Published Papers - Kusunose Kenya

Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice.

Byambasuren Ganbaatar, Daiju Fukuda, Masakazu Shinohara, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Ken-Ichi Hirata, Masataka Sata

European journal of pharmacology   875   173040 - 173040   2020.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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 E2 and thromboxane B2 (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.

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Deep Learning for Assessment of Left Ventricular Ejection Fraction from Echocardiographic Images.

Kenya Kusunose, Akihiro Haga, Natsumi Yamaguchi, Takashi Abe, Daiju Fukuda, Hirotsugu Yamada, Masafumi Harada, Masataka Sata

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography   33 ( 5 ) 632 - 635   2020.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Clinically Feasible and Accurate View Classification of Echocardiographic Images Using Deep Learning.

Kenya Kusunose, Akihiro Haga, Mizuki Inoue, Daiju Fukuda, Hirotsugu Yamada, Masataka Sata

Biomolecules   10 ( 5 )   2020.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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.

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Atherosclerotic Coronary Plaque Is Associated With Adventitial Vasa Vasorum and Local Inflammation in Adjacent Epicardial Adipose Tissue in Fresh Cadavers.

Hiroyuki Ito, Tetsuzo Wakatsuki, Koji Yamaguchi, Daiju Fukuda, Yutaka Kawabata, Tomomi Matsuura, Kenya Kusunose, Takayuki Ise, Takeshi Tobiume, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Yoshihiro Tsuruo, Masataka Sata

Circulation journal : official journal of the Japanese Circulation Society   84 ( 5 ) 769 - 775   2020.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: The coronary adventitia has recently attracted attention as a source of inflammation because it harbors nutrient blood vessels, termed the vasa vasorum (VV). This study assessed the link between local inflammation in adjacent epicardial adipose tissue (EAT) and coronary arterial atherosclerosis in fresh cadavers.Methods and Results:Lesion characteristics in the left anterior descending coronary artery of 10 fresh cadaveric hearts were evaluated using integrated backscatter intravascular ultrasound (IB-IVUS), and the density of the VV and levels of inflammatory molecules from the adjacent EAT were measured for each of the assessed lesions. The lesions were divided into lipid-rich, lipid-moderate, and lipid-poor groups according to percentage lipid volume assessed by IB-IVUS. Higher expression of inflammatory molecules (i.e., vascular endothelial growth factor A [VEGFA] andVEGFB) was observed in adjacent EAT of lipid-rich (n=11) than in lipid-poor (n=11) lesions (7.99±3.37 vs. 0.45±0.85 arbitrary units [AU], respectively, forVEGFA; 0.27±0.15 vs. 0.11±0.07 AU, respectively, forVEGFB; P<0.05). The density of adventitial VV was greater in lipid-rich than lipid-poor lesions (1.50±0.58% vs. 0.88±0.23%; P<0.05). CONCLUSIONS: Lipid-rich coronary plaques are associated with adventitial VV and local inflammation in adjacent EAT in fresh cadavers. This study suggests that local inflammation of EAT is associated with coronary plaque progression via the VV.

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Study protocol for prospect trial to elucidate the utility of echocardiography-based cardiac output in acute heart failure (PREDICT).

Hiroyuki Iwano, Kentaro Shibayama, Takeshi Kitai, Kenya Kusunose, Tetsuari Onishi, Hidekazu Tanaka, Toshihisa Anzai

Journal of echocardiography   18 ( 4 ) 235 - 239   2020.04 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Early worsening heart failure (WHF), defined as worsening of symptoms and signs of heart failure requiring intensification of medical or mechanical therapy during an admission for acute decompensated heart failure (ADHF), has recently been recognized as a risk of morbidity or mortality after the discharge. Although echocardiographic parameters of left ventricular (LV) output has been shown to be associated with long-term outcome in heart failure patients, its predictive value for early WHF has not been elucidated. METHODS: Prospect trial to Elucidate the utility of EchocarDiography-based Cardiac output in acute heart failure (PREDICT) is a multicenter, nonrandomized, prospective observational study to test the predictive value of echocardiographic LV output parameters for early WHF in ADHF patients. We will enroll patients admitted to 16 participating hospitals due to ADHF who did not receive positive inotropic agents as an initial therapy. Primary outcome will be set at early WHF defined as need for initiation of positive inotropic agents within 7 days after the admission. Predictive accuracy will be compared between Doppler echocardiographic LV output (stroke distance, stroke volume index, and cardiac index) and low perfusion findings assessed by physical examination. RESULTS: N/A. CONCLUSIONS: The PREDICT is expected to provide large data set to test the predictive value of echocardiographic LV output for early WHF in ADHF patients.

