrillation, The American Journal of Cardiology, Vol.168, 71-77, 2022.
(Summary)
The effects of catheter ablation on exercise tolerance and quality of life in patients with atrial fibrillation (AF) have been reported. We assessed cardiac function in more detail using the leg positive pressure (LPP) technique and found that contractile reserve is particularly important in relation to exercise tolerance and prognosis. In this study, we used the LPP technique to examine changes in contractile reserve immediately after ablation and 6 months later. We prospectively enrolled patients who underwent catheter ablation for AF at 2 institutes. We performed LPP stress echocardiography 2 to 3 days after (FU-1) and 6 months after (FU-2) ablation to examine changes in cardiac function indexes. The primary end point was improvement in contractile reserve. Ultimately, 109 patients (mean age 67.4 ± 9.6 years; 70% men) underwent 2 sessions of LPP stress echocardiography. The median CHADS-VAS score was 2 (interquartile range 13). From FU-1 to FU-2, the change in the stroke volume index after the LPP maneuver increased in patients with paroxysmal and persistent AF with low CHADS-VAS scores (both p <0.05). Regardless of AF subtype, contractile reserve at FU-2 improved in patients with low CHADS-VAS scores compared with that at FU-1. In contrast, patients with high CHADS-VAS scores had no change. In conclusion, patients with AF with a low CHADS-VAS score had improved contractile reserve after ablation, whereas patients with high scores did not show any improvement. Aggressive interventions in patients with high scores may lead to better management after catheter ablation.
(Keyword)
Aged / Atrial Fibrillation / Catheter Ablation / Echocardiography, Stress / Female / Humans / Male / Middle Aged / Predictive Value of Tests / Quality of Life / Risk Assessment / Risk Factors / Treatment Outcome
Kenya Kusunose, H Yoshida, A Tanaka, H Teragawa, Y Akasaki, Y Fukumoto, K Eguchi, H Kamiya, K Kario, Hirotsugu Yamada, Masataka Sata, K Node and Munehide Matsuhisa : Effect of febuxostat on left ventricular diastolic function in patients with asymptomatic hyperuricemia: a sub analysis of the PRIZE Study, Hypertension Research, Vol.45, No.1, 106-115, 2022.
Cerebrovascular diseases including stroke and cardiovascular diseases are the leading causes of death in Japan, which together account for 23.2% of the total number of deaths in 2018. The major causes of the need for long-term care in Japan are also cerebrovascular disease(16.1%)and cardiovascular disease(4.5%), which together account for more than one-fifth of the total. Medical expenses for both cerebrovascular and cardiovascular disease account for ≈20% of the total, which is the highest by injury/illness classification. The Cerebrovascular and Cardiovascular Disease Control Act, of Japanese national law, was promulgated by a legislative act on December 14, 2018, and enacted on December 1, 2019. On the basis of the Cerebrovascular and Cardiovascular Disease Control Act, the Ministry of Health, Labour and Welfare, Japan, published the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease on October 27, 2020. It has indicated both problems in the current situation and individual measures to address the problems. The Japanese National Plan includes 3 major measures : spreading awareness of prevention measures and accurate information on cerebrovascular and cardiovascular disease ; enhancing service provision systems related to health, medical care, and welfare services ; and promoting research on cerebrovascular and cardiovascular disease. The 2 main goals of the Japanese National Plan are to extend healthy life expectancy by 3 years by 2040 compared with 2016 and to decrease age-adjusted mortality of cerebrovascular and cardiovascular disease. The average life expectancy and healthy life expectancy for both men and women increased by 0.67 to 1.72 years from 2010 to 2016 in Japan. In 2016, the unhealthy period which is defined as differences between healthy life expectancy(men, 72.14 years ; women, 74.49 years)and average life expectancy(men, 80.98 years ; women, 87.14 years)was large : ≈8.8 years for men and ≈12.4 years for women. Therefore, extending healthy life expectancy is a primary goal of the Japanese National Plan. Based on this national plan, the Tokushima Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases is developed through the meetings of the Tokushima Council for Promotion of Measures Against Cerebrovascular and Cardiovascular Diseases, parliamentary associated meetings, and public comments. The council is composed of patients with cerebrovascular or cardiovascular disease ; those engaged in emergency services and health, medical, or welfare services ; and those with academic experience. Here, we describe outline of the Tokushima Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease.
Kumiko Suto, Daiju Fukuda, Masakazu Shinohara, Byambasuren Ganbaatar, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Ken-Ichi Hirata and Masataka Sata : Pemafibrate, A Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator, Reduces Plasma Eicosanoid Levels and Ameliorates Endothelial Dysfunction in Diabetic Mice., Journal of Atherosclerosis and Thrombosis, Vol.28, No.12, 1349-1360, 2021.
(Summary)
Various pathological processes related to diabetes cause endothelial dysfunction. Eicosanoids derived from arachidonic acid (AA) have roles in vascular regulation. Fibrates have recently been shown to attenuate vascular complications in diabetics. Here we examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, on plasma eicosanoid levels and endothelial function in diabetic mice. Diabetes was induced in 7-week-old male wild-type mice by a single injection of streptozotocin (150 mg/kg). Pemafibrate (0.3 mg/kg/day) was administered orally for 3 weeks. Untreated mice received vehicle. Circulating levels of eicosanoids and free fatty acids were measured using both gas and liquid chromatography-mass spectrometry. Endothelium-dependent and endothelium-independent vascular responses to acetylcholine and sodium nitroprusside, respectively, were analyzed. Pemafibrate reduced both triglyceride and non-high-density lipoprotein -cholesterol levels (P<0.01), without affecting body weight. It also decreased circulating levels of AA (P<0.001), thromboxane B (P<0.001), prostaglandin E, leukotriene B (P<0.05), and 5-hydroxyeicosatetraenoic acid (P<0.001), all of which were elevated by the induction of diabetes. In contrast, the plasma levels of 15-deoxy-Δ-prostaglandin J, which declined following diabetes induction, remained unaffected by pemafibrate treatment. In diabetic mice, pemafibrate decreased palmitic acid (PA) and stearic acid concentrations (P<0.05). Diabetes induction impaired endothelial function, whereas pemafibrate ameliorated it (P<0.001). The results of ex vivo experiments indicated that eicosanoids or PA impaired endothelial function. Pemafibrate diminished the levels of vasoconstrictive eicosanoids and free fatty acids accompanied by a reduction of triglyceride. These effects may be associated with the improvement of endothelial function by pemafibrate in diabetic mice.
Sirt7 is a recently identified sirtuin and has important roles in various pathological conditions, including cancer progression and metabolic disorders. It has previously been reported that Sirt7 is a key molecule in acute myocardial wound healing and pressure overload-induced cardiac hypertrophy. In this study, the role of Sirt7 in neointimal formation after vascular injury is investigated.Methods and Results:Systemic (Sirt7) and smooth muscle cell-specific Sirt7-deficient mice were subjected to femoral artery wire injury. Primary vascular smooth muscle cells (VSMCs) were isolated from the aorta of wild type (WT) and Sirt7mice and their capacity for cell proliferation and migration was compared. Sirt7 expression was increased in vascular tissue at the sites of injury. Sirt7mice demonstrated significant reduction in neointimal formation compared to WT mice. In vitro, Sirt7 deficiency attenuated the proliferation of serum-induced VSMCs. Serum stimulation-induced upregulation of cyclins and cyclin-dependent-kinase 2 (CDK2) was significantly attenuated in VSMCs of Sirt7compared with WT mice. These changes were accompanied by enhanced expression of the microRNA 290-295 cluster, the translational negative regulator of CDK2, in VSMCs of Sirt7mice. It was confirmed that smooth muscle cell-specific Sirt7-deficient mice showed significant reduction in neointima compared with control mice. Sirt7 deficiency attenuates neointimal formation after vascular injury. Given the predominant role in vascular neointimal formation, Sirt7 is a potentially suitable target for treatment of vascular diseases.
Kenya Kusunose, Miharu Arase, Robert Zheng, Yukina Hirata, Susumu Nishio, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Clinical Utility of Overlap Time for Incomplete Relaxation to Predict Cardiac Events in Heart Failure: Incomplete relaxation in heart failure, Journal of Cardiac Failure, Vol.27, No.11, 1222-1230, 2021.
(Summary)
The overlap time of transmitral flow can be a novel marker of subclinical left ventricular (LV) dysfunction for predicting adverse events in heart failure (HF). We aimed to 1) investigate the role of overlap time of E-A wave in association with clinical parameters, and 2) evaluate whether the overlap time could add prognostic information with respect to other conventional clinical prognosticators in HF. We prospectively evaluated 153 patients hospitalized with HF (mean age 68±15 years; 63% male). The primary endpoint was readmission following HF and cardiac death. During a median period of 25 months, 43 patients were either readmitted or died. Overlap time appeared to be associated with worse outcomes. After adjustment for readmission score and ratio of diastolic filling period and cardiac cycle length in a Cox proportional-hazards model, overlap time was associated with event free survival, independent of elevated left atrial pressure (LAP) based on guidelines. When overlap time was added to the model based on clinical variables and elevated LAP, the C-statistic significantly improves from 0.70 (95% CI: 0.63-0.77) to 0.77 (95% CI: 0.69-0.83, compared P=0.035). This preliminary study suggested that prolonged overlap time may have potential for predicting readmission and cardiac mortality risk assessment in HF.
Y Higashikuni, W Liu, T Obana and Masataka Sata : Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications, International Journal of Molecular Sciences, Vol.22, No.21, 12081, 2021.
(Summary)
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic with a great impact on social and economic activities, as well as public health. In most patients, the symptoms of COVID-19 are a high-grade fever and a dry cough, and spontaneously resolve within ten days. However, in severe cases, COVID-19 leads to atypical bilateral interstitial pneumonia, acute respiratory distress syndrome, and systemic thromboembolism, resulting in multiple organ failure with high mortality and morbidity. SARS-CoV-2 has immune evasion mechanisms, including inhibition of interferon signaling and suppression of T cell and B cell responses. SARS-CoV-2 infection directly and indirectly causes dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction, which interact with each other and are exacerbated by cardiovascular risk factors. In this review, we summarize current knowledge on the pathogenic basis of thromboinflammation and endothelial injury in COVID-19. We highlight the distinct contributions of dysregulated immune responses, platelet hyperactivation, and endothelial dysfunction to the pathogenesis of COVID-19. In addition, we discuss potential therapeutic strategies targeting these mechanisms.
Robert Zheng, Kenya Kusunose, Y Okushi, Y Okayama, M Nakai, Y Sumita, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Impact of cancer on short-term in-hospital mortality after primary acute myocardial infarction, Open Heart, Vol.8, No.2, e00186, 2021.
Kenya Kusunose, Hironori Takahashi, Susumu Nishio, Yukina Hirata, Robert Zheng, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi and Masataka Sata : Predictive value of left atrial function for latent paroxysmal atrial fibrillation as the cause of embolic stroke of undetermined source, Journal of Cardiology, Vol.78, No.5, 355-361, 2021.
(Summary)
In patients with embolic stroke of undetermined source (ESUS), paroxysmal atrial fibrillation (AF) is often diagnosed, however, the risk of paroxysmal AF in ESUS has not been well described. Several studies have suggested a linkage between left atrial (LA) functional parameters and risk of AF in stroke patients. The aim of this study was to assess the role of LA functional parameters as predictors of latent paroxysmal AF in ESUS on admission. Between January 2015 and December 2019, consecutive stroke patients with suspected ESUS at admission were prospectively included in this study. They were under hospital electrocardiographic monitoring for detection of new-onset AF. Various echocardiographic parameters including left atrial strain were assessed for association with new-onset AF. We gathered 1082 consecutive patients with ischemic stroke. After exclusions, 121 patients with suspected ESUS at admission formed the study cohort. New-onset AF was detected in 46 (38%) patients during hospital electrocardiographic monitoring (median follow-up: 18 days). LA pump and reservoir strains were significantly and independently associated with new-onset AF. Receiver operating characteristic analysis for the association with new-onset AF showed that the areas under the curve (AUCs) of clinical parameters plus one of each strain (LA pump strain: AUC: 0.86±0.04 and LA reservoir strain: AUC: 0.76±0.05) models were significantly better than plus LA volume index (AUC: 0.68±0.04, compared p-values <0.05). LA strain was significantly associated with new development of AF. Patients with impaired LA function at admission should be carefully monitored to find AF.
Rie Tsutsumi, Yuki Yamasaki, Jiro Takeo, Hiroko Miyahara, Mayu Sebe, Masahiro Bando, Yousuke Tanba, Yuna Mishima, Kana Takeji, Nanako Ueshima, Masashi Kuroda, Saeko Masumoto, Nagakatsu Harada, Daiju Fukuda, Ryoko Yoshimoto, Yasuo M. Tsutsumi, Ken-ichi Aihara, Masataka Sata and Hiroshi Sakaue : Long-chain monounsaturated fatty acids improve endothelial function with altering microbial flora, Translational Research : The Journal of Laboratory and Clinical Medicine, Vol.237, 16-30, 2021.
(Summary)
Fish oil-derived long-chain monounsaturated fatty acids (LCMUFAs) with a carbon chain length longer than 18 units ameliorate cardiovascular risk in mice. In this study, we investigated whether LCMUFAs could improve endothelial functions in mice and humans. In a double-blind, randomized, placebo-controlled, parallel-group, multi-center study, healthy subjects were randomly assigned to either an LCMUFA oil (saury oil) or a control oil (olive and tuna oils) group. Sixty subjects were enrolled and administrated each oil for 4 weeks. For the animal study, ApoE mice were fed a Western diet supplemented with 3% of either gadoleic acid (C20:1) or cetoleic acid (C22:1) for 12 weeks. Participants from the LCMUFA group showed improvements in endothelial function and a lower trimethylamine-N-oxide level, which is a predictor of coronary artery disease. C20:1 and C22:1 oils significantly improved atherosclerotic lesions and plasma levels of several inflammatory cytokines, including IL-6 and TNF-α. These beneficial effects were consistent with an improvement in the gut microbiota environment, as evident from the decreased ratio of Firmicutes and/ or Bacteroidetes, increase in the abundance of Akkermansia, and upregulation of short-chain fatty acid (SCFA)-induced glucagon-like peptide-1 (GLP-1) expression and serum GLP-1 level. These data suggest that LCMUFAs alter the microbiota environment that stimulate the production of SCFAs, resulting in the induction of GLP-1 secretion. Fish oil-derived long-chain monounsaturated fatty acids might thus help to protect against cardiovascular disease.
Kenya Kusunose, Yuichiro Okushi, Yoshihiro Okayama, Robert Zheng, Michikazu Nakai, Yoko Sumita, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Use of Echocardiography and Heart Failure In-Hospital Mortality from Registry Data in Japan., Journal of Cardiovascular Development and Disease, Vol.8, No.10, 124, 2021.
(Summary)
Echocardiography requires a high degree of skill on the part of the examiner, and the skill may be more improved in larger volume centers. This study investigated trends and outcomes associated with the use and volume of echocardiographic exams from a real-world registry database of heart failure (HF) hospitalizations. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). A first analysis was performed to assess the trend of echocardiographic examinations between 2012 and 2016. A secondary analysis was performed to assess whether echocardiographic use was associated with in-hospital mortality in 2015. During this period, the use of echocardiography grew at an average annual rate of 6%. Patients with echocardiography had declining rates of hospital mortality, and these trends were associated with high hospitalization costs. In the 2015 sample, a total of 52,832 echocardiograms were examined, corresponding to 65.6% of all HF hospital admissions for that year. We found that the use and volume of echocardiography exams were associated with significantly lower odds of all-cause hospital mortality in heart failure (adjusted odds ratio (OR): 0.48 for use of echocardiography and 0.78 for the third tertile; both < 0.001). The use of echocardiography was associated with decreased odds of hospital mortality in HF. The volumes of echocardiographic examinations were also associated with hospital mortality.
Shusuke Yagi, T Takahashi, K Murakami, M Azuma, M Sugano, R Miyamoto, M Niki, Hirotsugu Yamada, Yutaka Kawabata, Tani Akihiro, Daiju Fukuda, Muneyuki Kadota, Takayuki Ise, Kenya Kusunose, Takeshi Tobiume, Tomomi Matsuura, Koji Yamaguchi, Takeshi Soeki, Tetsuzo Wakatsuki, H Hata and Masataka Sata : Infective Endocarditis from Furuncle with Meningitis Complication Caused by Methicillin-resistant Staphylococcus aureus, Internal Medicine, Vol.60, No.20, 3251-3255, 2021.
Kenya Kusunose, T Imai, A Tanaka, K Dohi, K Shiina, T Yamada, K Kida, K Eguchi, H Teragawa, Y Takeishi, N Ohte, Hirotsugu Yamada, Masataka Sata and K Node : Effects of canagliflozin on NT-proBNP stratified by left ventricular diastolic function in patients with type 2 diabetes and chronic heart failure: a sub analysis of the CANDLE trial, Cardiovascular Diabetology, Vol.20, No.1, 186, 2021.
(Summary)
Identification of the effective subtypes of treatment for heart failure (HF) is an essential topic for optimizing treatment of the disorder. We hypothesized that the beneficial effect of SGLT2 inhibitors (SGLT2i) on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) might depend on baseline diastolic function. To elucidate the effects of SGLT2i in type 2 diabetes mellitus (T2DM) and chronic HF we investigated, as a post-hoc sub-study of the CANDLE trial, the effects of canagliflozin on NT-proBNP levels from baseline to 24 weeks, with the data stratified by left ventricular (LV) diastolic function at baseline. Patients (n = 233) in the CANDLE trial were assigned randomly to either an add-on canagliflozin (n = 113) or glimepiride treatment groups (n = 120). The primary endpoint was a comparison between the two groups of the changes from baseline to 24 weeks in NT-pro BNP levels, stratified according to baseline ventricular diastolic function. The change in the geometric mean of NT-proBNP level from baseline to 24 weeks was 0.98 (95% CI 0.89-1.08) in the canagliflozin group and 1.07 (95% CI 0.97-1.18) in the glimepiride group. The ratio of change with canagliflozin/glimepiride was 0.93 (95% CI 0.82-1.05). Responder analyses were used to investigate the response of an improvement in NT-proBNP levels. Although the subgroup analyses for septal annular velocity (SEP-e') showed no marked heterogeneity in treatment effect, the subgroup with an SEP-e' < 4.7 cm/s indicated there was an association with lower NT-proBNP levels in the canagliflozin group compared with that in the glimepiride group (ratio of change with canagliflozin/glimepiride (0.83, 95% CI 0.66-1.04). In the subgroup with a lower LV diastolic function, canagliflozin showed a trend of reduced NT-pro BNP levels compared to that observed with glimepiride. This study suggests that the beneficial effects of canagliflozin treatment may be different in subgroups classified by the severity of LV diastolic dysfunction.
Yuta Torii, Kenya Kusunose, Yukina Hirata, Susumu Nishio, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Left Atrial Strain Associated with Functional Recovery in Patients Receiving Optimal Treatment for Heart Failure, Journal of the American Society of Echocardiography, Vol.34, No.9, 966-975, 2021.
(Summary)
Heart failure with recovered ejection fraction (HFrecEF) has been reported in several previous studies to have a better prognosis than heart failure with reduced ejection fraction (HFrEF). However, the factors associated with HFrecEF have not been identified. The aim of this study was to test the hypothesis that left atrial (LA) strain could help identify patients with recovered ejection fraction (EF) among those with heart failure (HF) with low EF on admission. One hundred consecutive patients hospitalized for the first time for new-onset HF were enrolled. Patients were clinically diagnosed with HFrEF on admission (left ventricular EF < 40%) and received optimal treatment for HF. Twenty-eight patients improved to HFrecEF during 6 months of follow-up. Regarding clinical background, there were significantly more women and a lower rate of atrial fibrillation in the HFrecEF group than in the HFrEF group. In a multivariate logistic regression analysis, LA strain was an independent predictor of HFrecEF, even after adjustment for gender and left ventricular EF (odds ratio: 4.06; 95% CI: 2.04-8.07; P < .001). A cutoff value of 10.8% for LA strain showed high sensitivity (96%) and specificity (82%) in identifying HFrecEF in patients with HF presenting with low EF on admission. During a follow-up period of 24 ± 13 months, 31 patients (31%) had cardiovascular death or readmission for HF. Patients with reduced LA strain (<10.8%) had significantly shorter event-free survival than those with preserved LA strain (P = .02). LA strain is a useful indicator for predicting HFrecEF and should be considered as a routine measurement in patients with HFrEF on admission.
Moriaki Yamanaka, Shoichiro Takao, Hideki Otsuka, Youichi Otomi, Saho Irahara, Yamato Kunikane, Satoru Takashi, Airi Yamamoto, Masataka Sata and Masafumi Harada : The Utility of a Combination of <sup>99m</sup>Tc-MIBI Washout Imaging and Cardiac Magnetic Resonance Imaging in the Evaluation of Cardiomyopathy, Annals of Nuclear Cardiology, Vol.7, No.1, 8-16, 2021.
(Summary)
Background: In cardiomyopathy, 99mTc-MIBI washout can reflect mitochondrial dysfunction and late gadolinium enhancement (LGE) on cardiac magnetic imaging (MRI) is associated with tissue fibrosis. We sought to determine the relationship between 99mTc-MIBI uptake, 99mTc-MIBI washout, and LGE on MRI in patients with cardiomyopathy. Methods: Twenty-one patients underwent rest myocardial perfusion scintigraphy at 45 minutes (early) and 4 hours (delayed) after intravenous 99mTc-MIBI administration and cardiac MRI. We assessed myocardial perfusion, 99mTc-MIBI washout, and LGE. We divided the left ventricle (LV) wall into 16 segments using a polar map. Then, we classified each segment into 5 groups according to 99mTc-MIBI uptake in early-rest images and washout. Additionally, we created a contingency table based on LGE presence/absence in the groups. Results: We evaluated 336 segments in 21 patients. 99mTc-MIBI uptake was decreased in 168 segments in the early-rest 99mTc-MIBI images. 99mTc-MIBI washout was observed in 108 segments with either normal perfusion or reduced perfusion in the early-rest 99mTc-MIBI images. LGE was positive in 104 segments. A contingency table analysis with Fisher窶冱 exact test showed that LGE was observed significantly more frequently in the segments with decreased 99mTc-MIBI uptake (p < 0.001). In segments without a decreased 99mTc-MIBI uptake, there was a significant correlation between increased 99mTc-MIBI washout and the presence of LGE (p = 0.033). Conclusions: In cardiomyopathy, the mitochondrial dysfunction in the early stage is shown as 99mTc-MIBI washout, and fibrotic changes in the myocardium in advanced stages are shown as LGE on cardiac MRI. The severity of myocardial damage and the clinical stage of cardiomyopathy can be evaluated using multimodal imaging.
(Keyword)
<sup>99m</sup>Tc-MIBI / Cardiomyopathy / Late gadolinium enhancement (LGE) / Washout
Sae X. Morita, Kenya Kusunose, Akihiro Haga, Masataka Sata, Kohei Hasegawa, Yoshihiko Raita, Muredach P. Reilly, Michael A. Fifer, Mathew S. Maurer and Yuichi J. Shimada : Deep Learning Analysis of Echocardiographic Images to Predict Positive Genotype in Patients With Hypertrophic Cardiomyopathy., Frontiers in Cardiovascular Medicine, Vol.8, 669860, 2021.
(Summary)
Genetic testing provides valuable insights into family screening strategies, diagnosis, and prognosis in patients with hypertrophic cardiomyopathy (HCM). On the other hand, genetic testing carries socio-economical and psychological burdens. It is therefore important to identify patients with HCM who are more likely to have positive genotype. However, conventional prediction models based on clinical and echocardiographic parameters offer only modest accuracy and are subject to intra- and inter-observer variability. We therefore hypothesized that deep convolutional neural network (DCNN, a type of deep learning) analysis of echocardiographic images improves the predictive accuracy of positive genotype in patients with HCM. In each case, we obtained parasternal short- and long-axis as well as apical 2-, 3-, 4-, and 5-chamber views. We employed DCNN algorithm to predict positive genotype based on the input echocardiographic images. We performed 5-fold cross-validations. We used 2 reference models-the Mayo HCM Genotype Predictor score (Mayo score) and the Toronto HCM Genotype score (Toronto score). We compared the area under the receiver-operating-characteristic curve (AUC) between a combined model using the reference model plus DCNN-derived probability and the reference model. We calculated the -value by performing 1,000 bootstrapping. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In addition, we examined the net reclassification improvement. We included 99 adults with HCM who underwent genetic testing. Overall, 45 patients (45%) had positive genotype. The new model combining Mayo score and DCNN-derived probability significantly outperformed Mayo score (AUC 0.86 [95% CI 0.79-0.93] vs. 0.72 [0.61-0.82]; < 0.001). Similarly, the new model combining Toronto score and DCNN-derived probability exhibited a higher AUC compared to Toronto score alone (AUC 0.84 [0.76-0.92] vs. 0.75 [0.65-0.85]; = 0.03). An improvement in the sensitivity, specificity, PPV, and NPV was also achieved, along with significant net reclassification improvement. In conclusion, compared to the conventional models, our new model combining the conventional and DCNN-derived models demonstrated superior accuracy to predict positive genotype in patients with HCM.
Tomomi Matsuura, Takeshi Soeki, Daiju Fukuda, Etsuko Uematsu, Takeshi Tobiume, Tomoya Hara, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Tetsuzo Wakatsuki and Masataka Sata : Activated Factor X Signaling Pathway via Protease-Activated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation, Circulation Journal, Vol.85, No.8, 1383-1391, 2021.
(Summary)
Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes. The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.
Pham Tran Phuong, Daiju Fukuda, Sachiko Nishimoto, JR Kim-Kaneyama, XF Lei, Yutaka Takahashi, Tomohito Sato, Kimie Tanaka, Kumiko Suto, Yutaka Kawabata, Koji Yamaguchi, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi, Michio Shimabukuro, Mitsutoshi Setou, Glen N Barber and Masataka Sata : STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases, European Heart Journal, Vol.42, No.42, 4336-4348, 2021.
(Summary)
Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.
B Ganbaatar, Daiju Fukuda, M Shinohara, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, KI Hirata and Masataka Sata : Inhibition of S1P Receptor 2 Attenuates Endothelial Dysfunction and Inhibits Atherogenesis in Apolipoprotein E-Deficient Mice, Journal of Atherosclerosis and Thrombosis, Vol.28, No.6, 630-642, 2021.
(Summary)
The bioactive lipid, sphingosine-1-phosphate (S1P), has various roles in the physiology and pathophysiology of many diseases. There are five S1P receptors; however, the role of each S1P receptor in atherogenesis is still obscure. Here we investigated the contribution of S1P receptor 2 (S1P2) to atherogenesis by using a specific S1P2 antagonist, ONO-5430514, in apolipoprotein E-deficient (Apoe) mice. Apoe mice fed with a western-type diet (WTD) received ONO-5430514 (30 mg/kg/day) or vehicle. To examine the effect on atherogenesis, Sudan IV staining, histological analysis, qPCR, and vascular reactivity assay was performed. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. WTD-fed Apoe mice had significantly higher S1P2 expression in the aorta compared with wild-type mice. S1P2 antagonist treatment for 20 weeks reduced atherosclerotic lesion development (p<0.05). S1P2 antagonist treatment for 8 weeks ameliorated endothelial dysfunction (p<0.05) accompanied with significant reduction of lipid deposition, macrophage accumulation, and inflammatory molecule expression in the aorta compared with vehicle. S1P2 antagonist attenuated the phosphorylation of JNK in the abdominal aorta compared with vehicle (p<0.05). In HUVEC, S1P promoted inflammatory molecule expression such as MCP-1 and VCAM-1 p<0.001), which was attenuated by S1P2 antagonist or a JNK inhibitor (p<0.01). S1P2 antagonist also inhibited S1P-induced JNK phosphorylation in HUVEC (p<0.05). Our results suggested that an S1P2 antagonist attenuates endothelial dysfunction and prevents atherogenesis. S1P2, which promotes inflammatory activation of endothelial cells, might be a therapeutic target for atherosclerosis.
Y Okushi, Kenya Kusunose, Y Okayama, Robert Zheng, M Nakai, Y Sumita, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Acute Hospital Mortality of Venous Thromboembolism in Patients With Cancer From Registry Data, Journal of the American Heart Association, Vol.10, No.11, e019373, 2021.
(Summary)
Background The prognosis of patients with cancer-venous thromboembolism (VTE) is not well known because of a lack of registry data. Moreover, there is also no knowledge on how specific types are related to prognosis. We sought to evaluate the clinical characteristics and outcomes of patients with cancer-associated VTE, compared with a matched cohort without cancer using real-world registry data of VTE. Methods and Results This study was based on the Diagnosis Procedure Combination database in the JROAD-DPC (Japanese Registry of All Cardiac and Vascular Diseases and the Diagnosis Procedure Combination). Of 5 106 151 total patients included in JROAD-DPC, we identified 49 580 patients who were first hospitalized with VTE from April 2012 to March 2017. Propensity score was estimated with a logistic regression model, with cancer as the dependent variable and 18 clinically relevant covariates. After propensity matching, there were 25 148 patients with VTE with or without cancer. On propensity score-matched analysis with 25 148 patients with VTE, patients with cancer had higher total in-hospital mortality within 7 days (1.3% versus 1.1%, odds ratio [OR], 1.66; 95% CI, 1.31-2.11; <0.0001), 14 days (2.5% versus 1.5%, OR, 2.07; 95% CI, 1.72-2.49; <0.0001), and 30 days (4.8% versus 2.0%, OR, 2.85; 95% CI, 2.45-3.31; <0.0001). On analysis for each type of cancer, in-hospital mortality in 11 types of cancer was significantly high, especially pancreas (OR, 12.96; 95% CI, 6.41-26.20), biliary tract (OR, 8.67; 95% CI, 3.00-25.03), and liver (OR, 7.31; 95% CI, 3.05-17.50). Conclusions Patients with cancer had a higher in-hospital acute mortality for VTE than those without cancer, especially in pancreatic, biliary tract, and liver cancers.
