Publications by authors named "Hiroshi Akazawa"

158 Publications

Axitinib Induces and Aggravates Hypertension Regardless of Prior Treatment With Tyrosine Kinase Inhibitors.

Circ Rep 2021 Mar 10;3(4):234-240. Epub 2021 Mar 10.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo Tokyo Japan.

Axitinib is a tyrosine kinase inhibitor (TKI) that inhibits vascular endothelial growth factor receptor signaling and is approved for second-line treatment of advanced renal cell carcinoma (RCC). Although the occurrence of hypertension with axitinib use has been documented, it is unclear whether a first-line TKI regimen can significantly affect the development of hypertension when axitinib is used as second-line therapy. In this single-center retrospective study, advanced RCC patients treated with axitinib after first-line chemotherapy were divided into 2 groups according to the use of TKIs as part of first-line treatment before the initiation of axitinib. Clinical outcomes were compared between patients who were treated with (TKI(+); n=11) or without (TKI(-); n=11) a TKI. Although 63.6% of all patients had hypertension at baseline, axitinib-induced hypertension developed in 81.8% of patients, and 36.4% of patients experienced Grade 3 hypertension. After initiation of axitinib, both systolic and diastolic blood pressures and the hypertension grade were significantly elevated both in the TKI(+) and TKI(-) groups, and the number of antihypertensive drugs was significantly increased among all patients. This study suggests the need for proper monitoring and management of blood pressure in RCC patients treated with axitinib, regardless of a prior regimen with or without TKIs.
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http://dx.doi.org/10.1253/circrep.CR-21-0008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024013PMC
March 2021

[Dawning of Onco-Cardiology].

Authors:
Hiroshi Akazawa

Gan To Kagaku Ryoho 2021 Jan;48(1):1-6

Dept. of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

Recent progress in cancer therapy has decreased all-cancer mortality, but cardiovascular adverse events owing to chemotherapy and radiotherapy have greater impact on clinical outcome and quality of life in cancer patients and survivors. There are a wide variety of cardiovascular adverse events related to cancer therapy, and the opportunities requiring specialized care by cardiovascular experts are increasing in clinical practice. Under such circumstances, onco-cardiology is becoming very important as a new discipline and attracting much attention in Japan. The Japanese Onco-Cardiology Society was established in 2017, and continues integration of academic activities to solve challenging problems in this field. Interdisciplinary collaborations between cardiologists and oncologists will be further progressed in medical care, clinical and basic research, and education.
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January 2021

Factors associated with left ventricular reverse remodelling after percutaneous coronary intervention in patients with left ventricular systolic dysfunction.

Sci Rep 2021 Jan 8;11(1):239. Epub 2021 Jan 8.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Percutaneous coronary intervention (PCI) is sometimes considered as an alternative therapeutic strategy to surgical revascularization in patients with coronary artery disease (CAD) and reduced left ventricular ejection fraction (LVEF). However, the types or conditions of patients that receive the clinical benefit of left ventricular reverse remodelling (LVRR) remain unknown. The purpose of this study was to investigate the determinants of LVRR following PCI in CAD patients with reduced LVEF. From 4394 consecutive patients who underwent PCI, a total of 286 patients with reduced LV systolic function (LVEF < 50% at initial left ventriculography) were included in the analysis. LVRR was defined as LV end-systolic volume reduction ≥ 15% and improvement of LVEF ≥ 10% at 6 months follow-up left ventriculography. Patients were divided into LVRR (n = 63) and non-LVRR (n = 223) groups. Multivariate logistic regression analysis revealed that unprotected left main coronary artery (LMCA) intervention was significantly associated with LVRR (P = 0.007, odds ratios [OR] 4.70, 95% confidence interval [CI] 1.54-14.38), while prior PCI (P = 0.001, OR 0.35, 95% CI 0.19-0.66), presence of in-stent restenosis (P = 0.016, OR 0.32, 95% CI 0.12-0.81), and presence of de-novo stenosis (P = 0.038, OR 0.36, 95% CI 0.14-0.95) were negatively associated with LVRR. These data suggest the potential prognostic benefit of unprotected LMCA intervention for LVRR and importance of angiographic follow-up in patients with CAD and LV systolic dysfunction.
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http://dx.doi.org/10.1038/s41598-020-80491-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794568PMC
January 2021

Inhibition of transforming growth factor-β signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome.

