Published Papers - Kusunose Kenya

Effectiveness of surveillance by echocardiography for cancer therapeutics-related cardiac dysfunction of patients with breast cancer

Okushi, Y; Saijo, Y; Yamada, H; Toba, H; Zheng, RB; Seno, H; Takahashi, T; Ise, T; Yamaguchi, K; Yagi, S; Soeki, T; Wakatsuki, T; Sata, M; Kusunose, K

JOURNAL OF CARDIOLOGY ( Journal of Cardiology )  82 ( 6 ) 467 - 472   2023.12 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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

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The Clinical Utility of Noninvasive Forrester Classification in Acute Heart Failure from PREDICT Study

Takahashi, T; Iwano, H; Shibayama, K; Kitai, T; Tanaka, H; Yamada, H; Sata, M; Kusunose, K

AMERICAN JOURNAL OF CARDIOLOGY ( American Journal of Cardiology )  207   75 - 81   2023.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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.

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Innate Immune System Regulated by Stimulator of Interferon Genes, a Cytosolic DNA Sensor, Regulates Endothelial Function.

Pham PT, Bavuu O, Kim-Kaneyama JR, Lei XF, Yamamoto T, Otsuka K, Suto K, Kusunose K, Yagi S, Yamada H, Soeki T, Shimabukuro M, Barber GN, Sata M, Fukuda D

Journal of the American Heart Association ( Journal of the American Heart Association )  12 ( 22 ) e030084   2023.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Value and challenges of lung ultrasound in stratifying ST-elevation myocardial infarction risk

Kusunose, K; Toma, Y

HEART ( Heart )  109 ( 21 ) 1580 - 1581   2023.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Correlation between energy loss index and B-type natriuretic peptide: a vector flow mapping study

Morita, S; Hirata, Y; Nishio, S; Takahashi, T; Saijo, Y; Yamada, H; Sata, M; Kusunose, K

JOURNAL OF ECHOCARDIOGRAPHY ( Journal of Echocardiography )    2023.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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. METHODS: 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. RESULTS: 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/m2 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). CONCLUSION: 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.

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Revolution of echocardiographic reporting: the new era of artificial intelligence and natural language processing

Kusunose, K

JOURNAL OF ECHOCARDIOGRAPHY ( Journal of Echocardiography )  21 ( 3 ) 99 - 104   2023.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Prognostic implications of pulmonary vascular resistance in transcatheter aortic valve implantation

Kusunose, K; Ikemiyagi, H

HEART ( Heart )  110 ( 1 ) 5 - 6   2023.08 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Olive mill wastewater and hydroxytyrosol inhibits atherogenesis in apolipoprotein E-deficient mice.

Tomoya Hara, Daiju Fukuda, Byambasuren Ganbaatar, Phuong Tran Pham, Kunduziayi Aini, Arief Rahadian, Kumiko Suto, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Masataka Sata

Heart and vessels   38 ( 11 ) 1386 - 1394   2023.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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.

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Artificial intelligence-assisted interpretation of systolic function by echocardiogram

Yamaguchi, N; Kosaka, Y; Haga, A; Sata, M; Kusunose, K

OPEN HEART ( Open Heart )  10 ( 2 )   2023.07 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: AI can assist with the interpretation of systolic function on an echocardiogram for level 1 readers from different institutions.

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Evaluation of the Accuracy of ChatGPT in Answering Clinical Questions on the Japanese Society of Hypertension Guidelines

Kusunose, K; Kashima, S; Sata, M

CIRCULATION JOURNAL ( 一般社団法人 日本循環器学会 )  87 ( 7 ) 1030 - 1033   2023.06

Type of publication: Research paper (scientific journal)

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<p><b><i>Background:</i></b> 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).</p><p><b><i>Methods and Results:</i></b> 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).</p><p><b><i>Conclusions:</i></b> ChatGPT has the potential to be a valuable tool for clinicians in the management of hypertension.</p>

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Intimal Sarcoma of the Pulmonary Artery as an Embolic Cause of Sudden Death.

Shusuke Yagi, Tomoya Hara, Hirotsugu Yamada, Kenya Kusunose, Takayuki Ise, Masataka Sata

Circulation journal : official journal of the Japanese Circulation Society   87 ( 7 ) 1036 - 1036   2023.06 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Deep learning approach for analyzing chest x-rays to predict cardiac events in heart failure

Kenya Kusunose, Yukina Hirata, Natsumi Yamaguchi, Yoshitaka Kosaka, Takumasa Tsuji, Jun'ichi Kotoku, Masataka Sata

Frontiers in Cardiovascular Medicine ( Frontiers Media SA )  10   2023.05 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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Background 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). Objectives 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. Methods 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. Results 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 (p &amp;lt; 0.001). In sequential Cox models, a model based on clinical data was improved by elevated LAP (p = 0.005), and increased further by probability of elevated PAWP (p &amp;lt; 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 p = 0.086). Conclusions 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.