T Ogata, H Shimada, T Inoue, S Takeshita, Y Tsuboi, N Uesugi, M Fujiwara, Masataka Sata and Hirotsugu Yamada : Quantification of Carotid Plaque Histology Using iPlaque Software, Ultrasound in Medicine & Biology, Vol.47, No.4, 928-931, 2021.
Daiju Fukuda and Masataka Sata : Frontiers of inflammatory disease research: inflammation in cardiovascular-cerebral diseases, Inflammation and Regeneration, Vol.41, No.1, 10, 2021.
Yukina Hirata, Kenya Kusunose, Takumasa Tsuji, Kohei Fujimori, Jun'ichi Kotoku and Masataka Sata : Deep Learning for Detection of Elevated Pulmonary Artery Wedge Pressure using Standard Chest X-Ray, The Canadian Journal of Cardiology, Vol.37, No.8, 1198-1206, 2021.
(Summary)
To accurately diagnose and control heart failure (HF), it is important to carry out a simple assessment of elevated pulmonary arterial wedge pressure (PAWP). The aim of this study was to develop and validate an objective method for detecting elevated PAWP by applying deep learning (DL) to a chest x-ray (CXR). We enrolled 1013 consecutive patients with a right-heart catheter between October 2009 and February 2020. We developed a convolutional neural network to identify patients with elevated PAWP (> 18 mm Hg) as the actual value of PAWP to be used in the dataset for training. In the prospective validation dataset used to detect elevated PAWP, the area under the receiver operating characteristic curve (AUC) was calculated using the DL model that evaluated the CXR. In the prospective validation dataset, the AUC of the DL model with CXR was not significantly different from the AUC produced by brain natriuretic peptide (BNP) and the echocardiographic left-ventricular diastolic dysfunction (DD) algorithm (DL model: 0.77 vs BNP: 0.77 vs DD algorithm: 0.70; respectively; P = NS for all comparisons); it was, however, significantly higher than the AUC of the cardiothoracic ratio (DL model vs cardiothoracic ratio [CTR]: 0.66, P = 0.044). The model based on 3 parameters (BNP, DD algorithm, and CTR) was improved by adding the DL model (AUC: from 0.80 to 0.86; P = 0.041). Applying the DL model based on a CXR (a classical, universal, and low-cost test) is useful for screening for elevated PAWP.
Miharu Arase, Kenya Kusunose, N Yamaguchi, Yukina Hirata, Susumu Nishio, Y Okushi, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Cardiac reserve by 6-minute walk stress echocardiography in systemic sclerosis., Open Heart, Vol.8, No.1, e001559, 2021.
Kenya Kusunose, Y Okushi, Y Okayama, Robert Zheng, M Abe, M Nakai, Y Sumita, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Association between Vitamin D and Heart Failure Mortality in 10,974 Hospitalized Individuals., Nutrients, Vol.13, No.2, 335, 2021.
(Summary)
A broad range of chronic conditions, including heart failure (HF), have been associated with vitamin D deficiency. Existing clinical trials involving vitamin D supplementation in chronic HF patients have been inconclusive. We sought to evaluate the outcomes of patients with vitamin D supplementation, compared with a matched cohort using real-world big data of HF hospitalization. This study was based on the Diagnosis Procedure Combination database in the Japanese Registry of All Cardiac and Vascular Datasets (JROAD-DPC). After exclusion criteria, we identified 93,692 patients who were first hospitalized with HF between April 2012 and March 2017 (mean age was 79 ± 12 years, and 52.2% were male). Propensity score (PS) was estimated with logistic regression model, with vitamin D supplementation as the dependent variable and clinically relevant covariates. On PS-matched analysis with 10,974 patients, patients with vitamin D supplementation had lower total in-hospital mortality (6.5 vs. 9.4%, odds ratio: 0.67, < 0.001) and in-hospital mortality within 7 days and 30 days (0.9 vs. 2.5%, OR, 0.34, and 3.8 vs. 6.5%, OR: 0.56, both < 0.001). In the sub-group analysis, mortalities in patients with age < 75, diabetes, dyslipidemia, atrial arrhythmia, cancer, renin-angiotensin system blocker, and β-blocker were not affected by vitamin D supplementation. Patients with vitamin D supplementation had a lower in-hospital mortality for HF than patients without vitamin D supplementation in the propensity matched cohort. The identification of specific clinical characteristics in patients benefitting from vitamin D may be useful for determining targets of future randomized control trials.
Gulinu Maimaituxun, Kenya Kusunose, Hirotsugu Yamada, Daiju Fukuda, Shusuke Yagi, Yuta Torii, Nao Yamada, Takeshi Soeki, H Masuzaki, Masataka Sata and Michio Shimabukuro : Deleterious Effects of Epicardial Adipose Tissue Volume on Global Longitudinal Strain in Patients With Preserved Left Ventricular Ejection Fraction, Frontiers in Cardiovascular Medicine, Vol.7, 607825, 2021.
Hironori Tanaka, Yoshihito Saijyo, Tetsu Tomonari, Takahiro Tanaka, Tatsuya Taniguchi, Shusuke Yagi, Koichi Okamoto, Hiroshi Miyamoto, Masahiro Sogabe, Yasushi Sato, Naoki Muguruma, Koichi Tsuneyama, Masataka Sata and Tetsuji Takayama : An Adult Case of Congenital Extrahepatic Portosystemic Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration, Internal Medicine, Vol.60, No.12, 1839-1845, 2021.
(Summary)
A 42-year-old woman visited our hospital due to syncope. Contrast-enhanced CT revealed portosystemic shunt, portal vein hypoplasia, and multiple liver nodules. The histological examination of a liver biopsy specimen exhibited portal vein hypoplasia and revealed that the liver tumor was positive for glutamine synthetase. The patient was therefore diagnosed with congenital extrahepatic portosystemic shunt type II, and with focal nodular hyperplasia (FNH)-like nodules. She had the complication of severe portopulmonary hypertension and underwent complete shunt closure by balloon-occluded retrograde transvenous obliteration (B-RTO). The intrahepatic portal vein was well developed at 1 year after B-RTO, and multiple liver nodules completely regressed. Her pulmonary hypertension also improved.
Akira Takashima, Shusuke Yagi, Koji Yamaguchi, Kiyoe Kurahashi, Yuko Kojima, Robert Zheng, Takayuki Ise, Kenya Kusunose, Sumiko Yoshida, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Ken-ichi Aihara, Masashi Akaike and Masataka Sata : Congenital Hypogonadotropic Hypogonadism with Early-Onset Coronary Artery Disease., The Journal of Medical Investigation : JMI, Vol.68, No.1.2, 189-191, 2021.
(Summary)
The patient with congenital hypogonadotropic hypogonadism (HH) shows low serum levels of androgen, which is a group of sex hormones including testosterone, caused by the decreased gonadotropin release in the hypothalamus. Recent reports showed androgens exert protective effects against insulin resistance or atherosclerotic diseases, such as diabetes mellitus or coronary artery disease. However, whether the juvenile hypogonadism affects the diabetes or cardiovascular disease is unclear. We report a case of a middle-aged man with congenital HH who had severe coronary artery disease complicated with metabolic disorders. J. Med. Invest. 68 : 189-191, February, 2021.
Yutaka Kawabata, Takeshi Soeki, Hiroyuki Ito, Tomomi Matsuura, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Takeshi Tobiume, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, M Kitani, K Kawano, Y Taketani and Masataka Sata : Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients, International Journal of Hypertension, 6653851, 2020.
Takeshi Tobiume, R Kato, Tomomi Matsuura, Kazuhisa Matsumoto, M Hara, N Takamori, Y Taketani, K Okwa, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Takeshi Soeki, Masataka Sata and K Matsumoto : Antegrade slow pathway mapping of typical atrioventricular nodal reentrant tachycardia based on direct slow pathway capture, Journal of Arrhythmia, Vol.37, No.1, 128-139, 2020.
K Tanaka, Daiju Fukuda and Masataka Sata : Roles of Epicardial Adipose Tissue in the Pathogenesis of Coronary Atherosclerosis - An Update on Recent Findings, Circulation Journal, Vol.85, No.1, 2-8, 2020.
(Summary)
Adipose tissue serves not only as an energy store or a mechanical cushion, but also as an endocrine organ. Recent evidence revealed that perivascular adipose tissue is involved in vascular homeostasis and pathophysiology of adjacent arteries by producing various adipokines. Epicardial adipose tissue (EAT) is located between the surface of the heart and the visceral layer of the pericardium and surrounds the coronary arteries. Many clinical studies suggest that an increase in EAT volume is associated with coronary artery disease. It has been reported that exercise and some antidiabetic drugs can reduce EAT volume. In this review, we outline recent findings on the roles of EAT in the pathogenesis of coronary atherosclerosis.
Eiichi Araki, Atsushi Tanaka, Nobuya Inagaki, Hiroshi Ito, Kohjiro Ueki, Toyoaki Murohara, Kenjiro Imai, Masataka Sata, Takehiro Sugiyama, Hideki Ishii, Shunsuke Yamane, Takashi Kadowaki, Issei Komuro and Koichi Node : Diagnosis, Prevention, and Treatment of Cardiovascular Diseases in People With Type 2 Diabetes and Prediabetes - A Consensus Statement Jointly From the Japanese Circulation Society and the Japan Diabetes Society, Circulation Journal, Vol.12, No.1, 1-51, 2020.
Kenya Kusunose, Yukina Hirata, T Tsuji, J Kotoku and Masataka Sata : Deep learning to predict elevated pulmonary artery pressure in patients with suspected pulmonary hypertension using standard chest X ray, Scientific Reports, Vol.10, No.1, 19311, 2020.
(Summary)
Accurate diagnosis of pulmonary hypertension (PH) is crucial to ensure that patients receive timely treatment. We hypothesized that application of artificial intelligence (AI) to the chest X-ray (CXR) could identify elevated pulmonary artery pressure (PAP) and stratify the risk of heart failure hospitalization with PH. We retrospectively enrolled a total of 900 consecutive patients with suspected PH. We trained a convolutional neural network to identify patients with elevated PAP (> 20 mmHg) as the actual value of PAP. The endpoints in this study were admission or occurrence of heart failure with elevated PAP. In an independent evaluation set for detection of elevated PAP, the area under curve (AUC) by the AI algorithm was significantly higher than the AUC by measurements of CXR images and human observers (0.71 vs. 0.60 and vs. 0.63, all p < 0.05). In patients with AI predicted PH had 2-times the risk of heart failure with PH compared with those without AI predicted PH. This preliminary work suggests that applying AI to the CXR in high risk groups has limited performance when used alone in identifying elevated PAP. We believe that this report can serve as an impetus for a future large study.
Yoshihito Saijyo, Kenya Kusunose, Y Okushi, Hirotsugu Yamada, Hiroaki Toba and Masataka Sata : Relationship between regional left ventricular dysfunction and cancer-therapy-related cardiac dysfunction, Heart, Vol.106, No.22, 1752-1758, 2020.
(Summary)
The aim of our study was to assess the association between risk of cancer-therapy-related cardiac dysfunction (CTRCD) after first follow-up and the difference in echocardiographic measures from baseline to follow-up. We retrospectively enrolled 87 consecutive patients (58±14 years, 55 women) who received anthracycline and underwent echocardiographic examinations both before (baseline) and after initial anthracycline administration (first follow-up). We measured absolute values of global longitudinal strain (GLS), apical longitudinal strain (LS), mid-LS and basal-LS at baseline and first follow-up, and per cent changes (Δ) of these parameters were calculated. Among 61 patients who underwent further echocardiographic examinations (second follow-up, third follow-up, etc), we assessed the association between regional left ventricular (LV) systolic dysfunction from baseline to follow-up and development of CTRCD, defined as LV ejection fraction (LVEF) under 53% and more absolute decrease of 10% from baseline, after first follow-up. LVEF (65%±4% vs 63±4%, p=0.004), GLS (23.2%±2.6% vs 22.2±2.4%, p=0.005) and basal-LS (21.9%±2.5% vs 19.9±2.4%, p<0.001) at first follow-up significantly decreased compared with baseline. Among the 61 patients who had further follow-up echocardiographic examinations, 13% developed CTRCD. In the Cox-hazard model, worse Δbasal-LS was significantly associated with CTRCD. By Kaplan-Meier analysis, patients with Δbasal-LS decrease of more than the median value (-9.7%) had significantly worse event-free survival than those with a smaller decrease (p=0.015). Basal-LS significantly decreased prior to development of CTRCD, and worse basal-LS was associated with development of CTRCD in patients receiving anthracycline chemotherapy.
N Tanabe, K Fukuda, H Matsubara, N Nakanishi, N Tahara, S Ikeda, T Kishi, T Satoh, KI Hirata, T Inoue, H Kimura, Y Okano, O Okazaki, Masataka Sata, I Tsujino, S Ueno, N Yamada, A Yao and T Kuriyama : Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients - A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study, Circulation Journal, Vol.84, No.10, 1866-1874, 2020.
(Summary)
Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm, whereas that in the placebo group was 26±180 dyn·s/cm. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm(P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index. Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).
Kenya Kusunose, nao Yamada, Hirotsugu Yamada, Susumu Nishio, Yoshihito Saijoh, Yukina Hirata, Yuta Torii, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Association between Right Ventricular Contractile Function and Cardiac Events in Isolated Post-capillary and Combined Pre- and Post-capillary Pulmonary Hypertension, Journal of Cardiac Failure, Vol.26, No.1, 43-51, 2020.
(Summary)
Recent studies have shown that patients with combined pre- and postcapillary pulmonary hypertension (CpcPH) had worse outcomes than those with isolated postcapillary pulmonary hypertension (IpcPH). However, the prognostic factors including right ventricular (RV) function have not been well documented. The aim of this study was to assess the differentiation of PH phenotypes, using echocardiography, and the association between RV longitudinal strain and cardiac events. We prospectively recruited consecutive patients who had undergone right heart catheterization. The primary endpoint was cardiovascular death or readmission due to heart failure. We included 137 patients with Group 2 PH. A RV longitudinal strain of 17% was sensitive (85%) and specific (70%) to determine the CpcPH. During a median period of 31 months, 43 patients experienced the primary endpoint during follow-up. In a multivariate analysis, RV longitudinal strain was associated with the primary endpoint in both CpcPH and IpcPH (HR: 0.84, P = 0.003; HR: 0.86, P = 0.001). Lower RV longitudinal strain was independently associated with worse outcomes in CpcPH and IpcPH. RV longitudinal strain may play a prognostic role in PH phenotypes.
Yukina Hirata, Susumu Nishio, Kenya Kusunose, Yukina Fujita, Miharu Arase, Hirotsugu Yamada and Masataka Sata : Comparison of Global Longitudinal Strain Measurement Among Recent Version Echocardiographic Machines and Vendor Independent Strain Analysis Software, Japanese Journal of Medical Ultrasound Technology, Vol.45, No.4, 405-413, 2020.
(Summary)
<p><b>Purpose</b>: Global longitudinal strain (GLS) assessed using the two-dimensional (2D) speckle tracking method is considered to be an accurate and reproducible measurement method for assessing the LV contractility. However, the measurement variability across different ultrasonography machines has been discussed. This study aimed to determine whether the measurement variability among newer echocardiographic machines is lower than that reported in previous studies.</p><p><b>Subjects and Methods</b>: We enrolled 34 healthy volunteers. Apical images were acquired using three types of latest ultrasonography machines at the Tokushima University Hospital. The GLS values were assessed and compared using the latest version of the vendor-specific software and one vendor-independent software packages (EchoInsight ver. 2.2.6.2230, Epsilon).</p><p><b>Results and Discussion</b>: The upgraded vendor-specific software showed good correlation in GLS [GE vs. Philips (r=0.678, p<0.001, Bias 1.1%, 2SD ±2.9%), GE vs. Canon (r=0.690, p<0.001, Bias 0.4%, 2SD ±2.5%), Philips vs. Canon (r=0.551, p<0.001, Bias 1.5%, 2SD ±3.2%)]. The GLS measured using vendor-independent software provided greater degree of correlation than that with each software alone.</p><p><b>Conclusion</b>: The measurement variability of GLS between devices was superior than that reported previously. Moreover, the GLS measured using the images acquired using each device with EchoInsight showed good inter-device correlation.</p>
Yuta Torii, Kenya Kusunose, Robert Zheng, Hirotsugu Yamada, Rie Amano, Rikizo Matsumoto, Yukina Hirata, Susumu Nishio, Nao Yamada, Takayuki Ise, Koji Yamaguchi, Takeshi Tobiume, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki, Yoshihiro Okayama and Masataka Sata : Association between Sarcopenia/Lower Muscle Mass and Short-Term Regression of Deep Vein Thrombosis Using Direct Oral Anticoagulants, International Heart Journal, Vol.61, No.4, 787-794, 2020.
(Summary)
Advanced age, obesity, and muscle weakness are independent factors in the onset of deep vein thrombosis (DVT). Recently, an association between sarcopenia and DVT has been reported. We hypothesized that sarcopenia related factors, observed by ultrasonography, are associated with the regression effect on the thrombus following anticoagulation therapy. The present study focused on gastrocnemius muscle (GCM) thickness and the GCM's internal echogenic brightness. We examined the association with DVT regression following direct oral anticoagulants (DOACs) treatment.The prospective cohort study period was between October 2017 and August 2018. We enrolled 46 patients diagnosed with DVT by ultrasonography, who were aged >60 years old and treated with DOACs. Sarcopenia was evaluated using the Asian Working Group for Sarcopenia flowchart. The average DOACs treatment period was 94 days, and 29 patients exhibited thrombus regression. On univariate logistic regression analysis, sarcopenia, average GCM diameter index, and gastrocnemius integrated backscatter index were significantly associated with thrombus regression. In a multivariate model, only the average GCM diameter index correlated with thrombus regression.The average GCM diameter index is associated with DVT regression treated with DOACs. Considering the GCM diameter during DVT treatment can be a marker to make a decision for the treatment of DVT.
(Keyword)
Aged / Aged, 80 and over / Factor Xa Inhibitors / female / Humans / male / Middle Aged / Muscle, Skeletal / Prospective Studies / Sarcopenia / Ultrasonography / Venous Thrombosis
S Nishimoto, Daiju Fukuda and Masataka Sata : Emerging roles of Toll-like receptor 9 in cardiometabolic disorders, Inflammation and Regeneration, Vol.40, 18, 2020.
(Summary)
Growing evidence suggests that damage-associated molecule patterns (DAMPs) and their receptors, pattern recognition receptors (PRRs), are associated with the progression of cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis. Cardiometabolic disorders share sterile chronic inflammation as a major cause; however, the exact mechanisms are still obscure. Toll-like receptor 9 (TLR9), one of the nucleic acid-sensing TLRs, recognizes DNA fragments derived from pathogens and contributes to self-defense by activation of the innate immune system. In addition, previous studies demonstrated that TLR9 recognizes DNA fragments released from host cells, accelerating sterile inflammation, which is associated with inflammatory diseases such as autoimmune diseases. In obese adipose tissue and atherosclerotic vascular tissue, various stresses release DNA fragments and/or nuclear proteins as DAMPs from degenerated adipocytes and vascular cells. Recent studies indicated that the activation of TLR9 in immune cells including macrophages and dendritic cells by recognition of these DAMPs promotes inflammation in these tissues, which causes cardiometabolic disorders. This review discusses recent advances in understanding the role of sterile inflammation associated with TLR9 and its endogenous ligands in cardiometabolic disorders. New insights into innate immunity may provide better understanding of cardiometabolic disorders and new therapeutic options for these major health threats in recent decades.
Kenya Kusunose, M Fujiwara, Hirotsugu Yamada, Susumu Nishio, Y Saijo, N Yamada, Yukina Hirata, Yuta Torii, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Deterioration of Biventricular Strain Is an Early Marker of Cardiac Involvement in Confirmed Sarcoidosis, European Heart Journal Cardiovascular Imaging, Vol.21, No.7, 796-804, 2020.
(Summary)
Risk assessment of developing cardiac involvement in systemic sarcoidosis can be challenging because of limited data. Recently, attention has been given to left ventricular and right ventricular (LV and RV) involvement in cardiac sarcoidosis (CS) and its prevalence, relevance, and prognostic value. The aim of this study was to assess the role of biventricular strain to predict prognosis in confirmed sarcoidosis patients. LV and RV longitudinal strains (LSs) were evaluated by 2D speckle tracking in 139 consecutive confirmed sarcoidosis patients without other pre-existing structural heart diseases, and 52 age- and gender-matched control subjects. The primary endpoint was CS-related events (cardiac death or development of cardiac involvement). Sarcoidosis without cardiac involvement had significantly lower LV and RV free wall LS compared with control subjects. Basal LS had a higher area under the curve for differentiation of sarcoidosis in patients without cardiac involvement compared to control (cut-off value: -18% with 89% sensitivity and 69% specificity). During a median period of 50 months, the occurrence of CS-related events was observed in 20 patients. In a multivariate analysis, basal LV LS and RV free wall LS were associated with the events [hazard ratio (HR) 0.72, P < 0.001 and HR: 0.83, P = 0.006, respectively]. Patients with impaired biventricular function had significantly shorter event-free survival than those with preserved biventricular function (P < 0.001). Deterioration of biventricular strain was associated with CS-related events. This information might be useful for clinical evaluation and follow-up in sarcoidosis.
Hirofumi Tomiyama, Charalambos Vlachopoulos, Panagiotis Xaplanteris, Hiroki Nakano, Kazuki Shiina, Tomoko Ishizu, Takahide Kohro, Yukihito Higashi, Bonpei Takase, Toru Suzuki, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koichi Node, Atsushi Tanaka, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito, Toshiaki Ohkuma, Toshiharu Ninomiya, Taishiro Chikamori, Akira Yamashina and Shin-Ichiro Ueda : Usefulness of the SAGE Score to Predict Elevated Values of Brachial-Ankle Pulse Wave Velocity in Japanese Subjects With Hypertension, Hypertension Research, Vol.43, No.11, 1284-1294, 2020.
(Summary)
The score based on the office systolic blood pressure, age, fasting blood glucose level, and estimated glomerular filtration rate (SAGE score) has been proposed as a useful marker to identify elevated values of carotid-femoral pulse wave velocity (PWV). The present cross-sectional study was conducted to examine whether the SAGE score is also a useful marker to identify subjects with elevated brachial-ankle PWV values in Japanese subjects with hypertension. We measured the brachial-ankle PWV and calculated the SAGE score in a total of 1019 employees of a Japanese company with hypertension and 817 subjects with hypertension derived from a multicenter study cohort. The analyses in this study were based on data from these two study groups as well as on a composite population of the two (n = 1836). The receiver operating characteristic curve analysis showed that the area under the curve to identify subjects with brachial-ankle PWV values of 1800 cm/s was over 0.70 in each of the three study groups. Even after adjustments, a SAGE score 7 had a significant odds ratio for identifying subjects with brachial-ankle PWV values 1800 cm/s in the 1836 study subjects from the composite occupational and multicenter study cohort (odds ratio = 2.1, 95% confidence interval = 1.4-3.0, P < 0.01). Thus, in Japanese subjects with hypertension, the SAGE score may be a useful marker for identifying subjects with elevated brachial-ankle PWV values.
Kenya Kusunose, Takashi Abe, Akihiro Haga, Daiju Fukuda, Hirotsugu Yamada, Masafumi Harada and Masataka Sata : A Deep Learning Approach for Assessment of Regional Wall Motion Abnormality From Echocardiographic Images, JACC. Cardiovascular Imaging, Vol.13, No.2, 374-381, 2020.
(Summary)
This study investigated whether a deep convolutional neural network (DCNN) could provide improved detection of regional wall motion abnormalities (RWMAs) and differentiate among groups of coronary infarction territories from conventional 2-dimensional echocardiographic images compared with that of cardiologists, sonographers, and resident readers. An effective intervention for reduction of misreading of RWMAs is needed. The hypothesis was that a DCNN trained using echocardiographic images would provide improved detection of RWMAs in the clinical setting. A total of 300 patients with a history of myocardial infarction were enrolled. From this cohort, 3 groups of 100 patients each had infarctions of the left anterior descending (LAD) artery, the left circumflex (LCX) branch, and the right coronary artery (RCA). A total of 100 age-matched control patients with normal wall motion were selected from a database. Each case contained cardiac ultrasonographs from short-axis views at end-diastolic, mid-systolic, and end-systolic phases. After the DCNN underwent 100 steps of training, diagnostic accuracies were calculated from the test set. Independently, 10 versions of the same model were trained, and ensemble predictions were performed using those versions. For detection of the presence of WMAs, the area under the receiver-operating characteristic curve (AUC) produced by the deep learning algorithm was similar to that produced by the cardiologists and sonographer readers (0.99 vs. 0.98, respectively; p = 0.15) and significantly higher than the AUC result of the resident readers (0.99 vs. 0.90, respectively; p = 0.002). For detection of territories of WMAs, the AUC by the deep learning algorithm was similar to the AUC by the cardiologist and sonographer readers (0.97 vs. 0.95, respectively; p = 0.61) and significantly higher than the AUC by resident readers (0.97 vs. 0.83, respectively; p = 0.003). From a validation group at an independent site (n = 40), the AUC by the deep learning algorithm was 0.90. The present results support the possibility of using DCNN for automated diagnosis of RWMAs in the field of echocardiography.
A Tanaka, I Hisauchi, I Taguchi, A Sezai, S Toyoda, H Tomiyama, Masataka Sata, S Ueda, JI Oyama, M Kitakaze, T Murohara and K Node : Effects of canagliflozin in patients with type 2 diabetes and chronic heart failure: a randomized trial (CANDLE), ESC Heart Failure, Vol.7, No.4, 1585-159, 2020.
Kenya Kusunose, Akihiro Haga, Mizuki Inoue, Daiju Fukuda, Hirotsugu Yamada and Masataka Sata : Clinically Feasible and Accurate View Classification of Echocardiographic Images Using Deep Learning, Biomolecules, Vol.10, No.5, E665, 2020.
(Summary)
A proper echocardiographic study requires several video clips recorded from different acquisition angles for observation of the complex cardiac anatomy. However, these video clips are not necessarily labeled in a database. Identification of the acquired view becomes the first step of analyzing an echocardiogram. Currently, there is no consensus whether the mislabeled samples can be used to create a feasible clinical prediction model of ejection fraction (EF). The aim of this study was to test two types of input methods for the classification of images, and to test the accuracy of the prediction model for EF in a learning database containing mislabeled images that were not checked by observers. We enrolled 340 patients with five standard views (long axis, short axis, 3-chamber view, 4-chamber view and 2-chamber view) and 10 images in a cycle, used for training a convolutional neural network to classify views (total 17,000 labeled images). All DICOM images were rigidly registered and rescaled into a reference image to fit the size of echocardiographic images. We employed 5-fold cross validation to examine model performance. We tested models trained by two types of data, averaged images and 10 selected images. Our best model (from 10 selected images) classified video views with 98.1% overall test accuracy in the independent cohort. In our view classification model, 1.9% of the images were mislabeled. To determine if this 98.1% accuracy was acceptable for creating the clinical prediction model using echocardiographic data, we tested the prediction model for EF using learning data with a 1.9% error rate. The accuracy of the prediction model for EF was warranted, even with training data containing 1.9% mislabeled images. The CNN algorithm can classify images into five standard views in a clinical setting. Our results suggest that this approach may provide a clinically feasible accuracy level of view classification for the analysis of echocardiographic data.
A Tanaka, I Taguchi, H Teragawa, N Ishizaka, Y Kanzaki, H Tomiyama, Masataka Sata, A Sezai, K Eguchi, T Kato, S Toyoda, R Ishibashi, K Kario, T Ishizu, S Ueda, K Maemura, Y Higashi, H Yamada, M Ohishi, K Yokote, T Murohara, JI Oyama and K Node : Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial, PLoS Medicine, Vol.17, No.4, e1003095, 2020.
(Summary)
An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.
B Ganbaatar, Daiju Fukuda, M Shinohara, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, KI Hirata and Masataka Sata : Empagliflozin Ameliorates Endothelial Dysfunction and Suppresses Atherogenesis in Diabetic Apolipoprotein E-deficient Mice, European Journal of Pharmacology, Vol.15, No.875, 173040, 2020.
(Summary)
Recent studies reported cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors; however, the underlying mechanisms are still obscure. Here, we investigated whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE) mice. Male streptozotocin (STZ) - induced diabetic ApoE mice were treated with empagliflozin for 12 or 8 weeks. Empagliflozin lowered blood glucose (P < 0.001) and lipid levels in diabetic ApoE mice. Empagliflozin treatment for 12 weeks significantly decreased atherosclerotic lesion size in the aortic arch (P < 0.01) along with reduction of lipid deposition (P < 0.05), macrophage accumulation (P < 0.001), and inflammatory molecule expression in plaques compared with the untreated group. Empagliflozin treatment for 8 weeks significantly ameliorated diabetes-induced endothelial dysfunction as determined by the vascular response to acetylcholine (P < 0.001). Empagliflozin reduced RNA expression of a macrophage marker, CD68, and inflammatory molecules such as MCP-1 (P < 0.05) and NADPH oxidase subunits in the aorta compared with the untreated group. Empagliflozin also reduced plasma levels of vasoconstrictive eicosanoids, prostaglandin E and thromboxane B (P < 0.001), which were elevated in diabetic condition. Furthermore, empagliflozin attenuated RNA expression of inflammatory molecules in perivascular adipose tissue (PVAT), suggesting the reduction of inflammation in PVAT. In in vitro studies, methylglyoxal (MGO), a precursor of AGEs, significantly increased the expression of inflammatory molecules such as MCP-1 and TNF-α in a murine macrophage cell line, RAW264.7. Our results indicated that empagliflozin attenuated endothelial dysfunction and atherogenesis in diabetic ApoE mice. Reduction of vasoconstrictive eicosanoids and inflammation in the vasculature and PVAT may have a role as underlying mechanisms at least partially.