PLoS One 2020 11;15(11):e0239908. Epub 2020 Nov 11.

Department of Cardiovascular Medicine, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan.

Increased transforming growth factor-β (TGF-β) signaling contributes to the pathophysiology of aortic aneurysm in Marfan syndrome (MFS). Recent reports indicate that a small but significant number of inflammatory cells are infiltrated into the aortic media and adventitia in MFS. However, little is known about the contribution of myeloid cells to aortic aneurysmal formation. In this study, we ablated the TGF-β type II receptor gene Tgfbr2 in myeloid cells of Fbn1C1039G/+ MFS mice (Fbn1C1039G/+;LysM-Cre/+;Tgfbr2fl/fl mice, hereinafter called Fbn1C1039G/+;Tgfbr2MyeKO) and evaluated macrophage infiltration and TGF-β signaling in the aorta. Aneurysmal formation with fragmentation and disarray of medial elastic fibers observed in MFS mice was significantly ameliorated in Fbn1C1039G/+;Tgfbr2MyeKO mice. In the aorta of Fbn1C1039G/+;Tgfbr2MyeKO mice, both canonical and noncanonical TGF-β signals were attenuated and the number of infiltrated F4/80-positive macrophages was significantly reduced. In vitro, TGF-β enhanced the migration capacity of RAW264.7 macrophages. These findings suggest that TGF-β signaling in myeloid cells promotes aortic aneurysmal formation and its inhibition might be a novel therapeutic target in MFS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239908PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657512PMC
January 2021

Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease.

Nat Genet 2020 11 5;52(11):1169-1177. Epub 2020 Oct 5.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study of 168,228 individuals of Japanese ancestry (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,781 CAD cases and 2,636 controls. We detected eight new susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a trans-ancestry meta-analysis and discovered 35 additional new loci. Using the meta-analysis results, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European genome-wide association studies. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improve the clinical characterization of CAD genetics and suggest the utility of trans-ancestry meta-analysis for PRS derivation in non-European populations.
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http://dx.doi.org/10.1038/s41588-020-0705-3DOI Listing
November 2020

Erratum: Diagnosing Heart Failure from Chest X-Ray Images Using Deep Learning.

Int Heart J 2020 ;61(5):1088

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

An error appeared in the article entitled "Diagnosing Heart Failure from Chest X-Ray Images Using Deep Learning" by Takuya Matsumoto, Satoshi Kodera, Hiroki Shinohara, Hirotaka Ieki, Toshihiro Yamaguchi, Yasutomi Higashikuni, Arihiro Kiyosue, Kaoru Ito, Jiro Ando, Eiki Takimoto, Hiroshi Akazawa, Hiroyuki Morita, Issei Komuro (Vol. 61, No. 4, 781-786, 2020). The Figure 5on page 784 should be replaced by the following figure.
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http://dx.doi.org/10.1536/ihj.61-5_ErrataDOI Listing
October 2020

A Fatal Case of Myocarditis Following Myositis Induced by Pembrolizumab Treatment for Metastatic Upper Urinary Tract Urothelial Carcinoma.

Int Heart J 2020 Sep 12;61(5):1070-1074. Epub 2020 Sep 12.

Department of Urology, Graduate School of Medicine, The University of Tokyo.