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Diastolic Mitral Regurgitation on Color M-Mode Echocardiography in a Patient With Complete Atrioventricular Block.

Akihiro Tani, Kenya Kusunose, Kazuhisa Matsumoto, Hirotsugu Yamada, Masataka Sata

Circulation reports   2 ( 3 ) 207 - 208   2020.02 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Association of Local Epicardial Adipose Tissue Depots and Left Ventricular Diastolic Performance in Patients With Preserved Left Ventricular Ejection Fraction

Maimaituxun, G; Yamada, H; Fukuda, D; Yagi, S; Kusunose, K; Hirata, Y; Nishio, S; Soeki, T; Masuzaki, H; Sata, M; Shimabukuro, M

CIRCULATION JOURNAL ( 一般社団法人 日本循環器学会 )  84 ( 2 ) 203 - 216   2020.01

Type of publication: Research paper (scientific journal)

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<p><b><i>Background:</i></b>Although full-volume quantification of epicardial adipose tissue (EAT) is a predictor of LV diastolic dysfunction (LVDD), how localized EAT depots are linked to LVDD remains unclear. We evaluated the effect of local EAT depots on LV diastolic function parameters in patients with preserved LV ejection fraction (LVEF).</p><p><b><i>Methods and Results:</i></b>From 423 consecutive patients who underwent cardiac CT angiography, we recruited 252 with sinus rhythm and normal LVEF. The EAT volume index (EATV/body surface area) and the localized EAT thickness around the right coronary artery (EAT_RCA), left anterior descending artery (EAT_LAD), left circumflex artery (EAT_LCX), right ventricle (EAT_RV), left ventricle (EAT_LV), right atrium (EAT_RA), and left atrium (EAT_LA) were measured using cardiac CT. In the LVDD group (n=71), the EATV index (75±30 vs. 64±28 mL/m², P=0.010), EAT_LCX(10.7±3.8 vs. 9.4±3.4 mm, P=0.008), and EAT_LV(2.6±1.6 vs. 2.1±1.4 mm, P=0.024) were greater than in the non-LVDD group (n=181). In contrast, EAT_LCXand EAT_LVwere markedly associated with decreased lateral e’ and increased lateral E/e’. Multiple regression analysis indicated that EAT_LCXand EAT_LVwere strongly associated with LV diastolic function parameters.</p><p><b><i>Conclusions:</i></b>Localized EAT depots are linked to altered mitral annular motion. Further study is warranted to clarify whether localized EAT depots are functionally linked to the clinical manifestations of LVDD.</p>

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Elderly Japanese Standard Data of Echocardiography; From J-LONG study

Yoshihiro Seo, Tomoko Ishizu, Masaki Ieda, Nobuyuki Ohte, Masako Asakawa, Chikage Oshita, Masanori Takada, Mitsufumi Furuya, Fumiko Sakamaki, Hitomi Hashimoto, Takako Minami, Harutoshi Tamura, Akiko Okunaga, Yuichi Oshima, Yoshie Omori, Takuma Aoyama, Takako Iino, Makoto Saito, Tetsuya Kasuga, Taro Minagawa, Satoshi Kibira, Hidekazu Tanaka, Yoshihisa Horizoe, Hiroyoshi Yamamoto, Shintaro Beppu, Misun Pak, Miyako Nagumo, Masaki Izumo, Atsushi Kobayashi, Shohei Kikuchi, Noriaki Iwahashi, Kotaro Numaguchi, Toshinari Onishi, Yuki Izumi, Hirotsugu Yamada, Kenya Kusunose, Hideo Kawakami, Hiroyuki Iwano