T Maruhashi, J Soga, N Fujimura, N Idei, S Mikami, Y Iwamoto, A Iwamoto, M Kajikawa, T Matsumoto, N Oda, S Kishimoto, S Matsui, H Hashimoto, Y Takaeko, T Yamaji, T Harada, Y Han, Y Aibara, F Yusoff Mohamad, T Hidaka, Y Kihara, K Chayama, K Noma, A Nakashima, C Goto, H Tomiyama, B Takase, T Kohro, T Suzuki, T Ishizu, S Ueda, T Yamazaki, T Furumoto, K Kario, T Inoue, S Koba, K Watanabe, Y Takemoto, T Hano, Masataka Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito, H Ikeda, A Yamashina and Y Higashi : Increased arterial stiffness and cardiovascular risk prediction in controlled hypertensive patients with coronary artery disease: post hoc analysis of FMD-J (Flow-mediated Dilation Japan) Study A, Hypertension Research, Vol.43, No.8, 781-790, 2020.
(Summary)
The usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, is not fully known for the management of treated hypertensive patients with a history of coronary artery disease (CAD) who have blood pressure less than 130/80 mmHg, a recommended blood pressure target in the updated major hypertension guidelines. We analyzed data for 447 treated hypertensive patients with CAD enrolled in FMD-J Study A for assessment of the predictive value of baPWV for future cardiovascular events. The primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 47.6 months, the primary outcome occurred in 64 patients. Blood pressure less than 130/80 mmHg was significantly associated with a lower risk of the composite outcome independent of other cardiovascular risk factors in treated hypertensive patients with CAD (hazard ratio, 0.59; 95% confidence interval (CI), 0.35-0.99; P = 0.04). In treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, baPWV above the cutoff value of 1731 cm/s, derived from receiver-operator characteristic curve analysis for the composite outcome was significantly associated with a higher risk of the composite outcome independent of conventional risk factors (hazard ratio, 2.83; 95% CI, 1.02-7.91; P = 0.04). baPWV was an independent predictor of cardiovascular events in treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, for whom measurement of baPWV is recommended for cardiovascular risk assessment.
Yoshihito Saijo, Kenya Kusunose, Nao Yamada, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata and Masataka Sata : Sequential speckle tracking imaging to detect early stage of cancer therapeutics-related cardiac dysfunction in a patient with breast cancer, Journal of Echocardiography, Vol.18, No.2, 134-135, 2020.
K Tanaka, Daiju Fukuda, Y Higashikuni, Y Hirata, I Komuro, T Saotome, Y Yamashita, T Asakura and Masataka Sata : Biodegradable Extremely-Small-Diameter Vascular Graft Made of Silk Fibroin can be Implanted in Mice, Journal of Atherosclerosis and Thrombosis, Vol.27, 1299-1309, 2020.
(Summary)
Synthetic vascular grafts are widely used in surgical revascularization, mainly for medium- to large-sized vessels. However, synthetic grafts smaller than 6 mm in diameter are associated with a high incidence of thrombosis. In this study, we evaluated silk fibroin, a major protein of silk, with high biocompatibility and biodegradability, as a useful material for extremely-small-diameter vascular grafts. A small-sized (0.9 mm inner diameter) graft was braided from a silk fibroin thread. The right carotid arteries of 8- to 14-week-old male C57BL/6 mice were cut at the midpoint, and fibroin grafts (5- to 7-mm in length) were transplanted using a cuff technique with polyimide cuffs. The grafts were harvested at different time points and analyzed histologically. CD31+ endothelial cells had already started to proliferate at 2 weeks after implantation. At 4 weeks, neointima had formed with α-smooth muscle actin+ cells, and the luminal surface was covered with CD31+endothelial cells. Mac3+ macrophages were accumulated in the grafts. Graft patency was confirmed at up to 6 months after implantation. This mouse model of arterial graft implantation enables us to analyze the remodeling process and biocompatibility of extremely-small-diameter vascular grafts. Biodegradable silk fibroin might be applicable for further researches using genetically modified mice.
Arief Rahadian, Daiju Fukuda, HM Salim, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Canagliflozin Prevents Diabetes-Induced Vascular Dysfunction in ApoE-Deficient Mice, Journal of Atherosclerosis and Thrombosis, Vol.27, No.11, 1141-1151, 2020.
(Summary)
Recent studies have demonstrated that selective sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce cardiovascular events, although their mechanism remains obscure. We examined the effect of canagliflozin, an SGLT2i, on atherogenesis and investigated its underlying mechanism. Canagliflozin (30 mg/kg/day) was administered by gavage to streptozotocin-induced diabetic apolipoprotein E-deficient (ApoE) mice. Sudan IV staining was performed at the aortic arch. Immunostaining, quantitative RT-PCR, and vascular reactivity assay were performed using the aorta. In vitro experiments using human umbilical vein endothelial cells (HUVECs) were also performed. Canagliflozin decreased blood glucose (P<0.001) and total cholesterol (P<0.05) levels. Sudan IV staining showed that 12-week canagliflozin treatment decreased atherosclerotic lesions (P<0.05). Further, 8-week canagliflozin treatment ameliorated endothelial dysfunction, as determined by acetylcholine-induced vasodilation (P<0.05), and significantly reduced the expressions of inflammatory molecules such as ICAM-1 and VCAM-1 in the aorta at the RNA and protein levels. Canagliflozin also reduced the expressions of NADPH oxidase subunits such as NOX2 and p22phox in the aorta and reduced urinary excretion of 8-OHdG, suggesting a reduction in oxidative stress. Methylglyoxal, a precursor of advanced glycation end products, increased the expressions of ICAM-1 and p22phox in HUVECs (P<0.05, both). Methylglyoxal also decreased the phosphorylation of eNOS and Akt but increased the phosphorylation of eNOS and p38 MAPK in HUVECs. Canagliflozin prevents endothelial dysfunction and atherogenesis in diabetic ApoE mice. Anti-inflammatory and antioxidative potential due to reduced glucose toxicity to endothelial cells might be its underlying mechanisms.
Kenya Kusunose, Akihiro Haga, Natsumi Yamaguchi, Takashi Abe, Daiju Fukuda, Hirotsugu Yamada, Masafumi Harada and Masataka Sata : Deep Learning for Assessment of Left Ventricular Ejection Fraction from Echocardiographic Images, Journal of the American Society of Echocardiography, Vol.33, No.5, 632-635, 2020.
Akihiro Tani, Kenya Kusunose, Kazuhisa Mastumoto, Hirotsugu Yamada and Masataka Sata : Diastolic Mitral Regurgitation on Color M-Mode Echocardiography in a Patient With Complete Atrioventricular Block., Circulation Reports, Vol.2, No.3, 207-208, 2020.
Gulinu Maimaituxun, Daiju Fukuda, Hirofumi Izaki, Y Hirata, HO Kanayama, H Masuzaki, Masataka Sata and Michio Shimabukuro : Levels of Adiponectin Expression in Peri-Renal and Subcutaneous Adipose Tissue and Its Determinants in Human Biopsied Samples, Frontiers in Endocrinology, No.10, 897, 2020.
平田 有紀奈, 西尾 進, 原田 修, 宮里 尚美, 原國 督, Kenya Kusunose, 伊藤 敦彦, Hirotsugu Yamada and Masataka Sata : Validation of Epicardial Adipose Tissue Thickness by Echocardiography for Predicting Coronary Artery Disease: a Multicenter Study, Japanese Journal of Medical Ultrasound Technology, Vol.45, No.1, 11-20, 2020.
Maimaituxun Gulinu, Hirotsugu Yamada, Daiju Fukuda, Shusuke Yagi, Kenya Kusunose, Hirata Yukina, Nishio Susumu, Takeshi Soeki, Masuzaki Hiroaki, Masataka Sata and Michio Shimabukuro : Association of Local Epicardial Adipose Tissue Depots and Left Ventricular Diastolic Performance in Patients With Preserved Left Ventricular Ejection Fraction, Circulation Journal, Vol.84, No.2, 203-216, 2020.
Tatsuya Maruhashi, Masato Kajikawa, Shinji Kishimoto, Haruki Hashimoto, Yuji Takaeko, Takayuki Yamaji, Takahiro Harada, Yiming Han, Yoshiki Aibara, Farina Mohamad Yusoff, Takayuki Hidaka, Yasuki Kihara, Kazuaki Chayama, Ayumu Nakashima, Chikara Goto, Hirofumi Tomiyama, Bonpei Takase, Takahide Kohro, Toru Suzuki, Tomoko Ishizu, Shinichiro Ueda, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Kentaro Watanabe, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koichi Node, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito, Hisao Ikeda, Akira Yamashina and Yukihito Higashi : Diagnostic Criteria of FlowMediated Vasodilation for Normal Endothelial Function and NitroglycerinInduced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery, Journal of the American Heart Association, Vol.9, No.8, e013915, 2020.
(Summary)
Background Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.
Arief Rahadian, Daiju Fukuda, HM Salim, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Thrombin inhibition by dabigatran attenuates endothelial dysfunction in diabetic mice, Vascular Pharmacology, Vol.124, 106632, 2020.
(Summary)
Diabetic patients have coagulation abnormalities, in which thrombin plays a key role. Whereas accumulating evidence suggests that it also contributes to the development of vascular dysfunction through the activation of protease-activated receptors (PARs). Here we investigated whether the blockade of thrombin attenuates endothelial dysfunction in diabetic mice. Induction of diabetes by streptozotocin (STZ) increased the expression of PAR1, PAR3, and PAR4 in the aorta. STZ-induced diabetic mice showed impairment of endothelial function, while the administration of dabigatran etexilate, a direct thrombin inhibitor, significantly attenuated endothelial dysfunction in diabetic mice with no alteration of metabolic parameters including blood glucose level. Dabigatran did not affect endothelium-independent vasodilation. Dabigatran decreased the expression of inflammatory molecules (e.g., MCP-1 and ICAM-1) in the aorta of diabetic mice. Thrombin increased the expression of these inflammatory molecules and the phosphorylation of IκBα, and decreased the phosphorylation of eNOS in human umbilical endothelial cells (HUVEC). Thrombin significantly impaired the endothelium-dependent vascular response of aortic rings obtained from wild-type mice. Inhibition of NF-κB attenuated thrombin-induced inflammatory molecule expression in HUVEC and ameliorated thrombin-induced endothelial dysfunction in aortic rings. Dabigatran attenuated the development of diabetes-induced endothelial dysfunction. Thrombin signaling may serve as a potential therapeutic target in diabetic condition.
Sayuri Doi, A Tamura, Takako Minagawa, A Osaka and Masataka Sata : Classification of physical activity in patients with heart failure categorized as New York Heart Association class I or II, The Journal of Medical Investigation : JMI, Vol.67, No.1.2, 124-133, 2020.
(Summary)
This study aimed that we were classification of physical activity in patients with heart failure categorized as New York Heart Association (NYHA) class I or II. We were a survey using a researcher- administered questionnaire, SF-8, the Specific Activity Scale (SAS), and the Scale to Measure Self-Care Behavior of Patients with Heart Disease. We included 70 patients who were treated in the Department of Cardiovascular Medicine at Hospital A. Regarding patient characteristics and clinical information after the cluster analysis, there were significant differences in the NYHA class (p = 0.001), BNP level (p = 0.012), self-management of medication adherence (p = 0.000), and exercise habits (p = 0.005). We summarized characteristics of each group as follows : Group A showed high tolerance to physical activity and near-perfect self-management; Group B showed moderate tolerance to physical activity but was not willing to commit to daily exercise and self-management; and Group C showed low tolerance to physical activity and often requested others to handle medication management. We needed that tolerance to physical activity and proposals for tailored instruction according to patient conditions, and needed that instructions tailored to the characteristics of heart failure patients in groups A-C. J. Med. Invest. 67 : 124-133, February, 2020.
Tomiyama Hirofumi, Ohkuma Toshiaki, Ninomiya Toshiharu, Nakano Hiroki, Matsumoto Chisa, Avolio Alberto, Kohro Takahide, Higashi Yukihito, Maruhashi Tetsuya, Takase Bonpei, Suzuki Toru, Ishizu Tomoko, Ueta Shinichiro, Yamazaki Tsutomu, Furumoto Tomoo, Kario Kazuomi, Inoue Teruo, Koba Shinji, Takemoto Yasuhiko, Hano Takuzo, Masataka Sata, Ishibashi Yutaka, Node Koichi, Maemura Koji, Ohya Yusuke, Furukawa Taiji, Ito Hiroshi, Chikamori Taishiro and Yamashina Akira : Brachial-Ankle Pulse Wave Velocity Versus Its Stiffness Index β-Transformed Value as Risk Marker for Cardiovascular Disease, Journal of the American Heart Association, Vol.8, No.24, e013004, 2019.
(Summary)
Background The difference in the predictive ability of the brachial-ankle pulse wave velocity (baPWV) and its stiffness index β-transformed value (β-baPWV, ie, baPWV adjusted for the pulse pressure) for the development of pathophysiological abnormalities related to cardiovascular disease or future occurrence of cardiovascular disease was examined. Methods and Results In study 1, a 7-year prospective observational study in cohorts of 3274 men and 3490 men, the area under the curve in the receiver operator characteristic curve analysis was higher for baPWV than for β-baPWV for predicting the development of hypertension (0.73, 95% CI=0.70 to 0.75 versus 0.59, 95% CI=0.56 to 0.62; <0.01) and/or the development of retinopathy (0.78, 95% CI=0.73 to 0.82 versus 0.66, 95% CI=0.60 to 0.71; <0.01) by the end of the study period. During study 2, a 3-year observation period on 511 patients with coronary artery disease, 72 cardiovascular events were confirmed. The C statistics of both markers for predicting the development of cardiovascular events were similar. Conclusions Stiffness index β transformation of the baPWV may attenuate the significance of the baPWV as a risk marker for development of pathophysiological abnormalities related to cardiovascular disease in male subjects.
K Aini, Daiju Fukuda, K Tanaka, Y Higashikuni, Yukina Hirata, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Vildagliptin, a DPP-4 Inhibitor, Attenuates Endothelial Dysfunction and Atherogenesis in Nondiabetic Apolipoprotein E-Deficient Mice, International Heart Journal, Vol.60, No.6, 1421-1429, 2019.
(Summary)
Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel antidiabetic agents with possible vascular protection effects. Endothelial dysfunction is an initiation step in atherogenesis. The purpose of this study was to investigate whether vildagliptin (Vilda) attenuates the development of endothelial dysfunction and atherosclerotic lesions in nondiabetic apolipoprotein E-deficient (ApoE) mice. Eight-week-old nondiabetic ApoE mice fed a Western-type diet received Vilda (50 mg/kg/day) for 20 weeks or 8 weeks. After 20 weeks of treatment, Vilda administration reduced atherogenesis in the aortic arch as determined by en face Sudan IV staining compared with the vehicle group (P < 0.05). Vilda also reduced lipid accumulation (P < 0.05) and vascular cell adhesion molecule-1 (VCAM-1) expression (P < 0.05) and tended to decrease macrophage infiltration (P = 0.05) into atherosclerotic plaques compared with vehicle. After 8 weeks of treatment, endothelium-dependent vascular reactivity was examined. Vilda administration significantly attenuated the impairment of endothelial function in nondiabetic ApoE mice compared with the vehicle group (P < 0.05). Vilda treatment did not alter metabolic parameters, including blood glucose level, in both study protocols. To investigate the mechanism, aortic segments obtained from wild-type mice were incubated with exendin-4 (Ex-4), a glucagon-like peptide-1 (GLP-1) analog, in the presence or absence of lipopolysaccharide (LPS). Ex-4 attenuated the impairment of endothelium-dependent vasodilation induced by LPS (P < 0.01). Furthermore, Ex-4 promoted phosphorylation of eNOS at Ser1177 which was decreased by LPS in human umbilical endothelial cells (P < 0.05). Vilda inhibited the development of endothelial dysfunction and prevented atherogenesis in nondiabetic ApoE mice. Our results suggested that GLP-1-dependent amelioration of endothelial dysfunction is associated with the atheroprotective effects of Vilda.
Kenya Kusunose, Yuta Torii, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata, Yoshihito Saijoh, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Association of Echocardiography Before Major Elective Non-Cardiac Surgery With Improved Postoperative Outcomes - Possible Implications for Patient Care., Circulation Journal, Vol.83, No.12, 2512-2519, 2019.
(Summary)
Whether preoperative echocardiography improves postoperative outcomes is not well established, so we examined the value of echocardiographic assessment on the onset of postoperative heart failure (HF), and determining which patients benefitted most from undergoing echocardiography prior to major elective non-cardiac surgery.Methods and Results:We identified all patients aged 50 years and older who had major elective non-cardiac surgery, and excluded patients with previously identified severe cardiovascular disease. The primary endpoint was the onset of HF during hospitalization. A total of 806 patients were included in the analysis. During hospitalization, 49 patients (6%) reached the primary endpoint. Within the matched cohort, preoperative echocardiography was associated with a statistically significant decrease in postoperative HF (hazard ratio: 0.46, P=0.01). In subgroup analyses, age, sex, body surface area, hypertension, diabetes mellitus, prior HF, surgical type, chronic kidney disease, pulmonary disease, and malignancy influenced the association of echocardiography with postoperative HF. The use of echocardiography in elderly patients with certain risk factors was associated with improved postoperative outcomes. The basis for this finding remains to be determined; particularly whether echocardiography is simply a marker of a population with better outcomes or whether it leads to better management that improves outcomes.
(Keyword)
Aged / Echocardiography / Female / Heart Failure / Humans / Incidence / Japan / Male / Middle Aged / Predictive Value of Tests / Preoperative Care / Retrospective Studies / Risk Assessment / Risk Factors / Surgical Procedures, Operative / Time Factors / Treatment Outcome
田中 君枝, 平田 陽一郎, Daiju Fukuda and Masataka Sata : Recent Advance in Atherosclerosis Research, The Journal of the Japanese Society of Internal Medicine, Vol.108, No.10, 1607-1615, 2019.
PT Pham, Daiju Fukuda, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice, Scientific Reports, Vol.9, No.1, 11206, 2019.
(Summary)
Activated factor X (FXa) plays a central role in the coagulation cascade, while it also mediates vascular function through activation of protease-activated receptors (PARs). Here, we examined whether inhibition of FXa by rivaroxaban, a direct FXa inhibitor, attenuates endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Induction of diabetes increased the expression of a major FXa receptor, PAR2, in the aorta (P < 0.05). Administration of rivaroxaban (10 mg/kg/day) to diabetic wild-type (WT) mice for 3 weeks attenuated endothelial dysfunction as determined by acetylcholine-dependent vasodilation compared with the control (P < 0.001), without alteration of blood glucose level. Rivaroxaban promoted eNOS phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2) mice did not affect endothelial function and eNOS phosphorylation in the aorta compared with non-diabetic PAR2 mice. FXa or a PAR2 agonist significantly impaired endothelial function in aortic rings obtained from WT mice, but not in those from PAR2 mice. FXa promoted JNK phosphorylation (P < 0.01) and reduced eNOS phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOS phosphorylation (P < 0.05) in HCAEC were partially ameliorated by a JNK inhibitor. Rivaroxaban ameliorated diabetes-induced endothelial dysfunction. Our results suggest that FXa or PAR2 is a potential therapeutic target.
Yuta Torii, Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata, Amano Rie, Yamao Masami, Zheng Robert, Yoshihito Saijoh, nao Yamada, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Updated Left Ventricular Diastolic Function Recommendations and Cardiovascular Events in Patients with Heart Failure Hospitalization, Journal of the American Society of Echocardiography, Vol.32, No.10, 1286-1297, 2019.
(Summary)
Evaluation of diastolic dysfunction is crucial in determining elevated left atrial pressure. However, a validation of the long-term prognostic value of the newly proposed algorithm updated in 2016 has not been performed. The aim of the present study was to investigate the relative value of the updated 2016 diastolic dysfunction grading system for the incidence of readmission in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). Two hundred thirty-two patients hospitalized with HF were retrospectively evaluated. Subjects were divided into two subgroups: those with HFrEF (n = 127) and those with HFpEF (n = 105). Readmission risk scores were calculated using the Yale Center for Outcomes Research and Evaluation HF, LACE index, and HOSPITAL scores. The primary end point was readmission following HF and cardiac death. Over a period of 24 months, 86 patients were either readmitted or died. Multivariate Cox analysis was performed on both the HFrEF and HFpEF groups. In the HFrEF group, both the 2009 and 2016 algorithms had superior incremental value for the association of the primary end point to several readmission risk scores. In the HFpEF group, only the 2016 algorithm led to significant improvement in association with the primary end point. The 2016 algorithm had incremental value over several readmission risk scores alone. The recommendations of the 2016 algorithm can be useful for readmission and cardiac mortality risk assessment in patients with HFrEF and HFpEF. The use of echocardiography to estimate elevated left atrial pressure appears to identify a higher risk group and may allow a more tailored approach to therapy.
M Kajikawa, T Maruhashi, T Hidaka, S Matsui, H Hashimoto, Y Takaeko, Y Nakano, S Kurisu, Y Kihara, FM Yusoff, S Kishimoto, K Chayama, C Goto, K Noma, A Nakashima, T Hiro, A Hirayama, K Shiina, H Tomiyama, Shusuke Yagi, Amano Rie, Hirotsugu Yamada, Masataka Sata and Y Higashi : Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes: A Prospective Multicenter Study, Scientific Reports, Vol.9, No.1, 10206, 2019.
(Summary)
The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function.
Akinori Nakanishi, Jouji Shunto, Reiko Shunto, Masataka Sata and Hiroshi Bando : A case of subacute thyroiditis associated with complete occlusion of right coronary artery, Journal of Diabetes, Metabolic Disorders & Control, Vol.6, No.3, 54-58, 2019.
Kenya Kusunose, Akihiro Haga, Takashi Abe and Masataka Sata : Utilization of Artificial Intelligence in Echocardiography, Circulation Journal, Vol.83, No.8, 1623-1629, 2019.
(Summary)
Echocardiography has a central role in the diagnosis and management of cardiovascular disease. Precise and reliable echocardiographic assessment is required for clinical decision-making. Even if the development of new technologies (3-dimentional echocardiography, speckle-tracking, semi-automated analysis, etc.), the final decision on analysis is strongly dependent on operator experience. Diagnostic errors are a major unresolved problem. Moreover, not only can cardiologists differ from one another in image interpretation, but also the same observer may come to different findings when a reading is repeated. Daily high workloads in clinical practice may lead to this error, and all cardiologists require precise perception in this field. Artificial intelligence (AI) has the potential to improve analysis and interpretation of medical images to a new stage compared with previous algorithms. From our comprehensive review, we believe AI has the potential to improve accuracy of diagnosis, clinical management, and patient care. Although there are several concerns about the required large dataset and "black box" algorithm, AI can provide satisfactory results in this field. In the future, it will be necessary for cardiologists to adapt their daily practice to incorporate AI in this new stage of echocardiography.
Rie Ueno, Shusuke Yagi, Mika Bando and Masataka Sata : Long-surviving Anomalous Origin of the Right Pulmonary Artery from the Ascending Aorta Complicated with Pulmonary Arteriovenous Fistula, Internal Medicine, Vol.58, No.18, 2749-2750, 2019.
Daiju Fukuda, Sachiko Nishimoto, Kunduziayi Aini, Atsushi Tanaka, Tsuyoshi Nishiguchi, Joo-Ri Kim-Kaneyama, Xiao-Feng Lei, Kiyoshi Masuda, Takuya Naruto, Kimie Tanaka, Yasutomi Higashikuni, Yoichiro Hirata, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Issei Imoto, Takashi Akasaka, Michio Shimabukuro and Masataka Sata : Toll-Like Receptor 9 Plays a Pivotal Role in Angiotensin II-Induced Atherosclerosis, Journal of the American Heart Association, Vol.8, No.7, e010860, 2019.
(Summary)
Background Toll-like receptor ( TLR ) 9 recognizes bacterial DNA , activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR 9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E-deficient ( Apoe ) mice. Methods and Results Tlr9-deficient Apoe ( Tlr9 Apoe ) mice and Apoe mice on a Western-type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double-stranded DNA, an endogenous ligand of TLR 9, in these mice. Genetic deletion or pharmacologic blockade of TLR 9 in angiotensin II-infused Apoe mice attenuated atherogenesis in the aortic arch ( P<0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR 9 in bone marrow in Tlr9 Apoe mice promoted atherogenesis in the aortic arch ( P<0.05). A TLR 9 agonist markedly promoted proinflammatory activation of Apoe macrophages, partially through p38 mitogen-activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe macrophages than in Tlr9 Apoe macrophages. Furthermore, in humans, circulating double-stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction ( P<0.05). Conclusions TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR 9 may serve as a potential therapeutic target for atherosclerosis.
Yukina Hirata, Kenya Kusunose, Hirotsugu Yamada, Sae Morita, Yuta Torii, Susumu Nishio, Robert Zheng, Yoshihito Saijo, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki and Masataka Sata : Left atrial functional response after a marathon in healthy amateur volunteers, The International Journal of Cardiovascular Imaging, Vol.35, No.4, 633-643, 2019.
(Summary)
Middle-aged marathon runners have an increased risk of developing atrial fibrillation (AF). A previous study described that repetitive marathon running was associated with left atrial (LA) dysfunction. However, whether this change is common in marathon runners and which runners are at risk of LA dysfunction remain unknown. The purpose of this study was to determine which factors could predict LA dysfunction. We prospectively examined 12 healthy amateur volunteers (9 males, 31 ± 8 years old) who participated in a full marathon. All echocardiographic measurements and speckle-tracking echocardiography were performed before and after the marathon. The endpoint was defined as reduced LA reservoir strain 1 day after the marathon (non-responder group). Seven participants were in the non-responder group. Age (35 ± 9 vs. 26 ± 2 years, p = 0.020), augmentation index (76 ± 12 vs. 55 ± 8, p = 0.002), and diastolic blood pressures (83 ± 11 vs. 70 ± 7 mmHg, p = 0.021) in the non-responder group were significantly higher compared with the responder group. In multivariate linear regression analysis, only the augmentation index was an independent predictor of reduced LA reservoir function after the marathon (β = - 0.646, p = 0.023). The augmentation index was a predictive marker for reduction in LA reservoir function after a marathon in healthy amateur volunteers.
M Kajikawa, T Maruhashi, S Kishimoto, S Matsui, H Hashimoto, Y Takaeko, FM Yusoff, Y Kihara, K Chayama, C Goto, K Noma, A Nakashima, H Tomiyama, B Takase, T Kohro, T Suzuki, T Ishizu, S Ueda, T Yamazaki, T Furumoto, K Kario, T Inoue, S Koba, K Watanabe, Y Takemoto, T Hano, Masataka Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito, H Ikeda, A Yamashina and Y Higashi : Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease - Post Hoc Analysis of the FMD-J Study A., Circulation Journal, Vol.83, No.5, 1064-1071, 2019.
(Summary)
Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL. Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.
Shusuke Yagi, Daisuke Kondo, Takayuki Ise, Daiju Fukuda, Koji Yamaguchi, Tetsuzo Wakatsuki, Yutaka Kawabata, Hiroyuki Ito, Yoshihito Saijo, Hiromitsu Seno, Kumiko Sutou, Rie Ueno, Takafumi Todoroki, Kenya Kusunose, Tomomi Matsuura, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Michio Shimabukuro, Ken-ichi Aihara, Masashi Akaike and Masataka Sata : Association of Decreased Docosahexaenoic Acid Level After Statin Therapy and Low Eicosapentaenoic Acid Level with In-Stent Restenosis in Patients with Acute Coronary Syndrome, Journal of Atherosclerosis and Thrombosis, Vol.26, No.3, 272-281, 2019.
(Summary)
It is speculated that statin therapy modulates the synthesis of polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, the data available on the effects of statin therapy on the serum levels of PUFA and the subsequent impact on in-stent restenosis (ISR) in patients with acute coronary syndrome (ACS) are limited. A total of 120 ACS patients who received emergent coronary stent implantation, follow-up coronary angiography to evaluate ISR, and new statin therapy were enrolled. We measured the serum levels of the PUFA and lipids at the onset of ACS and at the follow-up coronary angiography. The follow-up coronary angiography revealed 38 ISR cases. New statin therapy significantly reduced the serum levels of DHA and low-density lipoprotein cholesterol (LDL-C), while it did not affect EPA level. Single regression analysis revealed that a decreased serum level of LDL-C was associated with decreased DHA level. The multiple logistic regression analysis revealed that the decreased DHA level after statin therapy and low serum level of EPA on admission were determinants of prevalence of ISR. Statin therapy decreased the serum level of DHA with a parallel reduction in LDL-C level in patients with ACS. Decreased DHA level after statin therapy and low EPA level on admission are risk factors for ISR, indicating that in patients with ACS, decreased serum levels of DHA may be a residual target for the prevention of ISR.