We report a case of lethal myocarditis and myositis after pembrolizumab treatment for advanced upper urinary tract urothelial carcinoma. A 69-year-old man underwent pembrolizumab therapy as a second-line treatment. He had myalgia and a slightly elevated creatinine kinase (CK) on the day of the second administration of pembrolizumab. Five days later, the patient was admitted with severe fatigue and an abnormal gait. Physical examination revealed reduced muscle reflexes and proximal muscle weakness. An electrocardiogram (ECG) demonstrated a wide QRS complex ventricular rhythm. A marked elevation of cardiac enzymes, including CK, myoglobin, and cardiac troponin I, was detected. Myocardial biopsy revealed inflammatory cell infiltration and the partial impairment of myocardial tissue. The electromyogram was normal, but inflammation in myofibers was noted in a muscle biopsy. Myocarditis and myositis as immune-related adverse events (irAEs) were suspected, and the patient began intravenous steroid therapy and plasma exchange. However, the patient underwent cardiac arrest three days after admission and began extracorporeal membrane oxygenation and intra-aortic balloon pumping therapy. Despite steroid pulse therapy, the patient demonstrated no sign of improvement and subsequently died 17 days after admission. Immune-mediated myocarditis is a rare but fatal irAE of an immune checkpoint inhibitor (ICI). The present case suggests that myositis precedes myocarditis. Therefore, if myositis is suspected, subsequent myocarditis may need attention. In conclusion, we found that myositis and myocarditis developed in a patient with advanced urothelial carcinoma after pembrolizumab treatment. A routine follow-up of CK and cardiac troponin I, as well as an ECG, should be performed to identify any possible ICI-induced myocarditis and myositis quickly.
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http://dx.doi.org/10.1536/ihj.20-162DOI Listing
September 2020

Cancer Therapeutics-Related Cardiac Dysfunction - Insights From Bench and Bedside of Onco-Cardiology.

Circ J 2020 08 29;84(9):1446-1453. Epub 2020 Jul 29.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

Improvements in the long-term survival of cancer patients have led to growing awareness of the clinical importance of cancer therapeutics-related cardiac dysfunction (CTRCD), which can have a considerable effect on the prognosis and quality of life of cancer patients and survivors. Under such circumstances, onco-cardiology/cardio-oncology has emerged as a new discipline, with the aim of best managing cardiovascular complications, including CTRCD. Despite the recent accumulation of epidemiological and clinical information regarding CTRCD, the molecular mechanisms underlying the pathogenesis of CTRCD by individual drugs remain to be determined. To achieve the goal of preventing cardiovascular complications in cancer patients and survivors, it is important to elucidate the pathogenic mechanisms and to establish diagnostic strategies with risk prediction and mechanism- and evidence-based therapies against CTRCD.
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http://dx.doi.org/10.1253/circj.CJ-20-0467DOI Listing
August 2020

Diagnosing Heart Failure from Chest X-Ray Images Using Deep Learning.

Int Heart J 2020 Jul 18;61(4):781-786. Epub 2020 Jul 18.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

The development of deep learning technology has enabled machines to achieve high-level accuracy in interpreting medical images. While many previous studies have examined the detection of pulmonary nodules in chest X-rays using deep learning, the application of this technology to heart failure remains rare. In this paper, we investigated the performance of a deep learning algorithm in terms of diagnosing heart failure using images obtained from chest X-rays. We used 952 chest X-ray images from a labeled database published by the National Institutes of Health. Two cardiologists verified and relabeled a total of 260 "normal" and 378 "heart failure" images, with the remainder being discarded because they had been incorrectly labeled. Data augmentation and transfer learning were used to obtain an accuracy of 82% in diagnosing heart failure using the chest X-ray images. Furthermore, heatmap imaging allowed us to visualize decisions made by the machine. Deep learning can thus help support the diagnosis of heart failure using chest X-ray images.
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http://dx.doi.org/10.1536/ihj.19-714DOI Listing
July 2020

The dawning of the digital era in the management of hypertension.

Hypertens Res 2020 11 13;43(11):1135-1140. Epub 2020 Jul 13.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Awareness, treatment, and control of hypertension are of the utmost importance in conquering stroke and cardiovascular disease. To reduce the global burden of hypertension, the Japanese Society of Hypertension (JSH) established the "JSH Future Plan" based on an increasing need to transform the strategy for combating hypertension. In addition to energizing conventional approaches in basic, translational, and clinical research, the application of rapidly evolving digital health technologies and artificial intelligence to hypertension healthcare and research (digital hypertension) holds promise for providing further insights into the pathophysiology and therapeutic targets and implementing predictive, personalized, and preemptive approaches in clinical practice. With great potential to revolutionize the landscape of hypertension, digital hypertension has some technical, legal, ethical, social, and financial issues to overcome. Given the multidisciplinary framework, digital hypertension requires comprehensive and strategic collaboration among industry, academia, and government to move forward toward the goal of "Future Medicine".
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http://dx.doi.org/10.1038/s41440-020-0506-1DOI Listing
November 2020

Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease.