Journal of Echocardiography   18 ( 3 ) 175 - 182   2020 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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© 2020, Japanese Society of Echocardiography. Background: Age-related changes in cardiac morphology and function have not been unknown in the elderly. The Japanese eLderly data Of Normal echocardioGraphy (J-LONG) study is a prospective multicenter cohort study and aimed to investigate the echocardiographic data in the healthy Japanese elderly. Methods: Thirty domestic facilities participated in this study, and 130 healthy subjects (57 men, 73 women, 79.6 ± 4.7 years, range 75–98 years, interquartile range 76–82 years) were enrolled in this cohort. Echocardiographic and clinical data sets were obtained in each facility, and total analyses were performed in the University of Tsukuba. Results: Almost all cardiac morphological data were significantly larger in men than those in women. However, corrected data by body surface area (BSA) were similar or closer between genders. As a gender difference, the negative correlation between BSA and age was observed in women only (r = − 0.46, p < 0.001), showing the independent determinant of women's left ventricular end-diastolic volume (LVEDV) was age (β = − 0.29, p = 0.01), but not BSA. In men, LVEDV was significantly correlated with BSA (β = 0.42, p = 0.001), but not with age (p = 0.10). Also, women had higher LV ejection fraction (70 ± 7.1 vs. 68 ± 4.9%, p = 0.02), lower E/A (0.67 ± 0.16 vs. 0.75 ± 0.21, p = 0.02), and higher E/eʹ (10 ± 2.7 vs. 8.9 ± 2.5, p = 0.03) as compared to men. Conclusions: The J-LONG study suggested that correction by the physique was needed to interpret echocardiographic data of the elderly. Also, gender differences and age-related changes in cardiac morphology and function were observed, and further studies are needed to confirm the clinical significance.

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Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients.

Yutaka Kawabata, Takeshi Soeki, Hiroyuki Ito, Tomomi Matsuura, Kenya Kusunose, Takayuki Ise, Koji Yamaguchi, Takeshi Tobiume, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Tetsuzo Wakatsuki, Mitsuhiro Kitani, Kazuhiro Kawano, Yoshio Taketani, Masataka Sata

International journal of hypertension   2020   6653851 - 6653851   2020 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Objectives: Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods: A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II-renin feedback were assessed. Results: After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (p < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1-7) (Ang-(1-7)) to angiotensin II in plasma than the amlodipine group (p < 0.05). Conclusions: The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1-7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.

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Improvement of global longitudinal strain following high-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with amyloid light-chain cardiac amyloidosis: a case report

Yukina Hirata, Kenya Kusunose, Hirokazu Miki, Hirotsugu Yamada

European Heart Journal - Case Reports ( Oxford University Press (OUP) )  3 ( 4 ) 1 - 6   2019.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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<title>Abstract</title> <sec> <title>Background</title> Cardiac amyloidosis (CA) is a secondary form of cardiomyopathy where abnormal accumulation of amyloid protein in the myocardial interstitium causes cardiac hypertrophy and myocardial fibrosis. If primary CA advances to heart failure, most patients do not survive for very long after the diagnosis. </sec> <sec> <title>Case summary</title> A 40-year-old man was admitted to our hospital for dyspnoea, progressive anaemia, and decreased appetite. He has diagnosed with amyloid light-chain (AL) amyloidosis. Although BD treatment (bortezomib + dexamethasone) and medical treatment were started, there was no sign of improvement. Then, high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) was initiated. Pretreatment echocardiography revealed typical findings of CA, such as ventricular wall thickening, valvular thickening, diastolic dysfunction, and pericardial effusion. Global longitudinal strain (GLS) was significantly reduced, and bull's-eye mapping showed typical apical sparing. After auto-PBSCT, GLS gradually improved and was almost normal after 2 years. Other echocardiographic parameters, functional status, and laboratory data also showed that there was significant regression of CA. </sec> <sec> <title>Discussion</title> Although the prognosis in primary CA is extremely poor, we achieved long-term survival in a patient with effective high-dose chemotherapy and auto-PBSCT. Global longitudinal strain may be a useful marker of prognosis, regression, and recovery. </sec>

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Noninvasive assessment of left-ventricular diastolic electromechanical coupling in hypertensive heart disease.

Saito Y, Yamada H, Kusunose K, Saito K, Sata M

Journal of echocardiography   17 ( 4 ) 206 - 212   2019.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

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Pulmonary Artery Hypertension-Specific Therapy Improves Exercise Tolerance and Outcomes in Exercise-Induced Pulmonary Hypertension.