Tamio Teramoto, Arihiro Kiyosue, Yasushi Ishigaki, Mariko Harada-Shiba, Yumiko Kawabata, Asuka Ozaki, Marie T. Baccara-Dinet and Masataka Sata : Efficacy and safety of alirocumab 150mg every 4 weeks in hypercholesterolemic patients on non-statin lipid-lowering therapy or lowest strength dose of statin: ODYSSEY NIPPON, Journal of Cardiology, Vol.73, No.3, 218-227, 2019.
(Summary)
Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, given every 2 weeks (Q2W), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in Japanese hypercholesterolemic patients on background statin. We evaluated alirocumab 150mg every 4 weeks (Q4W) in patients on lowest-dose statin or non-statin lipid-lowering therapy (LLT). ODYSSEY NIPPON was a double-blind study conducted in Japanese patients with LDL-C ≥100mg/dL (heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia with coronary heart disease) or ≥120mg/dL (non-familial hypercholesterolemia, Japan Atherosclerosis Society category III) on atorvastatin 5mg/day or non-statin LLT. Patients were randomized (1:1:1) to subcutaneous alirocumab 150mg Q4W, alirocumab 150mg Q2W, or placebo for the 12-week double-blind treatment period (DBTP), followed by a 52-week open-label treatment period (OLTP). At entry into the OLTP, patients received alirocumab 150mg Q4W, with possible up-titration to 150mg Q2W at Week 24. Least-square mean percent change in LDL-C from baseline at Week 12 (primary efficacy endpoint) was -43.8% for alirocumab Q4W, -70.1% for Q2W, and -4.3% for placebo. During the OLTP, mean LDL-C change from baseline was -45.1% at Week 20, with a further reduction at Week 36, with achieved levels maintained to Week 64. Percent of patients with ≥1 adverse event (DBTP) was 51.9% with alirocumab Q4W, 47.2% with Q2W, and 46.4% with placebo. Most common adverse events were infections and infestations (25.9%, 22.6%, 17.9%, respectively), gastrointestinal disorders (13.0%, 9.4%, 12.5%), nervous system disorders (5.6%, 7.5%, 10.7%), and general disorders and administration-site conditions (3.7%, 11.3%, 5.4%). Hypercholesterolemic Japanese patients who tolerate only lowest-strength dose statin or non-statin LLT can achieve robust LDL-C reduction with alirocumab 150mg Q4W, in addition to their current LLT. Alirocumab 150mg Q4W dosing was efficacious and generally well tolerated without new safety concerns. (ClinicalTrials.gov number: NCT02584504).
Yuko Saito, Hirotsugu Yamada, Kenya Kusunose, Ken Saito and Masataka Sata : Noninvasive assessment of left-ventricular diastolic electromechanical coupling in hypertensive heart disease,, Journal of Echocardiography, Vol.17, No.4, 206-212, 2019.
(Summary)
There is a need to stratify patients who may develop heart failure because of the current "heart failure pandemic". We hypothesized that noninvasive assessment of diastolic electromechanical coupling by electrocardiography and Doppler echocardiography may be clinically useful for risk stratification of hypertensive patients who may develop heart failure. We measured the time from the peak to end of the T wave (TpTe) as an electrophysiological parameter, and peak early diastolic mitral flow (E) and lateral annular (e') velocities as mechanical parameters in 109 patients with hypertension. Relationships between these parameters and their association with the prognosis were evaluated. The e' was inversely correlated with TpTe (p < 0.001) and QTc (p < 0.014), whereas E/e' was positively correlated with TpTe (p < 0.001) and QTc (p < 0.001). The TpTe predicted patients with E/e' > 12. There were 24 cardiovascular events during follow-up (57 ± 20 months), and Kaplan-Meier analysis showed that outcome was worse (p = 0.003) in patients with higher E/e' than lower E/e'; however, there was no difference between patients with longer TpTe (≧72 ms) and shorter TpTe (< 72 ms). The correlation of TpTe with e' and E/e' in hypertensive patients suggests that these parameters reflect diastolic ventricular electromechanical coupling. The E/e' predicted outcome, and an elevated E/e' should be suspected when TpTe is prolonged (> 72 ms). Noninvasive evaluation of diastolic electromechanical coupling is clinically useful in patients with hypertension for predicting their outcome.
Atsuko Yoshida, Takashi Kaji, Hirotsugu Yamada, Naoto Yonetani, Eishi Sogawa, Masami Yamao, Kazuhisa Maeda, Masataka Sata and Minoru Irahara : Measurement of hemodynamics immediately after vaginal delivery in healthy pregnant women by electrical cardiometry., The Journal of Medical Investigation : JMI, Vol.66, No.1.2, 75-80, 2019.
(Summary)
Few reports have focused on hemodynamics around delivery in pregnant women because of the difficulty of continuous and noninvasive measurement. Electrical cardiometry allows noninvasive continuous monitoring of hemodynamics and has recently been used in non-pregnant subjects. We compared the use of electrical cardiometry versus transthoracic echocardiography in healthy pregnant women and evaluated hemodynamics immediately after vaginal delivery. In Study 1, electrical cardiometry and transthoracic echocardiography were used to measure cardiac output in 20 pregnant women with threatened premature delivery. A significant correlation was found between the two methods, with electrical cardiometry showing the higher cardiac output. In Study 2, heart rate, stroke volume, and cardiac output were continuously measured in 15 women during vaginal delivery up to 2 h postpartum. Cardiac output increased markedly because of an increased heart rate and stroke volume at the time of newborn delivery. The heart rate then immediately returned to baseline, while cardiac output remained elevated for at least 2 h after delivery because of a sustained high stroke volume. Electrical cardiometry was as readily available as transthoracic echocardiography for evaluating hemodynamics and allowed for continuous measurement during labor. High intrapartum cardiac output was sustained for at least 2 h after vaginal delivery. J. Med. Invest. 66 : 75-80, February, 2019.
Shusuke Yagi, Seiichi Nishiyama, Toshio Abe and Masataka Sata : Recurrent venous thromboembolism after discontinuation of rivaroxaban therapy in a patient with antiphospholipid syndrome, BMJ Case Reports, Vol.12, No.1, e227663, 2019.
(Summary)
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by thromboembolic events including venous thromboembolism (VTE) in association with the presence of antiphospholipid antibodies. The standard treatment of VTE historically consists of anticoagulation therapy with warfarin, a vitamin K antagonist. Recently, direct oral anticoagulants, including rivaroxaban have become available for the treatment of VTE. However, the choice of anticoagulant, and the duration of anticoagulation in patients with APS has not been determined yet due to lack of evidence. Here, we report a case of recurrent venous thrombosis after discontinuation of rivaroxaban therapy and avoiding sedentary lifestyle in a patient with APS. We suggest that indefinite anticoagulation therapy might be needed even in low-risk APS cases.
Mina Takahashi, Takeshi Tobiume, Kazuhisa Matsumoto, Tomomi Matsuura, Takeshi Soeki, 藤本 裕太, 原田 貴文, Zengu Robahto, 數藤 久美子, 西條 良仁, 上野 理絵, Yutaka Kawabata, Mika Bando, nao Yamada, Hiroyuki Ito, 轟 貴史, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki and Masataka Sata : A successful case of catheter ablation against ventricular tachycardia storm due to old myocardial infarction in a patient with aortic valve replacement, Shikoku Acta Medica, Vol.74, No.56, 201-208, 2019.
(Summary)
A 68-year-old woman with VT storm and frequent appropriate ICD therapy was referred for catheter ablation. Her past history was notable for aortic valve replacement by mechanical valve due to infectious endocarditis 17 years prior to presentation and left ventricular apical old myocardial infarction with unknown onset. At 67 years old, She admitted to the prior hospital due to ventricular tachycardia with LBBB and superior axis at heart rate of 210 per minutes. Administration of amiodarone and magnesium sulfate was ineffective and cardioversion of 200J was successfully terminated the tachycardia. Intra-cardiac defibrillator was implanted and the administration of amiodarone and mexiletine was started. 5 months after, she admitted to the hospital due to the frequent appropriate shock against the same ventricular tachycardia. Administration of lidocaine, sotalol, pilsicainide, and magnesium sulfate could not control the tachycardia and she was referred to our hospital for catheter ablation. During the first session, ventricular tachycardia was easily induced and electroanatomical mapping was performed both during tachycardia and during sinus rhythm. Late diastolic potential preceding the onset of QRS wave by 45ms was detected at the infero-septal side of the apical aneurysm. 7 5s of the RF energy application at this site could terminate the tachycardia and thereafter no ventricular tachycardia was induced. But after dose-reduction or cessation of some anti-arrhythmic drugs, ventricular tachycardia was recurred and second session was performed. This time, no ventricular tachycardia was induced, then we performed isthmus transection and core isolation against the apical aneurysm. Thereafter no ventricular tachycardia was occurred in spite of dose-reduction or cessation of some anti-arrhythmic drugs.
松本 力三, 西尾 進, 平田 有紀奈, 湯浅 麻美, Yuta Torii, 天野 里江, 山尾 雅美, Miharu Arase, Kenya Kusunose, Hirotsugu Yamada and Masataka Sata : 糖尿病性腎症の各病期における超音波指標の比較, Japanese Journal of Medical Ultrasound Technology, Vol.44, No.4, 447-455, 2019.
Shusuke Yagi, Robert Zheng, Seiichi Nishiyama, Yutaka Kawabata, Takayuki Ise, Kosuke Sugiura, Haruhiko Yoshinari, Toshihiko Nishisho, Yoshimi Bando, Kumiko Kagawa, Daiju Fukuda, Tomohiro Soga, Yoshihito Saijoh, Kenya Kusunose, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Shinji Kawahito, Masashi Akaike and Masataka Sata : Osteolytic primary bone lymphoma in the multiple bones, The Journal of Medical Investigation : JMI, Vol.66, No.3,4, 347-350, 2019.
(Summary)
Primary non-Hodgkin bone lymphoma (PBL) can involve solitary or multiple destructive bone lesions such as those of the femur or pelvis humerus, and some cases have osteolytic lesions. PBL is a rare disease in adults. Thus, PBL is rarely considered a differential diagnosis of the osteolytic tumor. In addition, PBL can be underdiagnosed because patients do not experience symptoms or show objective abnormalities in the early stage. Here, we reported an elderly patient with PBL in multiple bones, including the cranial and femoral bones that were fractured due to falling. J. Med. Invest. 66 : 347-350, August, 2019.
Shusuke Yagi, Itsuro Endo, Taichi Murakami, Tetsuya Hida, Yousuke Yamamoto, Tomohiro Soga, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Shinji Kawahito and Masataka Sata : Adult onset of Immunoglobulin A vasculitis - A case report,, The Journal of Medical Investigation : JMI, Vol.66, No.3,4, 344-346, 2019.
(Summary)
Immunoglobulin A vasculitis (IgAV), formerly known as Henoch-Schönlein purpura, primarily occurs during childhood between the ages of 3 and 15 years and is the most common form of systemic vasculitis in children ; its occurrence in adults has been rarely reported. Such low incidence could be attributable to either under-diagnosis or misdiagnosis. Thus, not only pediatricians but also physicians should be able to diagnose IgAV accurately to manage the patients appropriately and avoid its associated complications. In addition, treatment of adult onset IgAV with renal involvement has not been fully established yet. We describe here a case of adult onset IgAV complicated by proteinuria and pharyngitis, which was cured by no specific treatment. J. Med. Invest. 66 : 344-346, August, 2019.
(Keyword)
Acetaminophen / Adult / Factor XIII / Humans / Immunoglobulin A / Male / Pharyngitis / Proteinuria / Purpura, Schoenlein-Henoch
Shusuke Yagi, Kumiko Kagawa, Eiki Fujimoto, Masataka Sata and Yoshihito Saijoh : Recurrent venous thrombosis during direct oral anticoagulant therapy in a patient with protein S deficiency, The Journal of Medical Investigation : JMI, Vol.66, No.1,2, 182-184, 2019.
(Summary)
Protein S (PS) deficiency is an inherited thrombophilia associated with an increased risk of venous thromboembolism (VTE). In Japan, unfractionated heparin followed by warfarin has been historically applied for the treatment of VTE. Recent evidence showed that direct oral anticoagulants (DOACs) were non-inferior to standard therapy with warfarin, with significantly less bleeding in patients with VTE. However, it is unknown whether DOACs are effective for the treatment of VTE in patients with thrombophilia, including protein S deficiency, due to lack of evidence. Here, we report a case of recurrent venous thrombosis during edoxaban therapy in a patient with protein S deficiency, which was successfully treated using high-dose apixaban therapy. J.Med. Invest. 66 : 182-184, February, 2019.
Shusuke Yagi, Rie Ueno, Kumiko Sutou, Tetsuzo Wakatsuki, Koji Yamaguchi, Yoshihito Saijo, Tomoya Hara, Takayuki Ise, Kenya Kusunose, Mika Bando, Tomomi Matsuura, Takeshi Tobiume, Hirotsugu Yamada, Daiju Fukuda, Takeshi Soeki, Masashi Akaike and Masataka Sata : Lambda-like J wave due to acute myocardial infarction of the diagonal branch, The Journal of Medical Investigation : JMI, Vol.66, No.1,2, 185-187, 2019.
(Summary)
The culprit lesion of acute myocardial infarction could be predicted by electrocardiogram findings. However, we experienced some cases with coronary angiographic finding in the area of ST-T elevation that was different from that predicted. The lambda-like J wave could be caused by ischemia although the mechanism has not been fully elucidated. We report a case of acute myocardial infarction that showed discrepancy between ST-T elevation with lambda-like ischemic J wave in a broad area and coronary angiographical finding of diagonal branch occlusion. J. Med. Invest. 66 : 185-187, February, 2019.
Shusuke Yagi, Yoshihito Saijo, Taku Matsuda, Yasuhisa Kanematsu and Masataka Sata : Spontaneous arteriovenous fistula of the superficial temporal artery, The Journal of Medical Investigation : JMI, Vol.66, No.1,2, 209-210, 2019.
(Summary)
An arteriovenous fistula of the superficial temporal artery (STA) is a direct and abnormal communication between the STA, feeding artery, and superficial temporal vein, draining veins that bypass the capillary network. Several cases of trauma-induced or iatrogenic-induced arteriovenous fistula (AVF) of the STA have been reported ; however, spontaneous AVF of the STA not associated with trauma or medical treatment are extremely rare. Herein, we present a case of spontaneous AVF of the STA diagnosed in old age. J. Med. Invest. 66 : 209-210, February, 2019.
Shusuke Yagi and Masataka Sata : Rupture of pes anserine bursa in a patient with pes anserine pain syndrome due to osteoarthritis, The Journal of Medical Investigation : JMI, Vol.66, No.1,2, 211-212, 2019.
(Summary)
Pes anserinus pain syndrome is a common, clinically defined condition that is characterized by pain around the medial knee and tenderness over the upper medial tibia. The anserine bursa could be the site of proliferative and inflammatory conditions due to knee osteoarthritis, leading to pain and fluid retention. However, rupture of the pes anserinus is rare. Herein, we present a case of rupture of the pes anserine bursa in a patient with pes anserine pain syndrome and osteoarthritis. Physicians should consider rupture of the pes anserine bursa as a differential diagnosis of acute unilateral lower leg swelling. J. Med. Invest. 66 : 211-212, February, 2019.
Yuishin Izumi, Ryosuke Miyamoto, Koji Fujita, Yuki Yamamoto, Hirotsugu Yamada, Tomoyasu Matsubara, Yuki Unai, Ai Tsukamoto, Naoko Takamatsu, Hiroyuki Nodera, Shinya Hayashi, Masaya Oda, Atsuko Mori, Yoshihiko Nishida, Shunsuke Watanabe, Hirohisa Ogawa, Hisanori Uehara, Shigeo Murayama, Masataka Sata and Ryuji Kaji : Distinct Incidence of Takotsubo Syndrome Between Amyotrophic Lateral Sclerosis and Synucleinopathies: A Cohort Study., Frontiers in Neurology, Vol.9, 1099, 2018.
(Summary)
Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by regional left ventricular dysfunction with a peculiar circumferential pattern, which typically results in apical ballooning. Evidence indicates a pivotal role of catecholamines in TTS, and researchers have discussed multiple hypotheses on the etiology, including multivessel coronary spasm, myocardial stunning, excessive transient ventricular afterload, and cardiac sympathetic overactivity with local noradrenaline spillover. Although central nervous system disorders, such as stroke and epilepsy, are known to trigger TTS, the incidence and clinical features of TTS in neurodegenerative disorders are poorly understood. Here, we retrospectively examined TTS cases in a single-center cohort composed of 250 patients with amyotrophic lateral sclerosis (ALS) and 870 patients with synucleinopathies [582 patients with Parkinson's disease (PD), 125 patients with dementia with Lewy bodies (DLB), and 163 patients with multiple system atrophy (MSA)] and identified 4 (1.6%, including 2 women) cases with ALS and no cases with synucleinopathies. Two ALS patients underwent autopsy and the pathological findings were compatible with the chronological changes identified in catecholamine-induced cardiomyopathy. A literature review identified 16 TTS cases with ALS, 1 case each with PD and DLB, and no cases with MSA. When current and previous TTS cases with ALS were concatenated: 55% (11/20) were female; 35% (7/20) had a bulbar-onset and 45% (9/20) had a limb-onset; the mean age of TTS onset was 63.3 ± 9.0 years and the mean interval time from ALS onset to TTS development was 4.9 ± 3.0 years; no (0/16) patients developed TTS within 12 months after ALS onset; 50% (10/20) underwent artificial ventilations; the mortality was 17% (3/18); and most cases had precipitating factors, and TTS development was associated with gastrostomy, tracheostomy, or infections in 45% (9/20) of the patients. This study demonstrated that ALS is a considerable predisposing factor of TTS and that synucleinopathies rarely cause TTS. The distinct TTS incidence between ALS and synucleinopathies may be due to cardiac sympathetic overactivity in ALS and may also be affected by cardiac sympathetic denervation in synucleinopathies. Moreover, the etiology of TTS in ALS may be reasonably explained by the two-hit theory.
Sachiko Nishimoto, Kunduziayi Aini, Daiju Fukuda, Yasutomi Higashikuni, Kimie Tanaka, Yoichiro Hirata, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Activation of Toll-Like Receptor 9 Impairs Blood Flow Recovery After Hind-Limb Ischemia, Frontiers in Cardiovascular Medicine, Vol.5, 144, 2018.
(Summary)
Peripheral artery disease causes significant functional disability and results in impaired quality of life. Ischemic tissue injury releases various endogenous ligands for Toll-like receptors (TLRs), suggesting the involvement of TLRs in blood flow recovery. However, the role of TLR9, which was originally known as a sensor for bacterial DNA, remains unknown. This study investigated the role of TLR9 in blood flow recovery in the ischemic limb using a mouse hind-limb ischemia model. Unilateral femoral artery ligation was performed in TLR9-deficient () mice and wild-type mice. In wild-type mice, femoral artery ligation significantly increased mRNA expression of TLR9 in the ischemic limb ( < 0.001) and plasma levels of cell-free DNA (cfDNA) as determined by single-stranded DNA (ssDNA) ( < 0.05) and double-stranded DNA (dsDNA) ( < 0.01), which are endogenous ligands for TLR9, compared with the sham-operated group. Laser Doppler perfusion imaging demonstrated significantly improved ratio of blood flow in the ischemic to non-ischemic limb in mice compared with wild-type mice at 2 weeks after ligation ( < 0.05). mice showed increased capillary density and reduced macrophage infiltration in ischemic limb. Genetic deletion of TLR9 reduced the expression of TNF-α, and attenuated NF-κB activation in ischemic muscle compared with wild-type mice ( < 0.05, respectively) at 3 days after the surgery. ODN1826, a synthetic agonistic oligonucleotide for TLR9, or plasma obtained from mice with ischemic muscle promoted the expression of TNF-α in wild-type macrophages ( < 0.05), but not in macrophages. ODN1826 also activated NF-κB signaling as determined by the degradation of IκBα in wild-type macrophages ( < 0.05), but not in macrophages. In vitro experiments using human umbilical vein endothelial cells demonstrated that TNF-α, or conditioned medium obtained from wild-type macrophages treated with ODN1826 accelerated cell death as determined by MTS assay ( < 0.05 and < 0.01, respectively). Our results suggest that ischemic muscle releases cfDNA, which activates TLR9 and enhances inflammation, leading to impairment of blood flow recovery in the ischemic limb. cfDNA-TLR9 signaling may serve as a potential therapeutic target in ischemic limb disease.
Noriko Sugasawa, Ayako Katagi, Hirotsugu Kurobe, Taisuke Nakayama, Chika Nishio, Hiroko Takumi, Fumiharu Higashiguchi, Ken-ichi Aihara, Michio Shimabukuro, Masataka Sata and Tetsuya Kitagawa : Inhibition of Atherosclerotic Plaque Development by Oral Administration of α-Glucosyl Hesperidin and Water-Dispersible Hesperetin in Apolipoprotein E Knockout Mice., Journal of the American College of Nutrition, 1-8, 2018.
(Summary)
Hesperidin, an abundant flavonoid in citrus fruit, and its aglycone, hesperetin, have been reported to possess various physiological activities, including antioxidant, anti-inflammatory, hypolipidemic, and antihypertensive activities. In this study, we investigated whether α-glucosyl hesperidin and water-dispersible hesperetin have protective effects on atherosclerotic progression in apolipoprotein E knockout (Apo-E KO) mice. Ten-week-old male Apo-E KO mice were randomly assigned a regular high-fat diet, a high-fat diet with 0.5% α-glucosyl hesperidin, or a high-fat diet with 0.1% water-dispersible hesperetin for 12 weeks. Measurement of plasma total cholesterol levels, histological staining of aortic root, and immunohistochemistry for macrophages were performed to evaluate atherosclerotic plaque formation. Vascular reactivity of mouse aortic rings was also measured. Both α-glucosyl hesperidin and water-dispersible hesperetin reduced plasma total cholesterol level. They also reduced plaque formation area, adipose deposition, and macrophage infiltration into atherosclerotic lesion. Vascular-endothelium-dependent relaxation in response to acetylcholine was improved in both experimental diet groups compared to the high-fat diet group. Our study suggests that both α-glucosyl hesperidin and water-dispersible hesperetin exert protective effects on atherosclerotic progression in Apo-E KO mice because they exhibit hypolipidemic activity, reduce inflammation through macrophages, and prevent endothelial dysfunction.
Yukina Hirata, Hirotsugu Yamada and Masataka Sata : Epicardial Fat and Pericardial Fat Surrounding the Heart Have Different Characteristics., Circulation Journal, Vol.82, No.10, 2475-2476, 2018.
Minetaka Maeda, Kageyuki Oba, Satoshi Yamaguchi, Osamu Arasaki, Masataka Sata, Hiroaki Masuzaki and Michio Shimabukuro : Usefulness of Epicardial Adipose Tissue Volume to Predict Recurrent Atrial Fibrillation After Radiofrequency Catheter Ablation, The American Journal of Cardiology, Vol.122, No.10, 1694-1700, 2018.
(Summary)
Although increasing evidence suggests that epicardial adipose tissue volume (EATV) is associated with post-ablation atrial fibrillation (AF), ranges of EATV predictive of post-ablation recurrence of AF remain unclear. In this study, we evaluated: (1) relationships between EATV and characteristics of AF, (2) impact of EATV on recurrent AF after radiofrequency ablation; , and (3) cut-off point for recurrent AF using a receiver operating characteristic curve. In 218 consecutive symptomatic patients undergoing who underwent ablation for AF (143 paroxysmal AF; 78 persistent AF), the EATV index (EATVI: EATV/body surface area, mL/m) was measured using 320-row multidetector computed tomography. The high EATV group showed specific cardiometabolic derangements as well as left atrial dilatation and left ventricular dysfunction. Multivariate regression analysis showed that the EATVI was an independent predictor of recurrent AF after catheter ablation. High EATV (EATVI 85 mL/m) or EATVI cutoff 116 mL/m can predict recurrent AF after catheter ablation, independent of other risk factors. In conclusion, EATVI was an independent predictor of recurrent AF after catheter ablation; a high EATV tertile or EATVI cutoff may be useful for prediction of recurrent AF after catheter ablation. Future studies should determine the utility of the EATVI in the clinical setting of AF ablation.
Kimie Tanaka and Masataka Sata : Possible Roles of Epicardial Adipose Tissue in the Pathogenesis of Coronary Atherosclerosis., Annals of Nuclear Cardiology, Vol.4, No.1, 5-10, 2018.
B Ganbaatar, Daiju Fukuda, HM Salim, Sachiko Nishimoto, K Tanaka, Y Higashikuni, Y Hirata, Shusuke Yagi, Takeshi Soeki and Masataka Sata : Ticagrelor, a P2Y12 antagonist, attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein-E-deficient mice., Atherosclerosis, Vol.275, 124-132, 2018.
(Summary)
Ticagrelor reduces cardiovascular events in patients with acute coronary syndrome (ACS). Recent studies demonstrated the expression of P2Y12 on vascular cells including endothelial cells, as well as platelets, and suggested its contribution to atherogenesis. We investigated whether ticagrelor attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein E-deficient (apoe) mice. Eight-week-old male apoe mice were fed a western-type diet (WTD) supplemented with 0.1% ticagrelor (approximately 120 mg/kg/day). Non-treated animals on WTD served as control. Atherosclerotic lesions were examined by en-face Sudan IV staining, histological analyses, quantitative RT-PCR analysis, and western blotting. Endothelial function was analyzed by acetylcholine-dependent vasodilation using aortic rings. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. Ticagrelor treatment for 20 weeks attenuated atherosclerotic lesion progression in the aortic arch compared with control (p < 0.05). Ticagrelor administration for 8 weeks attenuated endothelial dysfunction (p < 0.01). Ticagrelor reduced the expression of inflammatory molecules such as vascular cell adhesion molecule-1, macrophage accumulation, and lipid deposition. Ticagrelor decreased the phosphorylation of JNK in the aorta compared with control (p < 0.05). Ticagrelor and a JNK inhibitor ameliorated impairment of endothelium-dependent vasodilation by adenosine diphosphate (ADP) in wild-type mouse aortic segments. Furthermore, ticagrelor inhibited the expression of inflammatory molecules which were promoted by ADP in HUVEC (p < 0.001). Ticagrelor also inhibited ADP-induced JNK activation in HUVEC (p < 0.05). Ticagrelor attenuated vascular dysfunction and atherogenesis through the inhibition of inflammatory activation of endothelial cells. These effects might be a potential mechanism by which ticagrelor decreases cardiovascular events in patients with ACS.
Yoshihito Saijo, Hirotsugu Yamada, Kenya Kusunose, Mika Bando, Susumu Nishio, Yuta Torii, Yukina Hirata, Hiromitsu Seno, Tomomi Matsuura, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : A clinical application of preload stress echocardiography for predicting future hemodynamic worsening in patients with early-stage heart failure., Echocardiography, Vol.35, No.10, 1587-1595, 2018.
(Summary)
To improve the prognosis of patients with heart failure, risk stratification in their early stage is important. We assessed whether the change in transmitral flow (TMF) velocity pattern during preload augmentation can predict future hemodynamic worsening in early-stage heart failure patients with impaired relaxation TMF pattern. We designed a prospective cohort study that included 155 consecutive patients with impaired relaxation (IR) pattern at rest. Preload stress echocardiography was achieved using leg-positive pressure (LPP), and changes in TMF pattern during the LPP was observed during baseline echocardiographic examination. The patients whose TMF pattern developed to pseudonormal (PN) pattern throughout the study period were classified into the change to PN group, and patients whose TMF pattern stayed in IR pattern were classified into the stay in IR group. The median follow-up period was 17 months. The average age was 68 ± 11 years old, and 97 patients (63%) were male. Among 155 patients, 27 were classified into the change to PN group. A Cox proportional hazard analysis confirmed that the change in the peak atrial systolic TMF velocity during the LPP (ΔA, hazard ratio = 0.58 per 1SD; 95% CI = 0.39-0.88, P = 0.010) was the powerful independent predictor of change into PN pattern. Kaplan-Meier analysis revealed that the patients with ΔA -7 cm/s had more likely to develop into PN pattern than patients with ΔA > -7 cm/s (P = 0.001). Evaluation of a response in TMF during the LPP might provide an incremental diagnostic value to detect future overt heart failure in patients with early-stage heart failure.
The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. We measured flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver-operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06-0.74; =0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09-0.79; =0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01-3.44; =0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23-3.90; =0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. URL: www.umin.ac.jp. Unique identifier: UMIN000012950.
Kenya Kusunose, Hiromitsu Seno, Hirotsugu Yamada, Susumu Nishio, Yuta Torii, Yukina Hirata, Y Saijo, Takayuki Ise, Koji Yamaguchi, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Right Ventricular Function and Beneficial Effects of Cardiac Rehabilitation in Patients With Systolic Chronic Heart Failure., The Canadian Journal of Cardiology, Vol.34, No.10, 1307-1315, 2018.