Circ Genom Precis Med 2020 06 29;13(3):e002670. Epub 2020 May 29.

Department of Cardiovascular Medicine, Graduate School of Medicine (H. Matsunaga, S.N., H. Ieki, H.M., H.A., I.K.), University of Tokyo.

Background: Genome-wide association studies provided many biological insights into coronary artery disease (CAD), but these studies were mainly performed in Europeans. Genome-wide association studies in diverse populations have the potential to advance our understanding of CAD.

Methods: We conducted 2 genome-wide association studies for CAD in the Japanese population, which included 12 494 cases and 28 879 controls and 2808 cases and 7261 controls, respectively. Then, we performed transethnic meta-analysis using the results of the coronary artery disease genome-wide replication and meta-analysis plus the coronary artery disease 1000 Genomes meta-analysis with UK Biobank. We then explored the pathophysiological significance of these novel loci and examined the differences in CAD-susceptibility loci between Japanese and Europeans.

Results: We identified 3 new loci on chromosome 1q21 (), 10q26 (), and 11q22 (-). Quantitative trait locus analyses suggested the association of and - with atherosclerotic immune cells. Tissue/cell type enrichment analysis showed the involvement of arteries, adrenal glands, and fat tissues in the development of CAD. We next compared the odds ratios of lead variants for myocardial infarction at 76 genome-wide significant loci in the transethnic meta-analysis and a moderate correlation between Japanese and Europeans, where 8 loci showed a difference. Finally, we performed tissue/cell type enrichment analysis using East Asian-frequent and European-frequent variants according to the risk allele frequencies and identified significant enrichment of adrenal glands in the East Asian-frequent group while the enrichment of arteries and fat tissues was found in the European-frequent group. These findings indicate biological differences in CAD susceptibility between Japanese and Europeans.

Conclusions: We identified 3 new loci for CAD and highlighted the genetic differences between the Japanese and European populations. Moreover, our transethnic analyses showed both shared and unique genetic architectures between the Japanese and Europeans. While most of the underlying genetic bases for CAD are shared, further analyses in diverse populations will be needed to elucidate variations fully.
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http://dx.doi.org/10.1161/CIRCGEN.119.002670DOI Listing
June 2020

[Onco-cardiology in the field of hematology].

Authors:
Hiroshi Akazawa

Rinsho Ketsueki 2019 ;60(9):1372-1377

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

Recent progress in cancer therapy has improved the long-term outcomes of cancer patients, and it has increased the importance of managing cardiovascular complications associated with cancer and cancer therapies. In the field of hematology, there is a serious concern about cardiovascular complications associated with a variety of chemotherapeutic drugs, such as anthracyclines, BCR-ABL tyrosine kinase inhibitors, and proteasome inhibitors. Despite the recent accumulation of epidemiological and clinical data and the fact that these are molecularly targeted drugs, molecular mechanisms underlying the pathogenesis of cardiovascular toxicities associated with individual drugs remain to be precisely defined. Recently emerging "onco-cardiology" will extend the interdisciplinary collaboration between oncology, hematology, and cardiology specialists in clinical practice, research, and education in order to protect cancer patients and survivors from cardiovascular complications.
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http://dx.doi.org/10.11406/rinketsu.60.1372DOI Listing
October 2019

Overview of the 83 Annual Scientific Meeting of the Japanese Circulation Society - Renaissance of Cardiology for the Creation of Future Medicine.

Circ J 2019 08 3;83(9):1829-1835. Epub 2019 Aug 3.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

The 83Annual Scientific Meeting of the Japanese Circulation Society was held in Yokohama, Japan, on March 29-31, 2019, just as the cherry blossoms came into full bloom. Because the environment around cardiovascular healthcare is rapidly changing, it becomes highly important to make a breakthrough at the dawn of a new era. The main theme of this meeting was "Renaissance of Cardiology for the Creation of Future Medicine". The meeting benefited from the participation of 18,825 people, and there were in-depth and extensive discussions at every session, focusing on topics covering clinical and basic research, medical care provision system, human resource development, and public awareness in cardiovascular medicine. The meeting was completed with great success, and we greatly appreciate the tremendous cooperation and support from all affiliates.
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http://dx.doi.org/10.1253/circj.CJ-19-0587DOI Listing
August 2019

Author Correction: Activated β-catenin in Foxp3 regulatory T cells links inflammatory environments to autoimmunity.