Kusunose K, Yamada H, Nishio S, Hirata Y, Saijo Y, Torii Y, Yamada N, Ise T, Yamaguchi K, Fukuda D, Yagi S, Soeki T, Wakatsuki T, Sata M

JACC. Cardiovascular imaging   12 ( 12 ) 2576 - 2579   2019.12 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Association of Echocardiography Before Major Elective Non-Cardiac Surgery With Improved Postoperative Outcomes - Possible Implications for Patient Care.

Kusunose K, Torii Y, Yamada H, Nishio S, Hirata Y, Saijo Y, Ise T, Yamaguchi K, Fukuda D, Yagi S, Soeki T, Wakatsuki T, Sata M

Circulation journal : official journal of the Japanese Circulation Society   83 ( 12 ) 2512 - 2519   2019.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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. CONCLUSIONS: 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.

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Vildagliptin, a DPP-4 Inhibitor, Attenuates Endothelial Dysfunction and Atherogenesis in Nondiabetic Apolipoprotein E-Deficient Mice.

Aini K, Fukuda D, Tanaka K, Higashikuni Y, Hirata Y, Yagi S, Kusunose K, Yamada H, Soeki T, Sata M

International heart journal   60 ( 6 ) 1421 - 1429   2019.11 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)

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Thrombin inhibition by dabigatran attenuates endothelial dysfunction in diabetic mice.

Rahadian A, Fukuda D, Salim HM, Yagi S, Kusunose K, Yamada H, Soeki T, Shimabukuro M, Sata M

Vascular pharmacology   124   106632 - 106632   2019.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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 eNOSSer1177 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.

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Updated Left Ventricular Diastolic Function Recommendations and Cardiovascular Events in Patients with Heart Failure Hospitalization.

Torii Y, Kusunose K, Yamada H, Nishio S, Hirata Y, Amano R, Yamao M, Zheng R, Saijo Y, Yamada N, Ise T, Yamaguchi K, Yagi S, Soeki T, Wakatsuki T, Sata M

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography   32 ( 10 ) 1286 - 1297.e2   2019.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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Association Between Right Ventricular Contractile Function and Cardiac Events in Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension.

Kusunose K, Yamada N, Yamada H, Nishio S, Saijo Y, Hirata Y, Torii Y, Ise T, Yamaguchi K, Fukuda D, Yagi S, Soeki T, Wakatsuki T, Sata M

Journal of cardiac failure   26 ( 1 ) 43 - 51   2019.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

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Deterioration of biventricular strain is an early marker of cardiac involvement in confirmed sarcoidosis.

Kusunose K, Fujiwara M, Yamada H, Nishio S, Saijo Y, Yamada N, Hirata Y, Torii Y, Ise T, Yamaguchi K, Fukuda D, Yagi S, Soeki T, Wakatsuki T, Sata M

European heart journal cardiovascular Imaging   21 ( 7 ) 796 - 804   2019.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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AIMS: 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. METHODS AND RESULTS: 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). CONCLUSION: Deterioration of biventricular strain was associated with CS-related events. This information might be useful for clinical evaluation and follow-up in sarcoidosis.

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Rivaroxaban, a specific FXa inhibitor, improved endothelium-dependent relaxation of aortic segments in diabetic mice.

Pham PT, Fukuda D, Yagi S, Kusunose K, Yamada H, Soeki T, Shimabukuro M, Sata M

Scientific reports   9 ( 1 ) 11206 - 11206   2019.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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 eNOSSer1177 phosphorylation in the aorta (P < 0.001). Induction of diabetes to PAR2-deficient (PAR2-/-) mice did not affect endothelial function and eNOSSer1177 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 eNOSSer1177 phosphorylation (P < 0.05) in human coronary artery endothelial cells (HCAEC). FXa-induced endothelial dysfunction in aortic rings (P < 0.001) and eNOSSer1177 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.

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SGLT2阻害薬canagliflozinは糖尿病発症性ApoE-/-マウスにおいて内皮機能障害とアテローム性動脈硬化症を軽減する(SGLT2 inhibitor, Canagliflozin, Ameliorate Endothelial Dysfunction and Atherosclerosis in Diabetic ApoE-/- Mice)

Arief Rahadian, 福田 大受, Hotima Salim, 八木 秀介, 楠瀬 賢也, 山田 博胤, 添木 武, 佐田 政隆

日本性機能学会雑誌 ( (一社)日本性機能学会 )  34 ( 2 ) 190 - 190   2019.08 [ Peer Review Accepted ]

Type of publication: Research paper (other science council materials etc.)