(Summary)
It has been recognized that a comprehensive cardiac rehabilitation (CR) program improves mortality in patients with chronic heart failure. On the other hand, the magnitude of the improvement in exercise capacity after CR differs among individuals. The aim of this study was to assess the echocardiographic determinants of responders to CR using preload stress echocardiography. We prospectively enrolled 58 chronic heart failure patients with reduced left ventricular ejection fraction (aged 62 ± 11 years; 69% male; left ventricular ejection fraction 43% ± 7%) who had received optimized medical treatment in a CR program for 5 months. We performed preload echocardiographic studies using leg positive pressure (LPP) to assess the echocardiographic parameters during preload augmentation. We defined 41 patients as a development cohort to assess the predictive value of echocardiographic variables. Next, we validated results in the remaining 17 patients as a validation cohort. In the development cohort, significant improvement in peak oxygen uptake (VO) (>10%) after CR was observed in 58% patients. In a multivariable logistic regression model, the significant predictor of improvement in exercise capacity was right ventricular (RV) strain during LPP (odds ratio: 3.96 per 1 standard deviation; P = 0.01). An RV strain value of -16% during LPP had a good sensitivity of 0.79 and a specificity of 0.71 to identify patients with improvement in peak VO. In the validation cohort, an optimal cutoff value of RV strain value was the same (area under the curve: 0.77, sensitivity: 0.78, specificity: 0.65). RV strain during LPP may be an echocardiographic parameter for assessing beneficial effects of CR.
Atsushi Tanaka, Atsushi Kawaguchi, Hirofumi Tomiyama, Tomoko Ishizu, Chisa Matsumoto, Yukihito Higashi, Bonpei Takase, Toru Suzuki, Shinichiro Ueda, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito, Akira Yamashina and Koichi Node : Cross-sectional and longitudinal associations between serum uric acid and endothelial function in subjects with treated hypertension., International Journal of Cardiology, Vol.272, 308-313, 2018.
(Summary)
The endothelial dysfunction-arterial stiffness-atherosclerosis continuum plays an important pathophysiological role in hypertension. The aim of this study was to investigate the cross-sectional association between serum uric acid (SUA) and vascular markers related to this continuum, and to assess the longitudinal association between SUA and endothelial function that represents the initial step of the continuum. We evaluated the baseline associations between SUA levels and vascular markers that included flow-mediated vasodilatation (FMD), brachial-ankle pulse wave velocity (baPWV), and common carotid artery intima-media thickness (CCA-IMT) in 648 subjects receiving antihypertensive treatment. The longitudinal association between baseline SUA levels and FMD measured at 1.5 and 3 yr of follow-up was also investigated. At baseline, modest, but significant correlations were observed between SUA and FMD in females (r = -0.171), baPWV in males with SUA >368.78 μmol/L (r = -0.122) and in females with a SUA level 362.83 μmol/L (r = 0.217), mean CCA-IMT in females with a SUA level 333.09 μmol/L (r = 0.139), and max CCA-IMT in females with SUA level 333.09 μmol/L (r = 0.138). A longitudinal association between SUA and FMD was less observed in males. In females, the baseline SUA was associated significantly with FMD values at 1.5 yr (r = -0.211), and SUA levels >237.92 μmol/L were associated significantly and independently with FMD values at 3 yr (r = -0.166). Lower SUA levels were associated with better vascular markers of the continuum, especially in females. Furthermore, we observed a longitudinal association between SUA and endothelial function, suggesting SUA level may be a potential marker of the continuum in hypertension.
Takeshi Soeki, Tomomi Matsuura, Takeshi Tobiume, Sachiko Bando, Matsumoto Kazuhisa, Hiromi Nagano, Etsuko Uematsu, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro and Masataka Sata : Clinical, Electrocardiographic, and Echocardiographic Parameter Combination Predicts the Onset of Atrial Fibrillation., Circulation Journal, Vol.82, No.9, 2253-2258, 2018.
(Summary)
The ability to identify risk markers for new-onset atrial fibrillation (AF) is critical to the development of preventive strategies, but it remains unknown whether a combination of clinical, electrocardiographic, and echocardiographic parameters predicts the onset of AF. In the present study, we evaluated the predictive value of a combined score that includes these parameters.Methods and Results:We retrospectively studied 1,040 patients without AF who underwent both echocardiography and 24-h Holter electrocardiography between May 2005 and December 2010. During a median follow-up period of 68.4 months (IQR, 49.9-93.3 months), we investigated the incidence of new-onset AF. Of the 1,040 patients, 103 (9.9%) developed AF. Patients who developed AF were older than patients who did not. Total heart beats, premature atrial contraction (PAC) count, maximum RR interval, and frequency of sinus pause quantified on 24-h electrocardiography were associated with new-onset AF. LA diameter (LAD) on echocardiography was also associated with the development of AF. On multivariate Cox analysis, age 58 years, PAC count 80 beats/day, maximum RR interval 1.64 s, and LAD 4.5 cm were independently associated with the development of AF. The incidence rate of new-onset AF significantly increased as the combined score (i.e., the sum of the risk score determined using hazard ratios) increased. A combined score that includes age, PAC count, maximum RR interval, and LAD could help characterize the risk of new-onset AF.
Kageyuki Oba, Minetaka Maeda, Gulinu Maimaituxun, Satoshi Yamaguchi, Osamu Arasaki, Daiju Fukuda, Shusuke Yagi, Hirata Yukina, Susumu Nishio, Takashi Iwase, Shoichiro Takao, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masafumi Harada, Hiroaki Masuzaki, Masataka Sata and Michio Shimabukuro : Effect of the Epicardial Adipose Tissue Volume on the Prevalence of Paroxysmal and Persistent Atrial Fibrillation., Circulation Journal, Vol.82, No.7, 1778-1787, 2018.
(Summary)
Although increasing evidence suggests that epicardial adipose tissue volume (EATV) is associated with atrial fibrillation (AF), it is controversial whether there is a dose-response relationship of increasing EATV along the continuum of AF. We evaluated the effect of the EATV on the prevalence of paroxysmal AF (PAF) and persistent AF (PeAF) and the relationships with cardiac structure and functional remodeling.Methods and Results:Subjects who underwent multidetector computed tomography (MDCT) coronary angiography because of symptoms suggestive of coronary artery disease were divided into sinus rhythm (SR) (n=112), PAF (n=133), and PeAF (n=71) groups. The EATV index (EATV/body surface area, mL/m) was strongly associated with the prevalence of PAF and PeAF on the model adjusted for known AF risk factors. The effect of the EATV index on the prevalence of PeAF, but not on that of PAF, was modified by the left atrial (LA) dimension, suggesting that extension of the LA dimension is related to EATV expansion in PeAF. The cutoff value of the EATV index for the prevalence was higher in PeAF than in PAF (64 vs. 55 mL/m, P<0.01). The EATV index is associated with the prevalence of PAF and PeAF, and its cutoff values are predictive for PAF and PeAF development independently of other AF risk factors.
Kenya Kusunose, Y Okushi, Hirotsugu Yamada, Susumu Nishio, Yuta Torii, Yukina Hirata, Y Saijo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Prognostic Value of Frailty and Diastolic Dysfunction in Elderly Patients., Circulation Journal, Vol.82, No.8, 2103-2110, 2018.
(Summary)
High prevalence of frailty and of diastolic dysfunction (DD) in heart failure and high mortality in frail adults have been noted. We characterized frailty by quantifying differences on echocardiography, and assessed the added prognostic utility of frailty and DD grade in an elderly population. One hundred and ninety-one patients 65 years who had at least 1 cardiovascular risk factor were prospectively recruited for clinically indicated echocardiography at the present institute. Weight loss, exhaustion, and deficits in physical activity, gait speed, and handgrip strength were used to categorize patients as frail (3 features), intermediately frail (1 or 2 features), or non-frail (0 features). DD grade 2 was defined as severe. Frailty was associated with larger left atrial volume, smaller stroke volume, and worse DD grade after adjustment for age. In a period of 14 months, 29 patients (15%) had cardiovascular events. The addition of frailty score and severe DD significantly improved the prognostic power of a model containing male gender (model 1, male gender, χ=6.4; model 2, model 1 plus frailty score, χ=16.7, P=0.004; model 3, model 2 plus severe DD, χ=25.5, P=0.015). Both frailty and DD grade were significantly associated with future cardiovascular events in an elderly population with preserved ejection fraction and 1 risk factor of cardiovascular disease.
Tomoya Hara, Pham Tran Phuong, Daiju Fukuda, Koji Yamaguchi, Chie Murata, Sachiko Nishimoto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Soeki Takeshi, Tetsuzo Wakatsuki, Issei Imoto, Michio Shimabukuro and Masataka Sata : Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice., Circulation, Vol.138, No.16, 1706-1719, 2018.
(Summary)
-The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X (FXa), are expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. -We generated apolipoprotein E-deficient ( ) mice lacking systemic PAR-2 expression ( ). mice which lack or express PAR-2 only in bone-marrow (BM) cells were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a western-type diet (WTD) by histological analyses, quantitative RT-PCR, and western blotting. In vitro experiments using BM-derived macrophages were performed to confirm pro-inflammatory roles of PAR-2. The association between plasma FXa level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. - mice showed reduced atherosclerotic lesions in the aortic arch (<0.05) along with features of stabilized atherosclerotic plaques such as less lipid deposition (<0.05), collagen loss (<0.01), macrophage accumulation (<0.05), and inflammatory molecule expression (<0.05) compared with mice. Systemic PAR2 deletion in mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that FXa or a specific peptide agonist of PAR-2 significantly increased expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of NF- κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma FXa level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score (<0.05) and plaque volume (<0.01). -PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in mice. This signaling pathway may also participate in atherogenesis in humans.
Gulinu Maimaituxun, Michio Shimabukuro, Daiju Fukuda, Shusuke Yagi, Yukina Hirata, Takashi Iwase, Shoichiro Takao, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Takeshi Tobiume, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masafumi Harada and Masataka Sata : Local Thickness of Epicardial Adipose Tissue Surrounding the Left Anterior Descending Artery Is a Simple Predictor of Coronary Artery Disease - New Prediction Model in Combination With Framingham Risk Score., Circulation Journal, Vol.82, No.5, 1369-1378, 2018.
(Summary)
Compared with global cardiac adiposity, the local accumulation of fat surrounding coronary arteries might have a more direct impact on coronary artery disease (CAD). Here, we compared the local epicardial adipose tissue (EAT) thickness and global cardiac adiposity volumes for predicting CAD.Methods and Results:A total of 197 consecutive subjects underwent 320-slice multi-detector computed tomography coronary angiography and were segregated into CAD (1 coronary artery branch stenosis 50%) and non-CAD groups. EAT thickness was measured at the right coronary artery (EAT), the left anterior descending artery (EAT), and the left circumflex artery (EAT). Although EATand EATwere similar between the 2 groups, EATwas larger in the CAD group than in the non-CAD group (5.45±2.16 mm vs. 6.86±2.19 mm, P<0.001). EAT, after correcting for confounding factors, was strongly associated with CAD (r=0.276, P<0.001) and Gensini score (r=0.239, P<0.001). On multiple regression analysis, Framingham risk score combined with EATwas a strong predictor of CAD (adjusted R=0.121; P<0.001). The local fat thickness surrounding the LAD is a simple and useful surrogate marker for estimating the presence, severity, and extent of CAD, independent of classical cardiovascular risk factors.
Shusuke Yagi, Y. Yamamoto, S. Nishiyama and Masataka Sata : An Occluded Hooklet of an Embedded Inferior Vena Cava Filter, Internal Medicine, Vol.57, No.15, 2275-2276, 2018.
H Tomiyama, . T Ishizu, T Kohro, C Matsumoto, Y Higashi, B Takase, T Suzuki, . S Ueda, T Yamazaki, T Furumoto, K Kario, T Inoue, S Koba, Y Takemoto, T Hano, Masataka Sata, M Sata, Y Ishibashi, K Node, K Maemura, Y Ohya, T Furukawa, H Ito and A Yamashina : Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension., International Journal of Cardiology, Vol.15, No.253, 161-166, 2018.
(Summary)
To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage. The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment. The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta=-0.07, p=0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta=0.06, p=0.04) measured at the end of the study period. In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension.
K Tanaka and Masataka Sata : Roles of Perivascular Adipose Tissue in the Pathogenesis of Atherosclerosis., Frontiers in Physiology, Vol.9, No.3, 3, 2018.
(Summary)
Traditionally, it is believed that white adipose tissues serve as energy storage, heat insulation, and mechanical cushion, whereas non-shivering thermogenesis occurs in brown adipose tissue. Recent evidence revealed that adipose tissue secretes many types of cytokines, called as adipocytokines, which modulate glucose metabolism, lipid profile, appetite, fibrinolysis, blood pressure, and inflammation. Most of the arteries are surrounded by perivascular adipose tissue (PVAT). PVAT has been thought to be simply a structurally supportive tissue for vasculature. However, recent studies showed that PVAT influences vasodilation and vasocontraction, suggesting that PVAT regulates vascular tone and diameter. Adipocytokines secreted from PVAT appear to have direct access to the adjacent arterial wall by diffusion or via vasa vasorum. In fact, PVAT around atherosclerotic lesions and mechanically-injured arteries displayed inflammatory cytokine profiles, suggesting that PVAT functions to promote vascular lesion formation. Many clinical studies revealed that increased accumulation of epicardial adipose tissue (EAT), which surrounds coronary arteries, is associated with coronary artery disease. In this review article, we will summarize recent findings about potential roles of PVAT in the pathogenesis of atherosclerosis, particularly focusing on a series of basic and clinical studies from our laboratory.
Tomoya Hara, Daiju Fukuda, K Tanaka, Y Higashikuni, Yukina Hirata, Shusuke Yagi, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Inhibition of activated factor X by rivaroxaban attenuates neointima formation after wire-mediated vascular injury., European Journal of Pharmacology, Vol.5, No.820, 222-228, 2018.
(Summary)
Accumulating evidence suggests that activated factor X (FXa), a key coagulation factor, plays an important role in the development of vascular inflammation through activation of many cell types. Here, we investigated whether pharmacological blockade of FXa attenuates neointima formation after wire-mediated vascular injury. Transluminal femoral artery injury was induced in C57BL/6 mice by inserting a straight wire. Rivaroxaban (5mg/kg/day), a direct FXa inhibitor, was administered from one week before surgery until killed. At four weeks after surgery, rivaroxaban significantly attenuated neointima formation in the injured arteries compared with control (P<0.01). Plasma lipid levels and blood pressure were similar between the rivaroxaban-treated group and non-treated group. Quantitative RT-PCR analyses demonstrated that rivaroxaban reduced the expression of inflammatory molecules (e.g., IL-1β and TNF-α) in injured arteries at seven days after surgery (P<0.05, respectively). In vitro experiments using mouse peritoneal macrophages demonstrated that FXa increased the expression of inflammatory molecules (e.g., IL-1β and TNF-α), which was blocked in the presence of rivaroxaban (P<0.05). Also, in vitro experiments using rat vascular smooth muscle cells (VSMC) demonstrated that FXa promoted both proliferation and migration of this cell type (P<0.05), which were blocked in the presence of rivaroxaban. Inhibition of FXa by rivaroxaban attenuates neointima formation after wire-mediated vascular injury through inhibition of inflammatory activation of macrophages and VSMC.
Yukina Hirata, Hirotsugu Yamada, Kenya Kusunose, Susumu Nishio, Yuta Torii, Yuki Horike and Masataka Sata : Provocation of clinically significant left ventricular outflow tract obstruction by postural change in patients with sigmoid septum., Journal of Echocardiography, Vol.16, No.4, 173-174, 2018.
Akira Hirono, Kenya Kusunose, Norihito Kageyama, Masayuki Sumitomo, Masahiro Abe, Hiroyuki Fujinaga and Masataka Sata : Development and validation of optimal cut-off value in inter-arm systolic blood pressure difference for prediction of cardiovascular events, Journal of Cardiology, Vol.71, No.20, 24-30, 2018.
(Summary)
An inter-arm systolic blood pressure difference (IAD) is associated with cardiovascular disease. The aim of this study was to develop and validate the optimal cut-off value of IAD as a predictor of major adverse cardiac events in patients with arteriosclerosis risk factors. From 2009 to 2014, 1076 patients who had at least one cardiovascular risk factor were included in the analysis. We defined 700 randomly selected patients as a development cohort to confirm that IAD was the predictor of cardiovascular events and to determine optimal cut-off value of IAD. Next, we validated outcomes in the remaining 376 patients as a validation cohort. The blood pressure (BP) of both arms measurements were done simultaneously using the ankle-brachial blood pressure index (ABI) form of automatic device. The primary endpoint was the cardiovascular event and secondary endpoint was the all-cause mortality. During a median period of 2.8 years, 143 patients reached the primary endpoint in the development cohort. In the multivariate Cox proportional hazards analysis, IAD was the strong predictor of cardiovascular events (hazard ratio: 1.03, 95% confidence interval: 1.01-1.05, p=0.005). The receiver operating characteristic curve revealed that 5mmHg was the optimal cut-off point of IAD to predict cardiovascular events (p<0.001). In the validation cohort, the presence of a large IAD (IAD ≥5mmHg) was significantly associated with the primary endpoint (p=0.021). IAD is significantly associated with future cardiovascular events in patients with arteriosclerosis risk factors. The optimal cut-off value of IAD is 5mmHg.
(Keyword)
Aged / Aged, 80 and over / Arm / blood pressure / Blood Pressure Determination / Cardiovascular Diseases / Female / Humans / Male / Middle Aged / Risk Factors / Systole
The results of previous clinical trials on the effects of ezetimibe-statin combination therapy on atherosclerosis are inconsistent, and the anti-atherosclerotic effect of ezetimibe remains controversial.Methods and Results:We conducted a prospective, randomized open-label study at 10 centers. One hundred and twenty-eight statin-naïve patients with acute coronary syndrome (ACS) undergoing intravascular ultrasound (IVUS)-guided percutaneous coronary intervention were randomized to receive either 2 mg/day pitavastatin plus 10 mg/day ezetimibe, or 2 mg/day pitavastatin. One hundred and 3 patients had evaluable IVUS of non-culprit coronary lesions at baseline and at follow-up. The primary endpoint was the percentage change in non-culprit coronary plaque volume (PV) and lipid PV on integrated backscatter IVUS. Mean low-density lipoprotein cholesterol was reduced from 123 mg/dL to 64 mg/dL in the combination therapy group (n=50) and 126 mg/dL to 87 mg/dL in the statin alone group (n=53; between-group difference, 16.9%, P<0.0001). The percent change in PV was -5.1% in the combination therapy group and -6.2% in the statin alone group (P=0.66), although both groups had reduction of PV compared with baseline (both P<0.01). The percent change in lipid PV did not differ between the groups (4.3 vs. -3.0%, P=0.37). In statin-naïve patients with ACS, combined therapy with ezetimibe and statin did not result in a significant change in coronary plaque regression or tissue component compared with statin alone. [Clinical Trial Registration: www.clinicaltrials.gov (NCT00549926)].
Tomoya Kinouchi, Keiko T. Kitazato, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Nobuhisa Matsushita, Yoshitaka Kurashiki, Junichiro Satomi, Masataka Sata and Shinji Nagahiro : Correction to: Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats., Translational Stroke Research, Vol.9, No.3, 317, 2017.
(Summary)
In the original publication of the article, the second author (Keiko T. Kitazato) was missing.
Baseline brachial artery (BBA) diameter has been reported to be a potential confounding factor of flow-mediated vasodilation (FMD). The purpose of this study was to evaluate the relationships between BBA diameter and cardiovascular risk factors and compare the diagnostic accuracy of BBA diameter in subjects without cardiovascular risk factors and patients with cardiovascular disease (CVD) with that of FMD. We measured BBA diameter and FMD in 5695 male subjects. In addition, we retrospectively investigated the incidence of cardiovascular events using another population sample consisting of 440 male subjects, to compare the accuracy of BBA diameter with that of FMD in predicting cardiovascular events. BBA diameter and FMD significantly correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose as well as Framingham risk score. The prevalence of cardiovascular risk factors and CVD increased with the increase in BBA diameter and FMD. Area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for BBA diameter to diagnose subjects without cardiovascular risk factors (0.59 vs. 0.62, p = 0.001) or patients with CVD (0.58 vs. 0.64, p < 0.001) was significantly lower than that for FMD. In the retrospective study, the AUC value of the ROC curve for BBA diameter to predict first major cardiovascular events was significantly lower than that of FMD (0.50 vs. 0.62, p = 0.03). In men, BBA diameter was inferior to FMD for assessment of cardiovascular risk.
Tomoya Kinouchi, Keiko T. Kitazato, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Nobuhisa Matsushita, Yoshitaka Kurashiki, Junichiro Satomi, Masataka Sata and Shinji Nagahiro : Treatment with the PPAR Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats., Translational Stroke Research, Vol.9, No.3, 306-316, 2017.
(Summary)
Neurogenesis is essential for a good post-stroke outcome. Exogenous stem cells are currently being tested to promote neurogenesis after stroke. Elsewhere, we demonstrated that treatment with the PPARγ agonist pioglitazone (PGZ) before cerebral ischemia induction reduced brain damage and activated survival-related genes in ovariectomized (OVX) rats. Here, we tested our hypothesis that post-ischemia treatment with PGZ inhibits brain damage and contributes to neurogenesis via activated stem cells. Bone marrow (BM) cells of 7-week-old Wistar female rats were replaced with BM cells from green fluorescent protein-transgenic (GFP) rats. Three weeks later, they were ovariectomized (OVX/GFP rats). We subjected 7-week-old Wistar male and 13-week-old OVX/GFP rats to 90-min cerebral ischemia. Male and OVX/GFP rats were divided into two groups, one was treated with PGZ (2.5 mg/kg/day) and the other served as the vehicle control (VC). In both male and OVX/GFP rats, post-ischemia treatment with PGZ reduced neurological deficits and the infarct volume. In male rats, PGZ decreased the mRNA level of IL-6 and M1-like macrophages after 24 h. In OVX/GFP rats, PGZ augmented the proliferation of resident stem cells in the subventricular zone (SVZ) and the recruitment of GFP stem cells on days 7-14. Both types of proliferated stem cells migrated from the SVZ into the peri-infarct area. There, they differentiated into mature neurons, glia, and blood vessels in association with activated Akt, MAP2, and VEGF. Post-ischemia treatment with PGZ may offer a new avenue for stroke treatment through contribution to neuroprotection and neurogenesis.
Hiromu Yamazaki, Shusuke Yagi, Yuta Torii, Rie Amano, Yasuyuki Oomichi, Teruaki Sangawa, Daiju Fukuda, Muneyuki Kadota, Takayuki Ise, Rie Ueno, Tomoya Hara, Kenya Kusunose, Tomomi Matsuura, Takeshi Tobiume, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masashi Akaike and Masataka Sata : Edoxaban improves acute venous thromboembolism while preserving protein C and protein S levels, Journal of Cardiology, Vol.71, No.3, 305-309, 2017.
(Summary)
It is well known that warfarin inhibits the synthesis of vitamin K-dependent anticoagulants, including thrombin, protein C and S, and factor Xa, leading, paradoxically, to an initial hypercoagulable state. Edoxaban, a direct inhibitor of activated factor X is widely used for the treatment of acute venous thromboembolism (VTE). However, the effect of edoxaban on circulating coagulation factors, in patients with acute VTE, remains unknown. We enrolled 57 patients with acute VTE with/without pulmonary embolism treated with edoxaban (n=37) or warfarin (n=20) in a clinical setting. Before treatment and 2 weeks after treatment, we evaluated thrombotic burden using ultrasound or computed tomography angiography. We also evaluated thrombin generation, represented by prothrombin fragment F1+2; thrombus degradation, represented by D-dimer; and levels of anticoagulants, including protein C, protein S, and antithrombin III. Both edoxaban and warfarin treatment improved thrombotic burden and decreased prothrombin fragment F1+2, and D-dimer. Edoxaban treatment preserved protein C and protein S levels. In contrast, warfarin decreased protein C and protein S levels. Neither treatment affected antithrombin III. Edoxaban improves VTE while preserving protein C and protein S levels, thereby indicating that edoxaban improves thrombotic burden while maintaining levels of anticoagulants.
Shusuke Yagi, Ken-ichi Aihara, Takeshi Kondo, Kiyoe Kurahashi, Sumiko Yoshida, Itsuro Endo, Daiju Fukuda, Yutaka Nakaya, Kin-Ichiro Suwaki, Takashi Takeji, Toshihiro Wada, Masdan Hotimah Salim, Saori Hama, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Munehide Matsuhisa, Michio Shimabukuro, Masashi Akaike and Masataka Sata : Predictors for the Treatment Effect of Sodium Glucose Co-transporter 2 Inhibitors in Patients with Type 2 Diabetes Mellitus., Advances in Therapy, Vol.35, No.1, 124-134, 2017.
(Summary)
Predictors for the effect of sodium glucose co-transporter 2 (SGLT2) inhibitors at lowering hemoglobin A1c (HbA1c) levels in type 2 diabetes mellitus patients remain unclear. We therefore aimed to elucidate these predictors in type 2 diabetes patients after 3 months of SGLT2 treatment. A total of 302 consecutive type 2 diabetes patients who had been treated with SGLT2 inhibitors as monotherapy or add-on therapy to existing antidiabetic treatments were enrolled retrospectively. After excluding 27 patients whose HbA1c levels could not be evaluated 3 months after treatment, the glucose-lowering effects of SGLT2 inhibitors were assessed in 275 patients by measuring HbA1c levels before and 3 months after treatment. The predictors for changes in HbA1c levels after 3 months of treatment were evaluated. SGLT2 inhibitor treatment for 3 months decreased HbA1c levels from 7.8 ± 1.2% to 7.4 ± 1.0% (p < 0.0001). A multiple regression analysis showed that the independent determinants for SGLT2 inhibitor treatment effect included decreased HbA1c levels after 1 month of treatment, high baseline HbA1c levels, and a high estimated glomerular filtration rate (eGFR). We show that type 2 diabetes patients who received the greatest glucose-lowering effect with SGLT2 inhibitor treatment were those with preserved renal function (high baseline eGFR) and high baseline HbA1c levels. Moreover, SGLT2 inhibitor treatment efficacy could be predicted by the patients' initial response to treatment.
Shusuke Yagi, Takeshi Soeki, Ken-Ichi Aihara, Daiju Fukuda, Takayuki Ise, Muneyuki Kadota, Sachiko Bando, Tomomi Matsuura, Takeshi Tobiume, Koji Yamaguchi, Kenya Kusunose, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro, Masashi Akaike and Masataka Sata : Low Serum Levels of Eicosapentaenoic Acid and Docosahexaenoic Acid are Risk Factors for Cardiogenic Syncope in Patients with Brugada Syndrome, International Heart Journal, Vol.58, No.5, 720-723, 2017.
(Summary)
The n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antiarrhythmic effects, possibly via modulation of the cardiac ion channels. Nevertheless, it is unknown whether low serum levels of n-3 PUFAs are risk factors for ventricular fibrillation in patients with Brugada syndrome (BrS). We retrospectively reviewed data from 62 men with BrS and evaluated their serum levels of EPA and DHA, and the risk factors for sudden cardiac death, including a history of cardiogenic syncope. Nineteen patients had a history of cardiogenic syncope, and their EPA and DHA levels were significantly lower than those of the patients without syncope. Multivariate logistic regression analysis revealed that low EPA and DHA levels were associated with the incidence of syncope. The receiver-operator characteristic curve showed the area under the curves of EPA and DHA for history of syncope were 0.84 and 0.72, respectively. In conclusion, low levels of EPA and DHA are risk factors for cardiogenic syncope in patients with BrS, which suggests that n-3 PUFAs play important roles in preventing ventricular fibrillation in BrS.
(Keyword)
Adult / Aged / Aged, 80 and over / Biomarkers / Brugada Syndrome / Chromatography, Gas / Docosahexaenoic Acids / Eicosapentaenoic Acid / Electrocardiography / Follow-Up Studies / Humans / Incidence / Japan / Male / Middle Aged / Prevalence / ROC Curve / Retrospective Studies / Risk Assessment / Risk Factors / Syncope / Young Adult
Yuriko Takagawa, Shusuke Yagi, Takayuki Ise, Ayumi Ishii, Koji Nishikawa, Daiju Fukuda, Kenya Kusunose, Tomomi Matsuura, Takeshi Tobiume, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro, Shinsuke Katoh, Ken-ichi Aihara, Masashi Akaike and Masataka Sata : Improved Exercise Capacity After Cardiac Rehabilitation Is Associated with Reduced Visceral Fat in Patients with Chronic Heart Failure., International Heart Journal, Vol.58, No.5, 746-751, 2017.
(Summary)
Participation in a comprehensive cardiac rehabilitation (CR) program has been shown to reduce mortality and improve exercise capacity and symptoms in patients with chronic heart failure (CHF). Reduced exercise capacity leads to a concomitant reduction of skeletal muscle mass and accumulation of body fat. However, it is currently unknown whether CR reduces visceral adipose tissue (VAT) and/or subcutaneous abdominal adipose tissue (SAT) in patients with CHF. In addition, the body composition associated with improved exercise capacity after CR in patients with CHF has not been previously studied. Nineteen CHF patients who were categorized as NYHA functional class II or III and had received optimal medical treatment including a CR program for 5 months were enrolled in this study. The CR program significantly increased peak VO and reduced B-type natriuretic peptide. In addition, fat and body composition analysis showed reductions in the visceral fat tissue (VAT) area, subcutaneous abdominal adipose tissue (SAT) area, body weight, and total fat weight after CR. There were no changes in total water weight and total muscle weight. Single regression analysis revealed that the amelioration of reduced exercise capacity seen after CR is associated with reduced VAT area but not with SAT area or body weight. In conclusion, CR reduces VAT and improves exercise capacity in patients with CHF. This suggests that reducing VAT is important for CR to be most effective in the treatment of CHF.
Shusuke Yagi, Yukina Hirata, Takayuki Ise, Kenya Kusunose, Hirotsugu Yamada, Daiju Fukuda, Salim Masdan Hotimah, G Maimaituxun, Susumu Nishio, Yuriko Takagawa, Saori Hama, Tomomi Matsuura, Koji Yamaguchi, Takeshi Tobiume, Takeshi Soeki, Tetsuzo Wakatsuki, Ken-ichi Aihara, Masashi Akaike, Michio Shimabukuro and Masataka Sata : Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus., Diabetology & Metabolic Syndrome, Vol.9, 78, 2017.