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The Impact of Coronary Plaque Progression Stage on Coronary Neovascularization Structures in Fresh Cadavers(タイトル和訳中)

川端 豊, 若槻 哲三, 山口 浩司, 坂東 遼, 西條 良仁, 上野 理絵, 門田 宗之, 原 知也, 松浦 朋美, 伊勢 孝之, 楠瀬 賢也, 八木 秀介, 山田 博胤, 添木 武, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   PJ005 - 1   2023.03 [ Peer Review Accepted ]

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

薬物治療可能な心筋症の非侵襲的画像診断:早期診断のための活用法(Utility of Periodic Echocardiographic Surveillance for Early Detection of Cardiac Dysfunction from Chemotherapy in Breast Cancer Patients)

西條 良仁, 大櫛 祐一郎, 楠瀬 賢也, 山田 博胤, ゼング ロバート, 高橋 智紀, 瀬野 弘光, 西尾 進, 上野 理絵, 門田 宗之, 原 知也, 川端 豊, 松浦 朋美, 伊勢 孝之, 山口 浩司, 八木 秀介, 添木 武, 若槻 哲三, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   SY11 - 3   2023.03 [ Peer Review Accepted ]

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

未来の医療機器・デバイスのために(Novel Home-based Cardiac Telerehabilitation System Using a Wearable Device and a Web Application)

伊勢 孝之, 八木 秀介, 上野 理絵, 門田 宗之, 大谷 啓太, 根岸 佑典, 宮本 亮太, 坂東 遼, ゼング ロバート, 瀬野 弘光, 高橋 智紀, 川端 豊, 西條 良仁, 松浦 朋美, 楠瀬 賢也, 山口 浩司, 山田 博胤, 添木 武, 若槻 哲三, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   SY03 - 4   2023.03 [ Peer Review Accepted ]

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

Two-year Outcomes of Drug-coated Balloon-only Strategy for De Novo Lesions in Large Coronary Vessels(タイトル和訳中)

坂東 遼, 若槻 哲三, 山口 浩司, 川端 豊, 宮本 亮太, ゼング ロバート, 高橋 智紀, 西條 良仁, 上野 理絵, 門田 宗之, 原 知也, 松浦 朋美, 伊勢 孝之, 楠瀬 賢也, 八木 秀介, 山田 博胤, 添木 武, 赤池 雅史, 佐田 政隆

日本循環器学会学術集会抄録集 ( (一社)日本循環器学会 )  87回   OJ32 - 1   2023.03 [ Peer Review Accepted ]

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

Benefits of guideline-directed medical therapy to loop diuretics in management of heart failure.

Kenya Kusunose, Yuichiro Okushi, Yoshihiro Okayama, Robert Zheng, Michikazu Nakai, Yoko Sumita, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata

The journal of medical investigation : JMI   70 ( 1.2 ) 41 - 53   2023 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: We sought to compare the outcomes of patients receiving combination therapy of diuretics and neurohormonal blockers, with a matched cohort with monotherapy of loop diuretics, using real-world big data. METHODS: 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 78,685 patients who were first hospitalized with heart failure (HF) between April 2015 and March 2017. Propensity score (PS) was estimated with logistic regression model, with neurohormonal blockers (angiotensin-converting enzyme inhibitor : ACEi or angiotensin receptor blocker : ARB, ?-blockers and mineralocorticoid receptor antagonists : MRA) as the dependent variable and 24 clinically relevant covariates to compare the in-hospital mortality between monotherapy of loop diuretics and combination therapies. RESULTS: On PS-matched analysis, patients with ACEi?/?ARB, ?-blockers, and MRA had lower total in-hospital mortality and in-hospital mortality within 7 days, 14 days and 30 days. In the sub-group analysis, regardless of clinical characteristics including elderly people and cancer, patients treated with a combination of loop diuretics and neurohormonal blockers had significantly lower in-hospital mortality than matched patients. CONCLUSIONS: Our data indicate the benefits of guideline-directed medical therapy to loop diuretics in the management of HF. J. Med. Invest. 70 : 41-53, February, 2023.

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Isoproterenol loading transesophageal echocardiography in atrial fibrillation.

Tomonori Takahashi, Kenya Kusunose, Shuji Hayashi, Robert Zheng, Natsumi Yamaguchi, Sae Morita, Yukina Hirata, Susumu Nishio, Yoshihito Saijo, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata

The international journal of cardiovascular imaging   39 ( 3 ) 511 - 518   2022.11 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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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.

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Association of Microluminal Structures Assessed by Optical Coherence Tomography With Local Inflammation in Adjacent Epicardial Adipose Tissue and Coronary Plaque Characteristics in Fresh Cadavers.

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

Circulation journal : official journal of the Japanese Circulation Society   87 ( 2 ) 329 - 335   2022.10 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: 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). CONCLUSIONS: 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.

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Esaxerenone, a selective mineralocorticoid receptor blocker, improves insulin sensitivity in mice consuming high-fat diet.

Oyunbileg Bavuu, Daiju Fukuda, Byambasuren Ganbaatar, Tomomi Matsuura, Takayuki Ise, Kenya Kusunose, Koji Yamaguchi, Shusuke Yagi, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Masataka Sata

European journal of pharmacology   931   175190 - 175190   2022.09 [ Peer Review Accepted ]

Type of publication: Research paper (scientific journal)

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BACKGROUND: Esaxerenone is a novel, non-steroidal selective mineralocorticoid receptor (MR) 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Esaxerenone ameliorated insulin resistance in HFD-fed mice. Reduction of inflammation and improvement in insulin signaling may underlie the beneficial effects of esaxerenone.

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