(Summary)
It is unknown whether canagliflozin, a selective sodium glucose co-transporter 2 inhibitor, reduces epicardial adipose tissue (EAT) thickness, which is associated with insulin resistance and is a risk factor for coronary artery disease. We administered 100 mg of canagliflozin for 6 months to 13 patients with type 2 diabetes mellitus. We evaluated glycemic control, visceral adipose tissue (VAT) area and subcutaneous adipose tissue (SAT) area, and skeletal muscle mass by using impedance methods, and EAT thickness by using echocardiography. Canagliflozin treatment for 6 months decreased hemoglobin A1c level from 7.1 ± 0.5% to 6.7 ± 0.6% (P < 0.05) and decreased EAT thickness from 9.3 ± 2.5 to 7.3 ± 2.0 mm (P < 0.001), along with a trend of decreasing VAT and SAT area. No association was found between any of these changes. Canagliflozin reduced EAT thickness in patients with type 2 diabetes mellitus independent of its effect on lowering blood glucose, suggesting that canagliflozin may have an effect in preventing cardiovascular events in these patients (UMIN000021327).
Shusuke Yagi, Daiju Fukuda, KI Aihara, Masashi Akaike, Michio Shimabukuro and Masataka Sata : n-3 Polyunsaturated Fatty Acids: Promising Nutrients for Preventing Cardiovascular Disease., Journal of Atherosclerosis and Thrombosis, Vol.24, No.10, 999-1010, 2017.
(Summary)
The adoption of the Western-style diet, with decreased fish intake and lack of exercise, has increased the prevalence of cardiovascular disease (CVD) in Japan. Statin treatment has been established to reduce the risk of cardiovascular events; however, 60%-70% of these events occur despite its use. Thus, the residual risk for CVD should be identified and resolved to reduce further cardiovascular events. The serum levels of n-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, are reportedly associated with an increased incidence of cardiovascular events and mortality, whereas the addition of n-3 PUFA treatment to the statin treatment decreases cardiovascular events. Similar to statins, n-3 PUFAs have pleiotropic effects in addition to lipid-modifying effects. Pre-clinical and clinical studies have shown that n-3 PUFAs prevent cardiovascular events by ameliorating endothelial function and attenuating lipid accumulation, vascular inflammation, and macrophage recruitment, thereby causing coronary plaque development and rupture. Taken together, n-3 PUFAs are comprehensively able to attenuate the atherogenic response. Therefore, n-3 PUFA intake is recommended to prevent cardiovascular events, particularly in patients with multiple cardiovascular risk factors.
Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Yuta Torii, Yukina Hirata, Hiromitsu Seno, Yoshihito Saijo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Preload Stress Echocardiography Predicts Outcomes in Patients With Preserved Ejection FractionandLow-GradientAorticStenosis, Circulation. Cardiovascular Imaging, Vol.10, No.10, 2017.
(Summary)
The projected aortic valve area (AVA) at a normal transvalvular flow rate using dobutamine is helpful to determine the actual severity of aortic stenosis (AS) and to predict risk of adverse events in low-gradient AS cases with unclear surgical indication. Our study aimed to identify the independent and incremental value of preload stress echocardiography-derived AVA to predict outcomes in patients with preserved ejection fraction and low-gradient AS. We prospectively performed echocardiographic studies in 79 patients with low-gradient AS (age, 77±7 years; 30% men) with preload stress echocardiography using leg positive pressure. AVA was calculated using AVA and transvalvular flow rate at baseline and during leg positive pressure. The primary end point was the decision for aortic valve surgery or cardiac death. During a median period of 19 months, 23 patients had the decision for aortic valve surgery, and none died during follow-up. In a stepwise multivariable analysis, indexed AVA (AVAi; hazard ratio, 2.00 per 0.1 cm/m decrease; 95% confidence interval, 1.36-2.96; <0.001) was associated with the primary end point. Using a receiver operating characteristic curve analysis, the best cutoff value of AVAi for predicting cardiac events was <0.72 cm/m. By incorporating AVAi into AVAi at baseline, continuous net reclassification index for cardiac events was 0.48 (=0.04). In patients with low-gradient AS, indexed AVA derived from preload stress echocardiography can be useful to predict risk of adverse events. The present article should be considered as a proof of concept study, and we think that larger multicenter studies are warranted.
(Keyword)
Aged / Aged, 80 and over / Aortic Valve / Aortic Valve Stenosis / Area Under Curve / Disease Progression / Disease-Free Survival / Echocardiography, Stress / Female / Humans / Kaplan-Meier Estimate / Male / Models, Cardiovascular / Predictive Value of Tests / Prospective Studies / ROC Curve / Severity of Illness Index / Stroke Volume / Time Factors / Ventricular Function, Left
Susumu Nishio, Kenya Kusunose, Hirotsugu Yamada, Yukina Hirata, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro and Masataka Sata : Echocardiographic Epicardial Adipose Tissue Thickness Is Associated with Symptomatic Coronary Vasospasm during Provocative Testing., Journal of the American Society of Echocardiography, Vol.30, No.10, 1021-1027, 2017.
(Summary)
Epicardial adipose tissue (EAT) is the ectopic visceral fat surrounding the heart, which plays an important role in atherosclerosis of the coronary arteries via endothelial damage. Several studies have also suggested that vasospasm with angina (VSA) causes endothelial dysfunction in the coronary arteries. The aim of this study was to evaluate the thickness of EAT in the anterior interventricular groove (EAT-AIG) using echocardiography in patients who had no obstructive coronary artery disease and were suspected of having VSA. Sixty-five patients who underwent intracoronary acetylcholine provocation testing for clinical indications were prospectively enrolled. VSA was diagnosed by coronary artery stenosis increase of >90% and the presentation of chest pain with ischemic changes on electrocardiography. Subjects were divided into two groups, with and without significant coronary spasm (VSA group, 30 patients; non-VSA group, 35 patients), consistent with acetylcholine provocation testing. EAT-AIG thickness was significantly greater in the VSA group than in the non-VSA group (8.2 2.7 vs 6.1 2.5 mm, P = .002). By receiver operating characteristic analysis, EAT-AIG thickness had a high C statistic (area under the curve = 0.81, P < .001) after adjustment for conventional risk factors (smoking, diabetes mellitus, and dyslipidemia). EAT-AIG thickness had incremental diagnostic value over other conventional risk factors (area under the curve = 0.81 vs 0.64, P for comparison = .020). EAT-AIG thickness, which is noninvasively and easily measured using transthoracic echocardiography, can be one of multiple clinical variables associated with VSA.
Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of <120 mm Hg, 7.5±2.8% for 120-129 mm Hg, 7.1±2.8% for 130-139 mm Hg, and 6.7±2.6% for ≥140 mm Hg; <0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6±3.1% in treated hypertensives with systolic blood pressure of <120 mm Hg, 4.8±2.7% for 120-129 mm Hg, 4.9±2.8% for 130-139 mm Hg, and 4.5±2.3% for ≥140 mm Hg; =0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.
Yukina Hirata, Kenya Kusunose, Hirotsugu Yamada, Rikuto Shimizu, Yuta Torii, Susumu Nishio, Yoshihito Saijo, Shoichiro Takao, Takeshi Soeki and Masataka Sata : Age-related changes in morphology of left atrial appendage in patients with atrial fibrillation., The International Journal of Cardiovascular Imaging, Vol.34, No.2, 321-328, 2017.
(Summary)
The purpose of this study was to evaluate the relationship between age and frequency of left atrial appendage (LAA) morphology in patients with atrial fibrillation (AF) compared with sinus rhythm (SR). We enrolled 145 AF patients, and 199 SR patients for the control group without any cardiovascular disease. LAA volume index (LAAVi) and morphology were assessed by electrocardiogram-gated computed tomography angiography. LAA morphology was classified into "chicken wing" or "non-chicken wing" according to the previously described classification. There was no significant trend in frequency of non-chicken wing morphology among ages in the SR group (p = 0.36 for trend), whereas the frequency was negatively related to age in the AF group (p = 0.002 for trend). In multivariable logistic regression, age > 65 (odds ratio [OR] 0.42, p = 0.002) and duration of AF (OR 0.53, p = 0.010) and LAAVi (OR 0.62, p = 0.017) were independent factors of non-chicken wing LAA morphology in the AF group. LAA morphology is affected by age, especially in patients with AF. When we utilize non-chicken wing LAA morphology as a stroke risk factor in patients with AF, we should pay attention to their age.
We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. Clinicaltrials.gov number: NCT00212017.
Shusuke Yagi, Minoru Mitsugi, Teruaki Sanagawa, Masashi Akaike and Masataka Sata : Paget-Schroetter Syndrome in a Baseball Pitcher., International Heart Journal, Vol.58, No.4, 637-640, 2017.
(Summary)
Paget-Schroetter syndrome (PSS) is thrombosis of the deep veins draining the upper extremity due to anatomic abnormalities of the thoracic outlet that cause subclavian compression and subsequent thrombosis, leading to thrombus formation in the subclavian vein. Vigorous arm activity in sports is a known risk factor. Here, we report a case of Paget-Schroetter syndrome in a 31-year-old male non-professional baseball pitcher.
Tamio Teramoto, Akira Kondo, Arihiro Kiyosue, Mariko Harada-Shiba, Yasushi Ishigaki, Kimimasa Tobita, Yumiko Kawabata, Asuka Ozaki, Marie T. Baccara-Dinet and Masataka Sata : Efficacy and safety of alirocumab in patients with hypercholesterolemia not adequately controlled with non-statin lipid-lowering therapy or the lowest strength of statin: ODYSSEY NIPPON study design and rationale., Lipids in Health and Disease, Vol.16, No.1, 121, 2017.
(Summary)
Statins are generally well-tolerated and serious side effects are infrequent, but some patients experience adverse events and reduce their statin dose or discontinue treatment altogether. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), which can produce substantial and sustained reductions of low-density lipoprotein cholesterol (LDL-C). The randomized, double-blind, placebo-controlled, parallel-group, phase 3 ODYSSEY NIPPON study will explore alirocumab 150 mg every 4 weeks (Q4W) in 163 Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin (5 mg/day) or are receiving a non-statin lipid-lowering therapy (LLT) (fenofibrate, bezafibrate, ezetimibe, or diet therapy alone). Hypercholesterolemia is defined as LDL-C ≥ 100 mg/dL (2.6 mmol/L) in patients with heterozygous familial hypercholesterolemia or non-familial hypercholesterolemia with a history of documented coronary heart disease, or ≥120 mg/dL (3.1 mmol/L) in patients with non-familial hypercholesterolemia classified as primary prevention category III (i.e. high-risk patients). During the 12-week double-blind treatment period, patients will be randomized (1:1:1) to receive alirocumab subcutaneously (SC) 150 mg Q4W alternating with placebo for alirocumab Q4W, or alirocumab 150 mg SC every 2 weeks (Q2W), or SC placebo Q2W. The primary efficacy endpoint is the percentage change in calculated LDL-C from baseline to week 12. The long-term safety and tolerability of alirocumab will also be investigated. The ODYSSEY NIPPON study will provide insights into the efficacy and safety of alirocumab 150 mg Q4W or 150 mg Q2W among Japanese patients with hypercholesterolemia who are on the lowest-strength dose of atorvastatin, or are receiving a non-statin LLT (including diet therapy alone). ClinicalTrials.gov number: NCT02584504.
Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata, Hiromitsu Seno, Y Saijo, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Echocardiographic Predictors for Worsening of Six-Minute Walk Distances in Patients With Systemic Sclerosis (Scleroderma), The American Journal of Cardiology, Vol.120, No.2, 315-321, 2017.
(Summary)
Change in 6-minute walk distance (6MWD) has been used as a clinical marker in pulmonary hypertension. Determinants and worsening of 6MWD remain a matter of debate because nonpulmonary factors have an impact on the 6MWD. We hypothesized that future reduction of 6MWD in patients with systemic sclerosis (SSc) was more closely associated with cardiac dysfunction. We prospectively performed standard clinical and echocardiographic evaluations in SSc patients with the 6-minute walk test at enrollment. Features associated with the 6MWD were sought in a multiple linear regression analysis and compared using standardized . Worsening of the 6MWD was defined as a 15% reduction and served as the primary outcome. Eighty-one patients were included. In the multivariate analysis, baseline 6MWD was related to SSc severity score ( = -0.250, p = 0.024), left atrial volume index ( = -0.222, p = 0.046), right ventricular fractional area change ( = 0.252, p = 0.025), and the ratio of mean pulmonary artery pressure and cardiac output ( = -0.31, p = 0.002). During follow-up, 20 patients reached the primary outcome. In sequential Cox models, a model based on right ventricular fractional area change at baseline (chi-square 4.8) was improved by left atrial volume index (chi-square 10.3, p = 0.007). In conclusion, determinants and worsening of 6MWD are explained by cardiac factors. When using the 6MWD as a clinical marker in pulmonary hypertension patients, their left ventricular diastolic function and right ventricular systolic function should be taken into consideration.
(Keyword)
Diastole / Disease Progression / Echocardiography, Doppler / Female / Follow-Up Studies / Humans / Hypertension, Pulmonary / Male / Middle Aged / Predictive Value of Tests / Prospective Studies / Scleroderma, Systemic / Stroke Volume / Systole / Time Factors / Ventricular Function, Left / Ventricular Function, Right / Walking
Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Ayumi Ishii, Yukina Hirata, Hiromitsu Seno, Yoshihito Saijo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : RV Myocardial Strain During Pre-Load Augmentation Is Associated With Exercise Capacity in Patients With Chronic HF, JACC. Cardiovascular Imaging, Vol.10, No.10, 1240-1249, 2017.
(Summary)
The aim of this study was to assess the relationship between right ventricular (RV) function during pre-load augmentation and exercise tolerance. Peak oxygen uptake (VO2) is a strong predictor of mortality in chronic heart failure. Cardiac function during pre-load augmentation is an important part of the phenomenon in the evaluation of exercise capacity. We prospectively performed echocardiographic studies in 68 chronic heart failure patients with cardiopulmonary exercise testing (mean age 60 ± 12 years; 69% male). After resting evaluations, echocardiographic parameters were repeated during leg positive pressure (LPP). Exercise capacity was assessed by peak VO2 in all patients (left ventricular ejection fraction: 43 ± 15%). Patients with severely reduced exercise capacity (peak VO2 <14 ml/kg/min) had significantly lower stroke volume index, left ventricular global longitudinal strain and RV strain and higher filling pressure (E/e' and pulmonary arterial systolic pressure) than the remainder. Stroke volume index ( = 0.49), global longitudinal strain ( = -0.61), E/e' ( = -0.32), pulmonary arterial systolic pressure ( = -0.57), and RV strain ( = -0.66) during LPP were independently correlated to peak VO2 (all p < 0.01). RV strain during LPP was the most powerful predictor in identifying patients with severely reduced exercise capacity (cut off value: -17%; sensitivity: 81%; specificity: 88%; areas under the curve: 0.88; p < 0.001) compared with other variables including resting parameters. RV strain during pre-load augmentation correlated independently to peak VO2 and was a powerful predictor in identifying patients with severely reduced exercise capacity.
Akihiro Tokushige, Shinichiro Ueda, Hirofumi Tomiyama, Mituru Ohishi, Takahide Kohro, Yukihito Higashi, Bonpei Takase, Toru Suzuki, Tomoko Ishizu, Tsutomu Yamazaki, Tomoo Furumoto, Kazuomi Kario, Teruo Inoue, Shinji Koba, Yasuhiko Takemoto, Takuzo Hano, Masataka Sata, Yutaka Ishibashi, Koichi Node, Koji Maemura, Yusuke Ohya, Taiji Furukawa, Hiroshi Ito and Akira Yamashina : Association Between Waist-to-Height Ratio and Endothelial Dysfunction in Patients With Morbidity A Report From the FMD-J Study, Circulation Journal, Vol.81, No.12, 1911-1918, 2017.
(Summary)
Waist circumference (WC), waist-to-height ratio (WHtR) and body mass index (BMI) are known as easy anthropometric markers of abnormal obesity and screening tools for predicting cardiovascular outcomes, but which indices are best is unclear. We therefore investigated the superiority and association between each index and low flow-mediated dilatation (FMD) as a surrogate marker for cardiovascular outcomes in patients with morbidity in a large Japanese prospective cohort.Methods and Results:A total of 1,645 Japanese patients who had coronary artery disease and hypertension or diabetes mellitus were enrolled, and 1,087 of them were analyzed. The high-WHtR group (≥0.5) showed greater morbidity and increased inflammation in association with atherosclerosis compared with the low-WHtR group. High WHtR and advanced age were identified as predictors of low FMD (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.02-1.88, P=0.037 and OR 1.55, 95% CI 1.19-2.01, P=0.001, respectively). However, WC was not associated with that risk in either sex (male: OR 1.37, 95% CI 0.97-1.93, P=0.076; female: OR 1.08, 95% CI 0.68-1.73, P=0.74), and no association was evident between high BMI and low FMD (OR 0.92, 95% CI 0.71-1.19, P=0.54). WHtR offers a superior predictor of decreased FMD than other anthropometric indices, and progression of arteriosclerosis might be detected more sensitively. Further study is needed to investigate the relationship between cardiovascular mortality and WHtR.
(Keyword)
Aged / Asian Continental Ancestry Group / atherosclerosis / Dilatation / Disease Progression / Endothelium / Female / Humans / Male / Middle Aged / Morbidity / Prospective Studies / Waist-Height Ratio
Michio Shimabukuro, Atsushi Tanaka, Masataka Sata, Kazuoki Dai, Yoshisato Sibata, Yohei Inoue, Hiroki Ikenaga, Shinji Kishimoto, Kozue Ogasawara, Akira Takashima, Toshiyuki Niki, Osamu Arasaki, Koichi Oshiro, Yutaka Mori, Masaharu Ishihara and Koichi Nobe : α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study., Cardiovascular Diabetology, Vol.16, No.1, 86, 2017.
(Summary)
Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables. This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG. Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700-1800 h), night-time (1800-0000 h), and bed-time (0000-0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment. In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients. Trial registration Unique Trial Number, UMIN000005874 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929 ).
Maimaituxun Gulinu, Michio Shimabukuro, Hotimah Masdan Salim, Minoru Tabata, Daisuke Yuji, Yoshihisa Morimoto, Takeshi Akasaka, Tomomi Matsuura, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Takaki Sugimoto, Masashi Tanaka, Shuichiro Takanashi and Masataka Sata : Gender-linked impact of epicardial adipose tissue volume in patients who underwent coronary artery bypass graft surgery or non-coronary valve surgery, PLoS ONE, Vol.12, No.6, e0177170, 2017.
(Summary)
Traditional and non-traditional risk factors for atherosclerotic cardiovascular disease (ASCVD) are different between men and women. Gender-linked impact of epicardial adipose tissue volume (EATV) in patients undergoing coronary artery bypass grafting (CABG) remains unknown. Gender-linked impact of EATV, abdominal fat distribution and other traditional ASCVD risk factors were compared in 172 patients (men: 115; women: 57) who underwent CABG or non-coronary valvular surgery (non-CABG). In men, EATV, EATV index (EATV/body surface area) and the markers of adiposity such as body mass index, waist circumference and visceral fat area were higher in the CABG group than in the non-CABG group. Traditional ASCVD risk factors were also prevalent in the CABG group. In women, EATV and EATV index were higher in the CABG group, but other adiposity markers were comparable between CABG and non-CABG groups. Multivariate logistic regression analysis showed that in men, CABG was determined by EATV Index and other ASCVD risk factors including hypertension, dyslipidemia, adiponectin, high sensitive C-reactive protein (hsCRP) and type 2 diabetes mellitus (Corrected R2 = 0.262, p < 0.0001), while in women, type 2 diabetes mellitus is a single strong predictor for CABG, excluding EATV Index (Corrected R2 = 0.266, p = 0.005). Our study found that multiple risk factors, including epicardial adipose tissue volume and traditional ASCVD factors are determinants for CABG in men, but type 2 diabetes mellitus was the sole determinant in women. Gender-specific disparities in risk factors of CABG prompt us to evaluate new diagnostic and treatment strategies and to seek underlying mechanisms.
S Bando, Takeshi Soeki, Tomomi Matsuura, Takeshi Tobiume, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Takashi Iwase, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro, Naoki Muguruma, Tetsuji Takayama, I Kishimoto, Kenji Kangawa and Masataka Sata : Plasma brain natriuretic peptide levels are elevated in patients with cancer, PLoS ONE, Vol.12, No.6, e0178607, 2017.
(Summary)
Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients.
Salim Masdan Hotimah, Daiju Fukuda, Yasutomi Higashikuni, Kimie Tanaka, Yoichiro Hirata, Shusuke Yagi, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Teneligliptin, a dipeptidyl peptidase-4 inhibitor, attenuated pro-inflammatory phenotype of perivascular adipose tissue and inhibited atherogenesis in normoglycemic apolipoprotein-E-deficient mice., Vascular Pharmacology, Vol.96-98, No.16, 19-25, 2017.
(Summary)
Dipeptidyl peptidase-4 (DPP-4) inhibitors have various cellular effects that are associated with vascular protection. Here, we examined whether teneligliptin alters the pro-inflammatory phenotype of perivascular adipose tissue (PVAT) and inhibits atherogenesis. Teneligliptin (60mg/kg/day) was administered orally to apolipoprotein-E-deficient (ApoE(-/-)) mice for 20weeks. Teneligliptin significantly inhibited the development of atherosclerosis in the aortic arch compared with vehicle (P<0.05), without alteration of blood glucose level or blood pressure. Histological analyses demonstrated that teneligliptin decreased lipid deposition and MCP-1 expression (P<0.05, respectively), and tended to decrease macrophage accumulation in atherosclerotic plaques. The results of quantitative RT-PCR analysis demonstrated that teneligliptin reduced the expression of inflammatory molecules such as TNF- and MCP-1 in the abdominal aorta. Furthermore, teneligliptin reduced the expression of a macrophage marker and Nox-4, a major NADPH oxidase subunit in adipocytes, in PVAT around the aortic arch. Administration of teneligliptin for 8weeks ameliorated endothelium-dependent vasodilation and reduced oxidative stress as determined by urinary 8-OHdG excretion (P<0.05) compared with vehicle. In vitro experiments demonstrated that exendin-4 (Ex-4), a GLP-1 analog, decreased the expression of inflammatory molecules in RAW264.7 cells. Also, Ex-4 decreased Nox4 expression in 3T3-L1 adipocytes. Teneligliptin inhibited atherogenesis with attenuation of the inflammatory phenotype in PVAT. A GLP-1 analog suppressed pro-inflammatory activation of macrophages and adipocytes. Suppression of the pro-inflammatory phenotype of PVAT might contribute, at least partially, to the cardioprotective effects of teneligliptin.
Hirotsugu Yamada, Atsushi Tanaka, Kenya Kusunose, Rie Amano, Munehide Matsuhisa, Hiroyuki Daida, Masaaki Ito, Hiroyuki Tsutsui, Mamoru Nanasato, Haruo Kamiya, K Yasuko Bando, Masato Odawara, Hisako Yoshida, Toyoaki Murohara, Masataka Sata and Koichi Node : Effect of sitagliptin on the echocardiographic parameters of left ventricular diastolic function in patients with type 2 diabetes: a subgroup analysis of the PROLOGUE study., Cardiovascular Diabetology, Vol.16, No.1, 63, 2017.
(Summary)
Diabetes is associated closely with an increased risk of cardiovascular events, including diastolic dysfunction and heart failure that leads to a shortening of life expectancy. It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function. However, the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern. We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub-analysis of the PROLOGUE study.
Yutaka Nakaya, Daiju Fukuda, Takashi Oyamada, Kazuo Ogawa, Nagakatsu Harada, Hironori Nakagami, Ryuichi Morishita, Masataka Sata and Hiroshi Sakaue : A novel lipoprotein (a) lowering drug, D-47, decreases neointima thickening after vascular injury., The Journal of Medical Investigation : JMI, Vol.64, No.1, 2, 64-67, 2017.
(Summary)
Although Lp(a) have been thought to be a cardiovascular risk factor, it is unclear whether lowering Lp(a) levels reduces the risk of cardiovascular diseases. No pharmacological agents which selectively reduce serum Lp(a) levels, and Lp(a) is present in primate but absent in common laboratory animals such as mice and pigs. In the present study we used transgenic mice of human Lp(a) and tested effect a novel Lp(a) lowering drug D-47 on neointima formation after vascular injury. D-47 successfully decreased plasma levels of Lp(a) and possibly inhibited neointima formation in Lp(a) transgenic mice. The results indicate that we can modulate plasma Lp(a) levels by pharmacologic agents and inhibit atherogenic properties of Lp(a) by reducing plasma levels of Lp(a). J. Med. Invest. 64: 64-67, February, 2017.
(Keyword)
lipoprotein a / atherosclerosis / cardiovascular events / low density lipoprotein
Kenya Kusunose, Yuta Torii, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata, Hiromitsu Seno, Yoshihito Saijo, Takayuki Ise, Koji Yamaguchi, Takeshi Tobiume, Shusuke Yagi, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Clinical Utility of Longitudinal Strain to Predict Functional Recovery in Patients With Tachyarrhythmia and Reduced LVEF., JACC. Cardiovascular Imaging, Vol.10, No.2, 118-126, 2017.
(Summary)
Objectives: The aim of this study was to assess the time course of presumptive TIC and the predictors of LV functional recovery in such patients.Background: Tachycardia-induced cardiomyopathy (TIC) is a potentially reversible cardiomyopathy with effective treatment of the tachyarrhythmia. However, cases without improvement of left ventricular (LV) systolic function were found occasionally. The diagnosis of TIC can be challenging, and the role of echocardiographic imaging in the prediction of LV functional recovery is limited.Methods: LV segmental longitudinal strains (LS) were evaluated by 2-dimensional speckle tracking in 71 consecutive patients (65±16 years; 61% men) with tachyarrhythmia and reduced LV ejection fraction (EF) without any other known cardiovascular disease, and 30 age and gender matched control subjects. Relative apical LS ratio (RALSR) was defined using the equation: average apical LS / (average basal LS + average mid LS) as a marker of strain distribution.Results: Compared to control subjects, patients with tachyarrhythmia had significantly lower global LS. Improvement in LVEF within 6 months after treatment of index arrhythmia was observed in 41 patients, and LVEF did not improve in 30 patients. In univariate analysis, lower LVEF at baseline (hazard ratio: HR: 0.59 per 1SD, p=0.04) and higher RALSR (HR: 11.2 per 1SD, p <0.001) were associated with no recovery in LVEF during follow-up. In a multivariate logistic regression model, the significant predictor of LV systolic functional recovery was RALSR (HR: 22.9 per 1SD, p=0.001). A RALSR of 0.61 was sensitive (71%) and specific (90%) in differentiating LV systolic functional recovery (area under the curve: 0.88).Conclusions: The RALSR was associated with LV systolic functional recovery. This information might be useful for clinical evaluation and follow-up in patients with reduced LVEF.
鳥居 裕太, 西尾 進, 松本 力三, 平田 有紀奈, 天野 里江, 山尾 雅美, Kenya Kusunose, Hirotsugu Yamada and Masataka Sata : 超音波検査が診断に有用であった右5指動静脈奇形の1例, Japanese Journal of Medical Ultrasound Technology, Vol.42, No.6, 726, 2017.
202.
Masataka Sata : 巻頭総説 冠動脈硬化における心外膜脂肪の役割 血管, 日本心脈管作動物質学会, Vol.40, No.4, 2017.
203.
K Sai, K Kajinami, H Akao, M Iwadare, R Sato-Ishida, Y Kawai, K Takeda, T Tanimoto, T Yamano, T Akasaka, T Ishida, K Hirata, K Saku, Shusuke Yagi, Takeshi Soeki, Masataka Sata, M Ueno, S Miyazaki, A Shiraki, J Oyama, K Node, K Sugamura, H Ogawa, K Kurose, K Maekawa, Y Matsuzawa, T Imatoh, R Hasegawa, Consortium Pharmacogenomics Data Science Japanese and Y Saito : A possible role for HLA-DRB1*04:06 in statin-related myopathy in Japanese patients., Drug Metabolism and Pharmacokinetics, Vol.31, No.6, 467-470, 2016.
Hirofumi Tomiyama, Takashi Miwa, Kenshi Kan, Munehide Matsuhisa, Haruo Kamiya, Mamoru Nanasato, Tomoki Kitano, Hiroaki Sano, Jun Ohno, Masato Iida, Masataka Sata, Hirotsugu Yamada, Koji Maemura, Atsushi Tanaka, Toyoaki Murohara and Koichi Node : Impact of glycemic control with sitagliptin on the 2-year progression of arterial stiffness: a sub-analysis of the PROLOGUE study., Cardiovascular Diabetology, Vol.15, No.1, 150, 2016.
(Summary)
No conclusive evidence has been obtained yet on the significance of the effects of dipeptidyl peptidase-4 (DPP-4 inhibitor) treatment on the arterial stiffness in clinical settings. In addition, the effects of good glycemic control on the arterial stiffness have also not been clarified yet. As a sub-analysis of the PROLOGUE study, we examined the effect of a DPP-4 inhibitor (sitagliptin) on the 2-year progression of the arterial stiffness and also to determine the effect of good glycemic control on the rate of progression of the arterial stiffness. In the PROLOGUE study, the study participants were either allocated to add-on sitagliptin treatment or to continued treatment with conventional anti-diabetic agents. Among the 463 participants of the PROLOGUE study, we succeeded in measuring the brachial-ankle pulse wave velocity (baPWV) at least two times during the 2-year study period in 96 subjects. The changes in the baPWV during the study period were similar between the both groups (i.e., with/without staglipitin), overall. On the other hand, when the study subjects were divided into two groups according to the glycemic control status during the study period {good glycemic control group (GC) = hemoglobin (Hb)A1c <7.0 at both 12 and 24 months after the treatment randomization; poor glycemic control group (PC) = HbA1c ≥7.0 at either 12 months, 24 months, or both}, the 2-year increase of the baPWV was marginally significantly larger in the PC group (144 ± 235 cm/s) as compared to that the GC group (-10 ± 282 cm/s) (p = 0.036). While the present study could not confirm the beneficial effect of sitagliptin per se on the arterial stiffness, the results suggested that good glycemic control appears to be beneficial for delaying the annual progression of the arterial stiffness. Trial registration University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.
HM Salim, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse., Frontiers in Cardiovascular Medicine, Vol.3, 43, 2016.
(Summary)
BACKGROUND: Endothelial dysfunction caused by increased oxidative stress is a critical initiator of macro- and micro-vascular disease development in diabetic patients. Ipragliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, offers a novel approach for the treatment of diabetes by enhancing urinary glucose excretion. The aim of this study was to examine whether ipragliflozin attenuates endothelial dysfunction in diabetic mice.METHODS: Eight-week-old male C57BL/6 mice were treated with streptozotocin (150mg/kg) by a single intraperitoneal injection to induce diabetes mellitus. At 3days of injection, ipragliflozin (3mg/kg/day) was administered via gavage for 3weeks. Vascular function was assessed by isometric tension recording. Human umbilical vein endothelial cells (HUVEC) were used for in vitro experiments. RNA and protein expression were examined by quantitative RT-PCR (qPCR) and western blot, respectively. Oxidative stress was determined by measuring urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) level.RESULTS: Ipragliflozin administration significantly reduced blood glucose level (P<0.001) and attenuated the impairment of endothelial function in diabetic mice, as determined by acetylcholine-dependent vasodilation (P<0.001). Ipragliflozin did not alter metabolic parameters, such as body weight and food intake. Ipragliflozin administration ameliorated impaired phosphorylation of Akt and eNOSSer1177 in the abdominal aorta and reduced reactive oxygen species generation as determined by urinary excretion of 8-OHdG in diabetic mice. Furthermore, qPCR analyses demonstrated that ipragliflozin decreased the expression of inflammatory molecules [e.g., monocyte chemoattractant protein-1 (MCP-1) vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule (ICAM)-1] in the abdominal aorta (P<0.05). In in vitro studies, incubation with methylglyoxal, one of the advanced glycation end products, significantly impaired phosphorylation of Akt and eNOSSer1177 (P<0.01) and increased the expression of MCP-1, VCAM-1, and ICAM-1 in HUVEC.CONCLUSION: Ipragliflozin improved hyperglycemia and prevented the development of endothelial dysfunction under a hyperglycemic state, at least partially by attenuation of oxidative stress.
A Takashima, Shusuke Yagi, Koji Yamaguchi, S Watanabe, N Yamamoto, H Ito, M Kadota, T Hara, H Yamazaki, Takayuki Ise, Kenya Kusunose, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Purulent pericarditis accompanying pericardial abscess induced by nocardia in an immunocompromised patient., Circulation Journal, Vol.80, No.11, 2409-2411, 2016.
A Takashima, Daiju Fukuda, K Tanaka, Y Higashikuni, Y Hirata, S Nishimoto, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Yutaka Taketani, Michio Shimabukuro and Masataka Sata : Combination of n-3 polyunsaturated fatty acids reduces atherogenesis in apolipoprotein E-deficient mice by inhibiting macrophage activation., Atherosclerosis, Vol.254, 142-150, 2016.
(Summary)
BACKGROUND AND AIMS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are major components of n-3 polyunsaturated fatty acids (n-3 PUFAs) which inhibit atherogenesis, although few studies have examined the effects of the combination of EPA and DHA on atherogenesis. The aim of this study was to investigate whether DHA has additional anti-atherosclerotic effects when combined with EPA.METHODS: Male 8-week-old apolipoprotein E-deficient (Apoe-/-) mice were fed a western-type diet supplemented with different amounts of EPA and DHA; EPA (2.5%, w/w), low-dose EPA + DHA (2.5%, w/w), or high-dose EPA + DHA (5%, w/w) for 20 weeks. The control group was fed a western-type diet containing no n-3 PUFA. Histological and gene expression analysis were performed in atherosclerotic lesions in the aorta. To address the mechanisms, RAW264.7 cells were used.RESULTS: All n-3 PUFA treatments significantly attenuated the development and destabilization of atherosclerotic plaques compared with the control. The anti-atherosclerotic effects were enhanced in the high-dose EPA + DHA group (p < 0.001), whereas the pure EPA group and low-dose EPA + DHA group showed similar results. EPA and DHA additively attenuated the expression of inflammatory molecules in RAW264.7 cells stimulated with LPS. DHA or EPA + DHA suppressed LPS-induced toll-like receptor 4 (TLR4) expression in lipid rafts on RAW264.7 cells (p < 0.05). Lipid raft disruption by methyl--cyclodextrin suppressed mRNA expression of inflammatory molecules in LPS-stimulated macrophages.CONCLUSION: n-3 PUFAs suppressed atherogenesis. DHA combined with EPA had additional anti-inflammatory effects and inhibited atherogenesis in Apoe-/- mice. The reduction of TLR4 expression in lipid rafts in macrophages by DHA might be involved in this mechanism, at least partially.
鳥居 裕太, 西尾 進, 玉井 佑里恵, 山崎 宙, Shoichiro Takao, Kenya Kusunose, Koji Yamaguchi, Tetsuzo Wakatsuki, Hirotsugu Yamada and Masataka Sata : 解剖学的異常を認めない膝窩動脈捕捉症候群の1例, Japanese Journal of Medical Ultrasound Technology, Vol.41, No.5, 513-520, 2016.
Zhi-Hong Yang, Masahiro Bando, Toshihiro Sakurai, Ye Chen, Beatrice Emma-Okon, Bree Wilhite, Daiju Fukuda, Boris Vaisman, Milton Pryor, Yoshiyuki Wakabayashi, Maureen Sampson, Zu-Xi Yu, Akiko Sakurai, Abdalrahman Zarzour, Hiroko Miyahara, Jiro Takeo, Hiroshi Sakaue, Masataka Sata and Alan T. Remaley : Long-chain monounsaturated fatty acid-rich fish oil attenuates the development of atherosclerosis in mouse models., Molecular Nutrition & Food Research, Vol.60, No.10, 2208-2218, 2016.
(Summary)
SCOPE: Fish oil-derived long-chain monounsaturated fatty acids (LCMUFA) containing chain lengths longer than 18 were previously shown to improve cardiovascular disease risk factors in mice. However, it is not known if LCMUFA also exerts anti-atherogenic effects. The main objective of the present study was to investigate the effect of LCMUFA on the development of atherosclerosis in mouse models.METHODS AND RESULTS: LDLR-KO mice were fed Western diet supplemented with 2% (w/w) of either LCMUFA concentrate, olive oil, or not (control) for 12 wk. LCMUFA, but not olive oil, significantly suppressed the development of atherosclerotic lesions and several plasma inflammatory cytokine levels, although there were no major differences in plasma lipids between the three groups. At higher doses 5% (w/w) LCMUFA supplementation was observed to reduce pro-atherogenic plasma lipoproteins and to also reduce atherosclerosis in ApoE-KO mice fed a Western diet. RNA sequencing and subsequent qPCR analyses revealed that LCMUFA upregulated PPAR signaling pathways in liver. In cell culture studies, apoB-depleted plasma from LDLR-K mice fed LCMUFA showed greater cholesterol efflux from macrophage-like THP-1 cells and ABCA1-overexpressing BHK cells.CONCLUSION: Our research showed for the first time that LCMUFA consumption protects against diet-induced atherosclerosis, possibly by upregulating the PPAR signaling pathway.
Tatsuya Maruhashi, Yukihito Higashi, Yasuki Kihara, Hirotsugu Yamada, Masataka Sata, Shinichiro Ueda, Masato Odawara, Yasuo Terauchi, Kazuoki Dai, Jun Ohno, Masato Iida, Hiroaki Sano, Hirofumi Tomiyama, Teruo Inoue, Atsushi Tanaka, Toyoaki Murohara and Koichi Node : Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study., Cardiovascular Diabetology, Vol.15, No.1, 134, 2016.
(Summary)
As a sub-analysis of the PROLOGUE study, we evaluated the long-term effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on endothelial function in the conduit brachial artery in patients with type 2 diabetes. In the PROLOGUE study, patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) or continued conventional antihyperglycemic treatment (conventional group). Among the 463 participants in the PROLOGUE study, FMD was measured in 17 patients in the sitagliptin group and 18 patients in the conventional group at the beginning and after 12 and 24 months of treatment. HbA1c levels were significantly decreased after 12 and 24 months of treatment compared to baseline values in both groups (7.0 0.4 vs. 6.6 0.3 and 6.6 0.4 % in the sitagliptin group; 7.0 0.6 vs. 6.6 0.7 and 6.6 0.7 % in the conventional group; P < 0.05, respectively). There was no significant difference between FMD values at baseline and after 12 and 24 months in the sitagliptin group (4.3 2.6 vs. 4.4 2.1 and 4.4 2.3 %, P = 1.0, respectively). Although FMD had a tendency to increase from 4.3 2.4 % at baseline to 5.2 1.9 % after 12 months and 5.1 2.2 % after 24 months in the conventional group, there was no significant difference between FMD values at baseline and after 12 and 24 months (P = 0.36 and 0.33, respectively). Add-on sitagliptin to conventional antihyperglycemic drugs in patients with type 2 diabetes did not alter endothelial function in the conduit brachial artery measured by FMD during a 2-year study period. Sitagliptin may be used without concern for an adverse effect on endothelial function in patients with type 2 diabetes. University hospital Medical Information Network (UMIN) Center: ID UMIN000004490.
(Keyword)
Aged / Biomarkers / Blood Glucose / Brachial Artery / Diabetes Mellitus, Type 2 / Dipeptidyl-Peptidase IV Inhibitors / Drug Therapy, Combination / Endothelium, Vascular / Female / Glycated Hemoglobin A / Humans / Japan / Male / Middle Aged / Prospective Studies / Sitagliptin Phosphate / Time Factors / Treatment Outcome / Vasodilation
A Tanaka, T Murohara, I Taguchi, K Eguchi, M Suzuki, M Kitakaze, Y Sato, T Ishizu, Y Higashi, Hirotsugu Yamada, M Nanasato, Michio Shimabukuro, H Teragawa, S Ueda, S Kodera, Munehide Matsuhisa, T Kadokami, K Kario, Y Nishio, T Inoue, K Maemura, J Oyama, M Ohishi, Masataka Sata, H Tomiyama, K Node and Investigators Study PROTECT : Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study., Cardiovascular Diabetology, Vol.15, No.1, 133, 2016.
(Summary)
BACKGROUND: Type 2 diabetes mellitus is associated strongly with an increased risk of micro- and macro-vascular complications, leading to impaired quality of life and shortened life expectancy. In addition to appropriate glycemic control, multi-factorial intervention for a wide range of risk factors, such as hypertension and dyslipidemia, is crucial for management of diabetes. A recent cardiovascular outcome trial in diabetes patients with higher cardiovascular risk demonstrated that a SGLT2 inhibitor markedly reduced mortality, but not macro-vascular events. However, to date there is no clinical evidence regarding the therapeutic effects of SGLT2 inhibitors on arteriosclerosis. The ongoing PROTECT trial was designed to assess whether the SGLT2 inhibitors, ipragliflozin, prevented progression of carotid intima-media thickness in Japanese patients with type 2 diabetes mellitus.METHODS: A total of 480 participants with type 2 diabetes mellitus with a HbA1c between 6 and 10 % despite receiving diet/exercise therapy and/or standard anti-diabetic agents for at least 3 months, will be randomized systematically (1:1) into either ipragliflozin or control (continuation of conventional therapy) groups. After randomization, ipragliflozin (50-100 mg once daily) will be added on to the background therapy in participants assigned to the ipragliflozin group. The primary endpoint of the study is the change in mean intima-media thickness of the common carotid artery from baseline to 24 months. Images of carotid intima-media thickness will be analyzed at a central core laboratory in a blinded manner. The key secondary endpoints include the change from baseline in other parameters of carotid intima-media thickness, various metabolic parameters, and renal function. Other cardiovascular functional tests are also planned for several sub-studies.DISCUSSION: The PROTECT study is the first to assess the preventive effect of ipragliflozin on progression of carotid atherosclerosis using carotid intima-media thickness as a surrogate marker. The study has potential to clarify the protective effects of ipragliflozin on atherosclerosis. Trial registration Unique Trial Number, UMIN000018440 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021348 ).
(Keyword)
Adult / Aged / Biomarkers / Carotid Artery Diseases / Carotid Artery, Common / Carotid Intima-Media Thickness / Clinical Protocols / Diabetes Mellitus, Type 2 / Diabetic Angiopathies / Drug Therapy, Combination / Female / Glucosides / Hemoglobin A, Glycosylated / Humans / Hypoglycemic Agents / Japan / Male / Middle Aged / Prospective Studies / Research Design / Sodium-Glucose Transporter 2 / Thiophenes / Time Factors / Treatment Outcome / Young Adult
T Ueda, Y Nakata, N Yamasaki, H Oda, K Sentani, A Kanai, N Onishi, K Ikeda, Y Sera, Z Honda, K Tanaka, Masataka Sata, S Ogawa, W Yasui, H Saya, J Takita and H Honda : ALKR1275Q perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN., Oncogene, Vol.35, No.34, 4447-4458, 2016.
(Summary)
Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK(R1275Q), an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK(R1275Q) knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK(R1275Q) globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK(R1275Q)/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK(R1275Q)-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK(R1275Q)/MYCN mice. These results collectively indicate that ALK(R1275Q) confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK(R1275Q)/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK(R1275Q)-positive tumors.
M Kadota, Takayuki Ise, Shusuke Yagi, Takashi Iwase, Masashi Akaike, R Ueno, Y Kawabata, T Hara, K Ogasawara, Mika Bando, S Bando, Tomomi Matsuura, Koji Yamaguchi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki and Masataka Sata : Response prediction and influence of tolvaptan in chronic heart failure patients considering the interaction of the renin-angiotensin-aldosterone system and arginine vasopressin., International Heart Journal, Vol.57, No.4, 461-465, 2016.
(Summary)
The renin-angiotensin-aldosterone system (RAAS) and arginine vasopressin (AVP) regulate body fluids. Although conventional diuretics have been used for treating heart failure, they activate RAAS and exacerbate renal function. Tolvaptan, a newly developed vasopressin-2 receptor antagonist, elicits aquaresis and improves volume overload in heart failure patients, however, the predictors of tolvaptan effectiveness and the influence on the RAAS and renal function according to tolvaptan therapy are not established. We evaluated 26 chronic heart failure patients receiving therapy with 15 mg/day tolvaptan and examined their laboratory and urinary data before and after tolvaptan therapy. A response to tolvaptan was defined as a body weight decrease by more than 2 kg in a week and a urine volume increase by 500 mL/ day compared with that before tolvaptan administration. Body weight, urine volume, and brain natriuretic peptide levels significantly improved (P < 0.05), without any worsening of renal function represented by serum creatinine, sodium, and potassium. Moreover, no significant changes were observed in the plasma renin activity and plasma aldosterone concentration (PAC). In the responder group, urine osmolality before tolvaptan administration was significantly higher (P < 0.05) but declined significantly after tolvaptan administration (P < 0.05). The AVP/PAC ratio before administration was positively correlated with the efficacy of tolvaptan. Tolvaptan treatment could prevent RAAS activation in chronic heart failure patients. Moreover, monitoring the AVP/PAC ratio may be useful in predicting the tolvaptan response.
(Keyword)
Adult / Aged / Aged, 80 and over / Antidiuretic Hormone Receptor Antagonists / Arginine Vasopressin / Benzazepines / Body Mass Index / Female / Heart Failure / Humans / Male / Middle Aged / Prospective Studies / Renin-Angiotensin System / Treatment Outcome
Michio Shimabukuro, H Sato, Hirofumi Izaki, Daiju Fukuda, E Uematsu, Y Hirata, Shusuke Yagi, Takeshi Soeki, Hiroshi Sakaue, Hiro-omi Kanayama, H Masuzaki and Masataka Sata : Depot- and gender-specific expression of NLRP3 inflammasome and toll-like receptors in adipose tissue of cancer patients., BioFactors, Vol.42, No.4, 397-406, 2016.
J Oyama, T Murohara, M Kitakaze, T Ishizu, Y Sato, K Kitagawa, H Kamiya, M Ajioka, M Ishiara, K Dai, M Nanasato, Masataka Sata, K Maemura, H Tomiyama, Y Higashi, K Kaku, Hirotsugu Yamada, Munehide Matsuhisa, K Yamashita, YK Bando, N Kashihara, S Ueda, T Inoue, K Node and Investigators Study PROLOGUE : The Effect of Sitagliptin on Carotid Artery Atherosclerosis in Type 2 Diabetes: The PROLOGUE Randomized Controlled Trial., PLoS Medicine, Vol.13, No.6, e1002051, 2016.
(Summary)
BACKGROUND: Experimental studies have suggested that dipeptidyl peptidase-4 (DPP-4) inhibitors provide cardiovascular protective effects. We performed a randomized study to evaluate the effects of sitagliptin added on to the conventional therapy compared with conventional therapy alone (diet, exercise, and/or drugs, except for incretin-related agents) on the intima-media thickness (IMT) of the carotid artery, a surrogate marker for the evaluation of atherosclerotic cardiovascular disease, in people with type 2 diabetes mellitus (T2DM).METHODS AND FINDINGS: We used a multicenter PROBE (prospective, randomized, open label, blinded endpoint) design. Individuals aged 30 y with T2DM (6.2% HbA1c < 9.4%) were randomly allocated to receive either sitagliptin (25 to 100 mg/d) or conventional therapy. Carotid ultrasound was performed at participating medical centers, and all parameters were measured in a core laboratory. Of the 463 enrolled participants with T2DM, 442 were included in the primary analysis (sitagliptin group, 222; conventional therapy group, 220). Estimated mean (± standard error) common carotid artery IMT at 24 mo of follow-up in the sitagliptin and conventional therapy groups was 0.827 ± 0.007 mm and 0.837 ± 0.007 mm, respectively, with a mean difference of -0.009 mm (97.2% CI -0.028 to 0.011, p = 0.309). HbA1c level at 24 mo was significantly lower with sitagliptin than with conventional therapy (6.56% ± 0.05% versus 6.72% ± 0.05%, p = 0.008; group mean difference -0.159, 95% CI -0.278 to -0.041). Episodes of serious hypoglycemia were recorded only in the conventional therapy group, and the rate of other adverse events was not different between the two groups. As it was not a placebo-controlled trial and carotid IMT was measured as a surrogate marker of atherosclerosis, there were some limitations of interpretation.CONCLUSIONS: In the PROLOGUE study, there was no evidence that treatment with sitagliptin had an additional effect on the progression of carotid IMT in participants with T2DM beyond that achieved with conventional treatment.TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry UMIN000004490.
Jun-Ichi Oyama, Atsushi Tanaka, Yasunori Sato, Hirofumi Tomiyama, Masataka Sata, Tomoko Ishizu, Isao Taguchi, Takanori Kuroyanagi, Hiroki Teragawa, Nobukazu Ishizaka, Yumiko Kanzaki, Mitsuru Ohishi, Kazuo Eguchi, Yukihito Higashi, Hirotsugu Yamada, Koji Maemura, Junya Ako, Yasuko K. Bando, Shinichiro Ueda, Teruo Inoue, Toyoaki Murohara and Koichi Node : Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat: the PRIZE study., Cardiovascular Diabetology, Vol.15, No.1, 87, 2016.
(Summary)
BACKGROUND: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia.METHODS: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness 1.1 mm will be randomized centrally to receive either febuxostat (10-60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, 65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, 8.0 mg/dL), and carotid intima-media thickness (<1.3, 1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging.CONCLUSIONS: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia. Trial Registration Unique trial Number, UMIN000012911 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000015081&language=E ).
Michio Shimabukuro, C Okawa, Hirotsugu Yamada, S Yanagi, E Uematsu, N Sugasawa, Hirotsugu Kurobe, Y Hirata, JR Kim-Kaneyama, XF Lei, S Takao, Y Tanaka, Daiju Fukuda, Shusuke Yagi, Takeshi Soeki, Tetsuya Kitagawa, H Masuzaki, M Sato and Masataka Sata : The pathophysiological role of oxidized cholesterols in epicardial fat accumulation and cardiac dysfunction: A study in swine fed a high caloric diet with an inhibitor of intestinal cholesterol absorption, ezetimibe., The Journal of Nutritional Biochemistry, Vol.35, 66-73, 2016.
(Summary)
Oxidized cholesterols (oxycholesterols) in food have been recognized as strong atherogenic components, but their tissue distributions and roles in cardiovascular diseases remain unclear. To investigate whether accumulation of oxycholesterols is linked to cardiac morphology and function, and whether reduction of oxycholesterols can improve cardiac performance, domestic male swine were randomized to a control diet (C), high caloric diet (HCD) or HCD+Ezetimibe, an inhibitor of intestinal cholesterol absorption, group (HCD+E) and evaluated for: (1) distribution of oxycholesterol components in serum and tissues, (2) levels of oxycholesterol-related enzymes, (3) paracardial and epicardial coronary fat thickness, and (4) cardiac performance. Ezetimibe treatment for 8weeks attenuated increases in oxycholesterols in the HCD group almost completely in liver, but reduced only levels of 4β-hydroxycholesterol in left ventricular (LV) myocardium. Ezetimibe treatment altered the expression of genes for cholesterol and fatty acid metabolism and decreased the expression of CYP3A46, which catabolizes cholesterol to 4β-hydroxycholesterol, strongly in liver. An increase in epicardial fat thickness and impaired cardiac performance in the HCD group were improved by ezetimibe treatment, and the improvement was closely related to the reduction in levels of 4β-hydroxycholesterol in LV myocardium. In conclusion, an increase in oxycholesterols in the HCD group was closely related to cardiac hypertrophy and dysfunction, as well as an increase in epicardial fat thickness. Ezetimibe may directly reduce oxycholesterol in liver and LV myocardium, and improve cardiac morphology and function.
Michio Shimabukuro, N Higa, H Masuzaki, Masataka Sata and S Ueda : Impact of individual metabolic risk components or its clustering on endothelial and smooth muscle cell function in men., Cardiovascular Diabetology, Vol.15, No.1, 77, 2016.
(Summary)
Impaired vasoreactivity is often observed in subjects with metabolic syndrome, a condition that includes the presence of a specific cluster of risk factors for obesity and cardiovascular disease. However, hierarchical causes in the impaired vasoreactivity have not been clarified. We evaluated the impact of individual metabolic risk components or its clustering under the condition of insulin resistance on endothelial and smooth muscle cell function. Vascular reactivity to acetylcholine (Ach), with or without nitric oxide synthase (NOS) inhibitor N (G)-monomethyl-L-arginine (L-NMMA), or sodium nitroprusside (SNP) by forearm venous occlusion plethysmography and insulin sensitivity index (M mg/kg/min) in euglycemic clamp were measured in men without (n = 18, control group) or with (n = 19, metabolic syndrome group) metabolic syndrome. (1) Ach-induced maximal forearm blood flow (maxFBF) was impaired in subjects with metabolic syndrome. In particular, the NOS-dependent component of Ach-induced maxFBF was selectively decreased, while the NOS-independent component remained relatively unchanged. (2) Ach-induced maxFBF and ∆Ach-induced maxFBF with L-NMMA were correlated with waist circumference, glucose, and triglycerides, and most strongly correlated with visceral fat area, adiponectin, and M. (3) Multivariate regression analysis indicated that individual metabolic risk components explained Ach-induced maxFBF by 4-21 %. Clustering of all metabolic risk components increased this to 35 %, and the presence of metabolic syndrome explained 30 %, indicating that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction. Endothelial dysfunction was correlated with individual metabolic risk components, but more strongly with clustering of the components under a condition with low insulin sensitivity. We suggest that in subjects with metabolic syndrome, endothelial function is impaired by multiple cardiovascular risk factors exclusively when under the condition of insulin insensitivity and also that defining metabolic syndrome can effectively predict impairment of endothelial dysfunction.
A Tanaka, T Inoue, M Kitakaze, J Oyama, Masataka Sata, I Taguchi, W Shimizu, H Watada, J Ako, Y Sakata, T Anzai, M Uematsu, M Suzuki, K Eguchi, A Yamashina, Y Saito, Y Sato, S Ueda, T Murohara and K Node : Rationale and design of a randomized trial to test the safety and non-inferiority of canagliflozin in patients with diabetes with chronic heart failure: the CANDLE trial., Cardiovascular Diabetology, Vol.15, No.1, 57, 2016.
(Summary)
Because type 2 diabetes mellitus is associated strongly with an increased risk of cardiovascular diseases, the number of patients with diabetes with chronic heart failure is increasing steadily. However, clinical evidence of therapeutic strategies in such patients is still lacking. A recent randomized, placebo-controlled trial in patients with type 2 diabetes with high cardiovascular risk demonstrated that the SGLT2 inhibitor, empagliflozin, reduced the incidence of hospitalization for heart failure. Because SGLT2 inhibitors cause a reduction in body weight and blood pressure in addition to improving glycemic control, they have the potential to exert beneficial effects on the clinical pathophysiology of heart failure. The aim of the ongoing CANDLE trial is to test the safety and non-inferiority of canagliflozin, another SGLT2 inhibitor, compared with glimepiride, a sulfonylurea agent, in patients with type 2 diabetes mellitus and chronic heart failure. A total of 250 patients with type 2 diabetes who are drug-naïve or taking any anti-diabetic agents and suffering from chronic heart failure with a New York Heart Association classification I to III will be randomized centrally into either canagliflozin or glimepiride groups (1: 1) using the dynamic allocation method stratified by age (<65, ≥65 year), HbA1c level (<6.5, ≥6.5 %), and left ventricular ejection fraction (<40, ≥40 %). After randomization, all the participants will be given the add-on study drug for 24 weeks in addition to their background therapy. The primary endpoint is the percentage change from baseline in NT-proBNP after 24 weeks of treatment. The key secondary endpoints after 24 weeks of treatment are the change from baseline in glycemic control, blood pressure, body weight, lipid profile, quality of life score related to heart failure, and cardiac and renal function. The CANDLE trial is the first to assess the safety and non-inferiority of canagliflozin in comparison with glimepiride in patients with type 2 diabetes with chronic heart failure. This trial has the potential to evaluate the clinical safety and efficacy of canagliflozin on heart failure. Trial registration Unique trial Number, UMIN000017669.
(Keyword)
Adult / Aged / Aged, 80 and over / Benzhydryl Compounds / Blood Glucose / Blood Pressure / Canagliflozin / Chronic Disease / Diabetes Mellitus, Type 2 / Female / Glucosides / Heart Failure / Humans / Hypoglycemic Agents / Male / Metformin / Middle Aged / Quality of Life / Sulfonylurea Compounds
HM Salim, Daiju Fukuda, Y Higashikuni, K Tanaka, Y Hirata, Shusuke Yagi, Takeshi Soeki, Michio Shimabukuro and Masataka Sata : Dipeptidyl peptidase-4 inhibitor, linagliptin, ameliorates endothelial dysfunction and atherogenesis in normoglycemic apolipoprotein-E deficient mice., Vascular Pharmacology, Vol.79, 16-23, 2016.
(Summary)
Background; The dipeptidyl peptidase-4 (DPP-4) inhibitors have vasoprotective effects. This study investigated whether a recently approved DPP-4 inhibitor, linagliptin (Lina), suppresses atherogenesis in non-diabetic apolipoprotein-E deficient (ApoE-/-) mice and examined its effects on endothelial function. Methods and Results; Lina (10 mg/kg/day) was administered orally to ApoE-/- mice for 20 weeks. Lina reduced atherogenesis without the alteration of metabolic parameters including blood glucose level compared with the control (P<0.05). Results of immunohistochemistry and quantitative RT-PCR demonstrated that Lina significantly decreased inflammatory molecule expression and macrophage infiltration in atherosclerotic aorta. Lina administration to ApoE-/- mice for 9 weeks ameliorated endothelium-dependent vasodilation compared with non-treated mice. Plasma active glucagon-like peptide-1 (GLP-1) level was significantly higher in the treated group (P<0.05). Exendin-4 (Ex-4), a GLP-1 analogue, ameliorated endothelium-dependent vasodilation impaired by palmitic acid (PA) in wild-type mouse aortic segments. Ex-4 promoted phosphorylation of eNOSSer1177 and Akt which are abrogated by PA in human umbilical vein endothelial cells. In addition, Lina administration to ApoE-/- mice decreased oxidative stress as determined by urinary 8-OHdG secretion and NADPH oxidase subunit expression in the abdominal aorta.Conclusion; Lina inhibited atherogenesis in non-diabetic ApoE-/- mice. Amelioration of endothelial dysfunction associated with the reduction of oxidative stress by GLP-1 contributes to the atheroprotective effects of Lina.
Sachiko Nishimoto, Daiju Fukuda, Yasutomi Higashikuni, Kimie Tanaka, Yoichiro Hirata, Chie Murata, Joo-Ri Kim-Kaneyama, Fukiko Sato, Masahiro Bando, Shusuke Yagi, Takeshi Soeki, Tetsuya Hayashi, Issei Imoto, Hiroshi Sakaue, Michio Shimabukuro and Masataka Sata : Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance., Science Advances, Vol.2, No.3, e1501332, 2016.
(Summary)
Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.
Kenya Kusunose, M Sato, Hirotsugu Yamada, Y Saijo, Mika Bando, Y Hirata, S Nishio, S Hayashi and Masataka Sata : Prognostic implications of non-invasive vascular function tests in high-risk atherosclerosis patients., Circulation Journal, Vol.80, No.4, 1034-1040, 2016.
(Summary)
BACKGROUND: The aim of this study was to assess the role of clinically available vascular function tests as predictors of cardiovascular events and decline in kidney function.MethodsandResults:One hundred and fourteen patients who had at least 2 cardiovascular risk factors were recruited for vascular function assessment including ankle-brachial blood pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), cardio-ankle vascular index (CAVI) and flow-mediated vasodilatation (%FMD). During a median period of 51 months, 35 patients reached the primary endpoint (29 cardiovascular events and 6 cardiac deaths), and 30 patients reached the secondary endpoint (decline in kidney function: defined as a 5% per year decline of estimated glomerular filtration rate). In sequential Cox models, a model on the basis of the Framingham risk score, hemoglobin, and high-sensitivity C-reactive protein (chi-squared, 16.6) was improved by the ABI (chi-squared: 21.5; P=0.047). The baPWV (hazard ratio: 1.42 per 1 SD increase; P=0.025) and the CAVI (hazard ratio: 1.52 per 1 SD increase; P=0.040) were associated with the secondary endpoint. The %FMD was only slightly associated with the primary and secondary endpoints.CONCLUSIONS: Both ABI and baPWV are significantly associated with future cardiovascular events in high-risk patients with cardiovascular disease. The predictive capabilities of these parameters are greater than that of other parameters in this cohort.
(Keyword)
Cardiovascular event / Endothelial function / Kidney function / Vascular function
Takeshi Soeki and Masataka Sata : Inflammatory biomarkers and atherosclerosis., International Heart Journal, Vol.57, No.2, 134-139, 2016.
(Summary)
Atherosclerosis has been regarded as a form of chronic vascular inflammation. Numerous biomarkers associated with inflammation have been identified as novel targets to monitor atherosclerosis and cardiovascular risk. C-reactive protein (CRP) is one of the most actively studied and established inflammatory biomarkers for cardiovascular events. However, CRP response is triggered by many disorders unrelated to cardiovascular disease, which interferes with the clinical application. This review describes established and traditional inflammatory biomarkers including CRP as well as novel inflammatory biomarkers reflective of local atherosclerotic inflammation. In addition, we focus on the potential usefulness of inflammatory biomarkers in developing anti-atherosclerotic therapeutic approaches.
Takeshi Soeki, Tomomi Matsuura, Sachiko Bando, Takeshi Tobiume, Etsuko Uematsu, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro and Masataka Sata : Relationship between local production of microRNA-328 and atrial substrate remodeling in atrial fibrillation., Journal of Cardiology, Vol.68, No.6, 472-477, 2016.
(Summary)
BACKGROUND: The underlying mechanism of atrial substrate remodeling in atrial fibrillation (AF) remains unknown. In this study, we investigated whether local and systemic levels of microRNA (miR) might be associated with the presence of AF and with left atrial (LA) substrate properties.METHODS: Blood from the periphery, pulmonary vein (PV), and left atrial appendage (LAA) was sampled from 30 patients with AF undergoing PV isolation, and from 10 control subjects with Wolff-Parkinson-White syndrome and without AF. We measured peripheral, PV, and LAA plasma levels of miR-1, -26, -133a, -328, and -590 by reverse transcription-polymerase chain reaction. LA global contact mapping during sinus rhythm was performed before PV isolation.RESULTS: Plasma levels of miR-328 were higher in patients with AF than in control subjects. Plasma miR-328 levels were significantly higher in the LAA than in the periphery and PV in patients with AF, but not in control subjects. Plasma miR-1 levels were also higher in the LAA than in the PV in AF patients. Interestingly, LAA plasma levels of miR-328 showed a positive correlation with the LA voltage zone index (area with voltage <0.5mV divided by total LA surface area) and a weak correlation with LA volume.CONCLUSION: Local production of miR-328 in the left atrium may be involved in the process of atrial remodeling in patients with AF.
Yuta Torii, Hirotsugu Yamada, Susumu Matsukuma, Susumu Nishio, Kenya Kusunose, Miho Abe and Masataka Sata : Left Ventricular lipomatous hamartoma mimicking a calcified amorphous tumor., Circulation, Vol.133, No.8, e408-e410, 2016.
Yoshihiro Hayakawa, Manabu Kawada, Hiroyoshi Nishikawa, Takahiro Ochiya, Hideyuki Saya, Hiroyuki Seimiya, Ryoji Yao, Masahiro Hayashi, Chieko Kai, Akira Matsuda, Tomoki Naoe, Atsushi Ohtsu, Taku Okazaki, Hideo Saji, Masataka Sata, Haruhiko Sugimura, Yuichi Sugiyama, Masakazu Toi and Tatsuro Irimura : Report on the use of non-clinical studies in the regulatory evaluation of oncology drugs., Cancer Science, Vol.107, No.2, 189-202, 2016.
(Summary)
Non-clinical studies are necessary at each stage of the development of oncology drugs. Many experimental cancer models have been developed to investigate carcinogenesis, cancer progression, metastasis, and other aspects in cancer biology and these models turned out to be useful in the efficacy evaluation and the safety prediction of oncology drugs. While the diversity and the degree of engagement in genetic changes in the initiation of cancer cell growth and progression are widely accepted, it has become increasingly clear that the roles of host cells, tissue microenvironment, and the immune system also play important roles in cancer. Therefore, the methods used to develop oncology drugs should continuously be revised based on the advances in our understanding of cancer. In this review, we extensively summarize the effective use of those models, their advantages and disadvantages, ranges to be evaluated and limitations of the models currently used for the development and for the evaluation of oncology drugs.
(Keyword)
Animals / Antineoplastic Agents / Disease Models, Animal / Drug Discovery / Humans / Medical Oncology / Neoplasms
Michio Shimabukuro, T Saito, H Masuzaki and Masataka Sata : Screening of coronary artery disease in diabetic patients: who and how? -reply-, Circulation Journal, Vol.80, No.2, 544, 2016.
Toshiyuki Niki, Tetsuzo Wakatsuki, Koji Yamaguchi, Yoshio Taketani, Hiroyasu Oeduka, Kenya Kusunose, Takayuki Ise, Takashi Iwase, Hirotsugu Yamada, Takeshi Soeki and Masataka Sata : Effects of the addition of eicosapentaenoic acid to strong statin therapy on inflammatory cytokines and coronary plaque components assessed by integrated backscatter intravascular ultrasound., Circulation Journal, Vol.80, No.2, 450-460, 2016.
(Summary)
BACKGROUND: The effects of eicosapentaenoic acid (EPA) on coronary artery disease have been previously reported; however, those of the addition of EPA to strong statins on coronary plaque components and local inflammatory cytokines are not known.METHODSANDRESULTS: A total of 95 patients who had been treated with strong statin for at least 6 months were randomized into 2 groups: an EPA group (additional treatment with EPA at 1,800 mg/day, n=48) or a control group (no additional treatment, n=47), for 6 months. The tissue characteristics of target coronary plaque in each patient were analyzed using IB-IVUS before and after treatment. We also measured plasma levels of inflammatory cytokines sampled in the coronary sinus (CS) and peripheral vein.A significant reduction in lipid volume (18.5±1.3 to 15.0±1.5 mm(3), P=0.007) and a significant increase in fibrous volume (22.9±0.8 to 25.6±1.1 mm(3), P=0.01) were observed in IB-IVUS image analyses in the EPA group, but no significant changes in the plaque components in the control group. CS levels of pentraxin 3 and monocyte chemoattractant protein-1 were lower after than before treatment with EPA (3.3±2.1 to 2.6±1.2 ng/ml, 120.4±26.2 to 110.2±26.8 pg/ml, P=0.015 and P=0.008, respectively); however, there were no significant changes in those inflammatory cytokines between pre- and post-treatment in the control group.CONCLUSIONS: The addition of EPA was associated with reduced lipid volume in coronary plaques and decreased inflammatory cytokines. (Circ J 2016; 80: 450-460).
Yuta Torii, Kenya Kusunose, Hirotsugu Yamada, Susumu Nishio, Yukina Hirata, Rie Amano, Masami Yamao, Mika Bando, Shuji Hayashi and Masataka Sata : Comparison of tricuspid annular plane systolic excursion in patients with atrial fibrillation vs sinus rhythm., The American Journal of Cardiology, Vol.117, No.2, 226-232, 2016.
(Summary)
Echocardiography now plays a central guiding role in the management of patients with atrial fibrillation (AF). However, the current guidelines mention little about the presence AF during the assessment of echocardiographic variables in the clinical setting. AF itself may impact on tricuspid annular plane systolic excursion (TAPSE) as a right ventricular systolic function compared with sinus rhythm (SR). The aim of this study was to compare and assess the echocardiographic parameters including TAPSE in patients with AF and SR. From January 1, 2013, to September 30, 2014, patients with AF without any cardiovascular disease were retrospectively evaluated using echocardiography. Age-, gender-, and left ventricular ejection fraction-matched patients with SR were selected from our database on the basis of a comprehensive history, physical examination, and echocardiographic findings. During the study period, we identified 239 patients with AF (74 ± 9 years; 65% men) and without any cardiac disease who underwent echocardiography. We also included 281 patients in the SR group (74 ± 8 years; 67% men). In all study subjects, TAPSE in AF was smaller than in SR regardless of age (17 ± 3 vs 20 ± 3 mm, p <0.001). In the stepwise multiple regression model, TAPSE was strongly associated with the presence of AF (standardized β = -0.362, p <0.001) and stroke volume index (standardized β = 0.173, p <0.001) after adjustment for age, gender, heart rate, left ventricular ejection fraction, and tricuspid regurgitant grade. In conclusions, patients with AF had lower TAPSE than those with SR regardless of age. When we assess TAPSE in the clinical setting, we must pay attention to the presence of AF.
Akira Takashima, Shusuke Yagi, Koji Yamaguchi, Eri Takagi, Tamotsu Kanbara, Hirohisa Ogawa, Takayuki Ise, Kenya Kusunose, Takeshi Tobiume, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Tetsuya Kitagawa and Masataka Sata : Vegetation in the coronary sinus that concealed the presence of a coronary arteriovenous fistula in a patient with infectious endocarditis., International Journal of Cardiology, Vol.207, 266-268, 2016.
S Hayashi, Hirotsugu Yamada, Makoto Fukui, Hiro-O Ito and Masataka Sata : Correlation between arteriosclerosis and periodontal condition assessed by lactoferrin and [alpha]1-antitrypsin levels in gingival crevicular fluid., International Heart Journal, Vol.56, No.6, 639-643, 2015.
(Summary)
Patients with periodontal disease exhibit exacerbated atherosclerosis, aortic stiffness, or vascular endothelial dysfunction. However, in a recent scientific statement, the American Heart Association noted that neither has periodontal disease been proven to cause atherosclerotic vascular disease nor has the treatment of periodontal disease been proven to prevent atherosclerotic vascular disease. Therefore, the aim of the present study was to examine the correlation between periodontal condition and arteriosclerosis in patients with coronary artery disease (CAD), which is usually accompanied by systemic arteriosclerosis.We measured levels of gingival crevicular fluid lactoferrin (GCF-Lf) and 1-antitrypsin (GCF-AT) in 72 patients (67 ± 8 years, 56 men) with CAD. Furthermore, we evaluated the maximum intima-media thickness (max IMT) and plaque score of the carotid arteries as well as brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) of the brachial artery, each of which is a parameter for determining arteriosclerosis status. The average level of GCF-Lf was 0.29 ± 0.36 µg/mL and that of GCF-AT was 0.31 ± 0.66 µg/mL, with significant correlation between the two (r = 0.701, P < 0.001). No significant difference in GCF-Lf and GCF-AT levels was observed between patients with single-, double-, and triple-vessel CAD. There were no significant correlations between the arteriosclerosis parameters (ie, max IMT, plaque score, baPWV, and FMD) and GCF-Lf or GCF-AT.No correlation between the GCF biomarkers and the severity of arteriosclerosis was detected. This result may suggest that worsening of the periodontal condition assessed by GCF biomarkers is not a major potential risk factor for arteriosclerosis.
Y Higashi, N Azuma, Y Takeishi, T Minamino, Y Kihara, K Node, Masataka Sata, Y Fukumoto, H Origasa, H Matsuo, H Naritomi, M Fujita and W Shimizu : Effect of a low-intensity pulsed ultrasound device, SX-1001, on clinical symptoms in buerger disease with limb ischemia., International Heart Journal, Vol.56, No.6, 632-638, 2015.
(Summary)
Buerger disease is a rare disease of unknown etiology and cannot be treated by bypass surgery or percutaneous re-endovascularization. Although the need for effective limb ischemia prevention strategies is increasingly being recognized, effective preventative strategies are insufficient. The aim of this study using a new pulsed ultrasound device, SX-1001, is to determine whether treatment using SX-1001 can mitigate rest pain and improve blood supply to ischemic legs in patients with Buerger disease. This study is a multicenter, double-blinded, parallel randomized clinical trial testing the efficacy and safety of SX-1001. Treatment using SX-1001 is expected to result in reduction of the visual analog scale score for pain in Buerger disease patients who have Fontaine stage III. A total of 44 patients from 20 hospitals in Japan will be enrolled. The primary endpoint of the trial is a change in rest pain intensity on the visual analog scale score from baseline to 24 weeks. This trial will be the first to show the safety and efficacy of low-intensity pulsed ultrasound using SX-1001 for clinical symptoms in patients with Buerger disease. Low-intensity pulsed ultrasound may be a new therapy for limb ischemia. Ethical approval has been obtained from each of the participating institutes. Study findings will be disseminated through peer-reviewed journals and at scientific conferences.This study is registered at UMIN Clinical Trial Registry (UMIN000014757).
Mika Bando, Hirotsugu Yamada, Kenya Kusunose, Shuji Hayashi, Yuriko Takagawa, Yoshihito Saijo, Susumu Nishio, Kozue Ogasawara and Masataka Sata : Pulmonary embolism due to right atrial free-floating thrombus during echocardiographic examination: a case of a pulmonary saddle thrombus., Journal of Echocardiography, Vol.13, No.4, 145-147, 2015.
(Summary)
A 69-year-old female with polymyositis was referred to our hospital with a chief complaint of dyspnea. Transthoracic echocardiography showed right ventricular overloading. In addition to two-dimensional echocardiography, observation of the abnormal free-floating string-like mass by three-dimensional echocardiography provided superior visualization of the features of the mass which protruded into the right ventricle across the tricuspid valve during diastole. These findings enabled us to confirm the diagnosis of venous thrombus. The thrombus disappeared during the echocardiographic examination. Multidetector-row computed tomography showed a string-like thrombus across the bifurcation of the main pulmonary artery. Anticoagulation therapy was initiated with heparin and warfarin, and fondaparinux was started on the fourth day. Three-dimensional echocardiography was useful in characterizing the motion and extent of the thrombus.
(Keyword)
Anticoagulation / Echocardiography / Pulmonary embolism / Right atrial thrombus
Y Kato, U Yokoyama, C Yanai, R Ishige, D Kurotaki, M Umemura, T Fujita, T Kubota, S Okumura, Masataka Sata, T Tamura and Y Ishikawa : Epac1 Deficiency Attenuated Vascular Smooth Muscle Cell Migration and Neointimal Formation., Arteriosclerosis, Thrombosis, and Vascular Biology, Vol.35, No.12, 2617-2625, 2015.
(Summary)
OBJECTIVE: Vascular smooth muscle cell (SMC) migration causes neointima, which is related to vascular remodeling after mechanical injury and atherosclerosis development. We previously reported that an exchange protein activated by cAMP (Epac) 1 was upregulated in mouse arterial neointima and promoted SMC migration. In this study, we examined the molecular mechanisms of Epac1-induced SMC migration and the effect of Epac1 deficiency on vascular remodeling in vivo.APPROACH AND RESULTS: Platelet-derived growth factor-BB promoted a 2-fold increase in SMC migration in a primary culture of aortic SMCs obtained from Epac1+/+ mice (Epac1+/+-ASMCs), whereas there was only a 1.2-fold increase in Epac1-/--ASMCs. The degree of platelet-derived growth factor-BB-induced increase in intracellular Ca2+ was smaller in Fura2-labeled Epac1-/--ASMCs than in Epac1+/+-ASMCs. In Epac1+/+-ASMCs, an Epac-selective cAMP analog or platelet-derived growth factor-BB increased lamellipodia accompanied by cofilin dephosphorylation, which is induced by Ca2+ signaling, whereas these effects were rarely observed in Epac1-/--ASMCs. Furthermore, 4 weeks after femoral artery injury, prominent neointima were formed in Epac1+/+ mice, whereas neointima formation was significantly attenuated in Epac1-/- mice in which dephosphorylation of cofilin was inhibited. The chimeric mice generated by bone marrow cell transplantation from Epac1+/+ into Epac1-/- mice and vice versa demonstrated that the genetic background of vascular tissues, including SMCs rather than of bone marrow-derived cells affected Epac1-mediated neointima formation.CONCLUSIONS: These data suggest that Epac1 deficiency attenuates neointima formation through, at least in part, inhibition of SMC migration, in which a decrease in Ca2+ influx and a suppression of cofilin-mediated lamellipodia formation occur.
Naoko Sawada, Hirotsugu Yamada, Kenya Kusunose, Shuji Hayashi, Takashi Iwase and Masataka Sata : 3D transthoracic echocardiography provides accurate cross-sectional area of the RV outflow tract., JACC. Cardiovascular Imaging, Vol.8, No.11, 1343-1345, 2015.
Masaru Hatano, Hidehiro Yamada, Keiichi Fukuda, Koichiro Yoshioka, Masanori Funauchi, Masataka Kuwana, Masataka Sata, Mutsugu Taniguchi, Norifumi Nakanishi, Takefumi Saito, Saji Tsutomu and Shigetake Sasayama : Effects of the endothelin receptor antagonist bosentan on hemodynamics and exercise capacity in Japanese patients with mildly symptomatic pulmonary arterial hypertension, Heart and Vessels, Vol.30, No.6, 798-804, 2015.
(Summary)
Pulmonary arterial hypertension (PAH) trial has mostly enrolled patients with World Health Organization functional class (WHO FC) III or IV. However, PAH is rapidly progressive in nature even in patients with less severe forms at diagnosis. Following the recent studies in Western population, here we assessed the efficacy of bosentan in Japanese patients with WHO FCII PAH. In this open-label trial, bosentan 125 mg twice daily was administered for 12 weeks in 16 patients, and a hemodynamic evaluation was performed. Treatment was continued for a further 12 weeks, where the effect on exercise capacity was assessed in 13 patients. In 16 patients, mean pulmonary arterial pressure decreased from 40.4 ± 10.4 to 35.6 ± 12.6 mmHg (p = 0.018) and cardiac index increased from 2.54 ± 0.73 to 2.96 ± 0.82 L/min/m2 (p = 0.023). Thus, pulmonary vascular resistance decreased from 792 ± 565 to 598 ± 558 dyn·sec/cm5 (p = 0.006). In 13 patients followed up for 24 weeks, 6-min walking distance increased from baseline at Week 12 (p = 0.003) and Week 24 (p = 0.011). All patients were mildly symptomatic at baseline with dyspnea index (Borg scale) of 2.50 ± 1.58 and the specific activity scale (SAS) of 5.0 ± 1.4 METs. These values remained unchanged throughout the study. These results suggest that bosentan treatment was beneficial for Japanese patients with WHO FC II PAH and treatment should be started in the early stage of the disease.
(Keyword)
Bosentan / Endothelin receptor antagonist / Pulmonary arterial hypertension / Hemodynamics / World Health Organization functional class
Shusuke Yagi, Ken-ichi Aihara, Daiju Fukuda, Akira Takashima, Mika Bando, Tomoya Hara, Sachiko Nishimoto, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Takeshi Tobiume, Takashi Iwase, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro, Masashi Akaike and Masataka Sata : Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome., Nutrition Journal, Vol.14, No.1, 111, 2015.
(Summary)
BACKGROUND: The hospitalization rate for acute coronary syndrome (ACS) for people aged 50 has remained stable over the past decade. Increased serum levels of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a decreased incidence of cardiovascular events and mortality in older patients; however, it is currently unknown whether reduced serum levels of n-3 PUFAs is also a risk factor for ACS in patients aged 50 years.METHODS AND RESULTS: We retrospectively reviewed 102 (male/ female 73/29) Japanese ACS patients whose serum levels of EPA/arachidonic acid (AA) and DHA/AA were evaluated on admission. The EPA/AA ratio was the lowest in patients aged 50 compared to patients aged 51-74 and 75. Pearson correlation analysis showed that early ACS onset was associated with low EPA/AA and DHA/AA ratios, and multiple regression analysis determined that decreased ratios of EPA/AA and DHA/AA, and male sex, current smoker status, increased body mass index and triglyceride levels, independently correlated with early ACS onset. Conversely, low-density and high-density lipoproteins, glycated hemoglobin, and hypertension did not correlate with early ACS onset. Subgroup analyses of male patients revealed that decreased ratios of EPA/AA and DHA/AA independently correlated with early ACS onset.CONCLUSION: Decreased EPA/AA and DHA/AA ratios may be risk factors for early onset of ACS, suggesting that reduced EPA/AA and DHA/AA may represent targets for preventing ACS in Japanese young people.
Michio Shimabukuro, T Saito, T Higa, K Nakamura, H Masuzaki, Masataka Sata and group Fukuoka diabetologists the : Risk stratification of coronary artery disease in asymptomatic diabetic subjects using multidetector computed tomography, Circulation Journal, Vol.79, No.11, 2422-2429, 2015.
(Summary)
BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) show a greater risk for coronary artery disease (CAD), but the risk stratification in asymptomatic CAD patients has not been established. This study investigated the prevalence and severity for asymptomatic CAD and predictors in T2DM patients.METHODSANDRESULTS: In a multiclinic group, diabetic patients (320 men, 186 women) without known symptoms suggestive of CAD were recruited for multidetector computed tomography (MDCT). Patients were categorized according to severity of coronary atherosclerosis: Grade 1 (normal findings), Grade 2 (mild atherosclerosis without significant stenosis), Grade 3 (moderate stenosis/atherosclerosis, 50-74% stenosis), Grade 4 (moderate stenosis/atherosclerosis, 75-89% stenosis), Grade 5 (severe stenosis/atherosclerosis, 90% stenosis). The trend for severity grade of CAD was slightly higher in men than women (P=0.054). For critical lesions (combined Grades 3-5), the prevalence was almost equal (men 44% vs. women 37%; P=0.113). Multivariate models showed that in men, HbA1c7.4%, dyslipidemia, duration of diabetes, retinopathy, and other type of cardiovascular diseases were predictors of critical lesions and in women, duration of diabetes and retinopathy were predictors.CONCLUSIONS: The prevalence and severity of asymptomatic CAD are comparably high in men and women with T2DM. Risk stratification by using MDCT might be useful to predict asymptomatic coronary lesions requiring coronary revascularization. (Circ J 2015; 79: 2422-2429).
S Bando, Daiju Fukuda, Takeshi Soeki, S Nishimoto, E Uematsu, Tomomi Matsuura, Takayuki Ise, Takeshi Tobiume, Koji Yamaguchi, Shusuke Yagi, Takashi Iwase, Hirotsugu Yamada, Tetsuzo Wakatsuki, Michio Shimabukuro and Masataka Sata : Expression of NLRP3 in subcutaneous adipose tissue is associated with coronary atherosclerosis., Atherosclerosis, Vol.242, No.2, 407-414, 2015.
(Summary)
ObjectivesThe promotion of adipose tissue inflammation by lifestyle-related diseases such as obesity and diabetes accelerates atherogenesis; however, the underlying mechanisms remain incompletely understood. Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome contributes to chronic inflammation in adipose tissue. Here, we investigated the link between NLRP3 expression in subcutaneous adipose tissue (SAT) and the severity of coronary atherosclerosis.Methods and resultsSAT was obtained from 72 patients who underwent heart device implantation and coronary angiography. Expression of NLRP3 inflammasome-related molecules (NLRP3, IL-1 and IL-18) in SAT were evaluated by quantitative RT-PCR. Laboratory markers related to lifestyle-related diseases were measured. Patients with obesity, dyslipidemia (P < 0.05, respectively), diabetes or hyperuricemia (P < 0.01, respectively) had significantly higher expression of NLRP3. Multivariate analysis demonstrated that body mass index and serum level of uric acid were predictors of NLRP3 expression in SAT. The expression of NLRP3 in SAT correlated negatively with serum adiponectin level (r = 0.23, P < 0.05). Patients with coronary artery disease showed higher NLRP3 expression than patients without significant stenosis (P < 0.01). Furthermore, the expression of NLRP3 in SAT correlated positively with the severity of coronary atherosclerosis as determined by Gensini score (r = 0.47, P < 0.0001) or SYNTAX score (r = 0.55, P < 0.0001). Multiple regression analysis revealed that the expression of NLRP3 in SAT remains as an independent predictors for the severity of coronary atherosclerosis.ConclusionsThe expression of NLRP3 in SAT, which is affected by lifestyle-related diseases, is associated with the severity of coronary atherosclerosis. Our results suggest that NLRP3 inflammasome in SAT may have a role in atherogenesis.
Tatsuo Motoki, Hirotsugu Kurobe, Yoichiro Hirata, Taisuke Nakayama, Hajime Kinoshita, Kevin A. Rocco, Hitoshi Sogabe, Takaki Hori, Masataka Sata and Tetsuya Kitagawa : PPAR-gamma agonist attenuates inflammation in aortic aneurysm patients., General Thoracic and Cardiovascular Surgery, Vol.63, No.10, 565-571, 2015.
(Summary)
Peroxisome proliferator-activated receptor (PPAR) -γ agonist, which is an anti-diabetes drug and reduces expression of tumor necrosis factor (TNF)-α, reported to have the effects for anti-inflammation in our body. In cardiovascular fields, this PPAR-γ agonist already reported to suppress progression of coronary atherosclerosis. Various cytokines, which is secreted from fat tissues around artery, promote atherosclerosis and/or aneurysmal changes in aorta/artery. Objective of our study is to clarify whether PPAR-γ agonist has anti-inflammatory effects in aorta of patients with aortic aneurysm (AA). The medical ethics committee in Tokushima University Hospital approved protocol for this study. Sixteen patients with AA (more than 5 cm in diameter, scheduled open surgery) were divided into two groups; one is PPAR-γ agonist administrating group [Formula: see text] n = 6, group P[Formula: see text], and another is the without group [Formula: see text] n = 10, group C[Formula: see text]. PPAR-γ agonist, whose dose was 15 mg/day, was administrated in the group P for more than 2 months before aneurysectomy and grafting (mean; 4.2 ± 3.4 months) (Supplemental Table 1). Biopsy specimens were obtained from abdominal subcutaneous fat, greater omentum, retroperitoneal periaortic fat and aneurysmal wall in surgical procedure. Blood examination also achieved before/after procedure. Harvested specimens were analyzed with histology (HE and EVG), immunohistochemistry (macrophage) and RT-PCR (adiponectin, MCP-1, TNF-α, CD68, matrix metalloprotease (MMP)-2, MMP-9). Macrophage infiltration in aortic wall and retroperitoneal periaortic fat among group P was significantly decreased compared to that among group C. Adiponectin expressions in both subcutaneous fat and retroperitoneal periaortic fat among the group P (adiponectin/β-actin) were significantly increased compared to those among the group C [subcutaneous fat; 16.8 ± 13.9 vs. 5.82 ± 2.94 (P = 0.04), retroperitoneal periaortic fat; 21.3 ± 24.1 vs. 2.12 ± 1.69 (P = 0.04)]. On the other hand, expressions of TNF-α, and MMP-9 in both aortic aneurysmal wall and retroperitoneal periaortic fat among group P were significantly decreased. [(Aortic aneurysmal wall; TNF-α; 0.45 ± 0.15 vs. 5.18 ± 3.49 (P = 0.02), MMP-9; 39.6 ± 69.0 vs. 721 ± 741 (P = 0.04)], [retroperitoneal periaortic fat; TNF-α; 1.14 ± 0.36 vs. 26.4 ± 25.0 (P = 0.048), MMP-9; 0.18 ± 0.21 vs. 50.0 ± 41.8 (P = 0.047)]. These data may indicate that PPAR-γ agonist become the way for preventing or delaying aortic aneurysm progression in patients. More studies will be needed to clarify this drug effects in detail.
Hara Tomoya, Daiju Fukuda, Tanaka Kimie, Higashikuni Yasutomi, Hirata Yoichiro, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Michio Shimabukuro and Masataka Sata : Rivaroxaban, a novel oral anticoagulant, attenuates atherosclerotic plaque progression and destabilization in ApoE-deficient mice., Atherosclerosis, Vol.242, No.2, 639-646, 2015.
(Summary)
OBJECTIVE: Activated factor X (FXa) plays a key role in the coagulation cascade, whereas accumulating evidence suggests that it also contributes to the pathophysiology of chronic inflammation on the vasculature. In this study, we assessed the hypothesis that rivaroxaban (Riv), a direct FXa inhibitor, inhibits atherogenesis by reducing macrophage activation.MET