Nat Immunol 2019 07;20(7):943

Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41590-019-0438-6DOI Listing
July 2019

High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload.

J Mol Cell Cardiol 2019 03 3;128:77-89. Epub 2019 Jan 3.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

Background: The heart responds to hemodynamic overload through cardiac hypertrophy and activation of the fetal gene program. However, these changes have not been thoroughly examined in individual cardiomyocytes, and the relation between cardiomyocyte size and fetal gene expression remains elusive. We established a method of high-throughput single-molecule RNA imaging analysis of in vivo cardiomyocytes and determined spatial and temporal changes during the development of heart failure.

Methods And Results: We applied three novel single-cell analysis methods, namely, single-cell quantitative PCR (sc-qPCR), single-cell RNA sequencing (scRNA-seq), and single-molecule fluorescence in situ hybridization (smFISH). Isolated cardiomyocytes and cross sections from pressure overloaded murine hearts after transverse aortic constriction (TAC) were analyzed at an early hypertrophy stage (2 weeks, TAC2W) and at a late heart failure stage (8 weeks, TAC8W). Expression of myosin heavy chain β (Myh7), a representative fetal gene, was induced in some cardiomyocytes in TAC2W hearts and in more cardiomyocytes in TAC8W hearts. Expression levels of Myh7 varied considerably among cardiomyocytes. Myh7-expressing cardiomyocytes were significantly more abundant in the middle layer, compared with the inner or outer layers of TAC2W hearts, while such spatial differences were not observed in TAC8W hearts. Expression levels of Myh7 were inversely correlated with cardiomyocyte size and expression levels of mitochondria-related genes.

Conclusions: We developed a new image-analysis pipeline to allow automated and unbiased quantification of gene expression at the single-cell level and determined the spatial and temporal regulation of heterogenous Myh7 expression in cardiomyocytes after pressure overload.
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http://dx.doi.org/10.1016/j.yjmcc.2018.12.018DOI Listing
March 2019

Pressure Overload Impairs Cardiac Function in Long-Chain Fatty Acid Transporter CD36-Knockout Mice.

Int Heart J 2019 Jan 5;60(1):159-167. Epub 2018 Dec 5.

Rinku General Medical Center.

CD36 is one of the important transporters of long-chain fatty acids (LCFAs) in the myocardium. We previously reported that CD36-deficient patients demonstrate a marked reduction of myocardial uptake of LCFA, while myocardial glucose uptake shows a compensatory increase, and are often accompanied by cardiomyopathy. However, the molecular mechanisms and functional role of CD36 in the myocardium remain unknown.The current study aimed to explore the pathophysiological role of CD36 in the heart. Methods: Using wild type (WT) and knockout (KO) mice, we generated pressure overload by transverse aortic constriction (TAC) and analyzed cardiac functions by echocardiography. To assess cardiac hypertrophy and fibrosis, histological and molecular analyses and measurement of ATP concentration in mouse hearts were performed.By applying TAC, the survival rate was significantly lower in KO than that in WT mice. After TAC, KO mice showed significantly higher heart weight-to-tibial length ratio and larger cross-sectional area of cardiomyocytes than those of WT. Although left ventricular (LV) wall thickness in the KO mice was similar to that in the WT mice, the KO mice showed a significant enlargement of LV cavity and reduced LV fractional shortening compared to the WT mice with TAC. A tendency for decreased myocardial ATP concentration was observed in the KO mice compared to the WT mice after TAC operation.These data suggest that the LCFA transporter CD36 is required for the maintenance of energy provision, systolic function, and myocardial structure.
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http://dx.doi.org/10.1536/ihj.18-114DOI Listing
January 2019

Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury.

JACC Basic Transl Sci 2018 Oct 12;3(5):639-653. Epub 2018 Nov 12.

Department of Cardiovascular Medicine, The University of Tokyo Hospital, Tokyo, Japan.

Accumulating data suggest that new cardiomyocytes in adults are generated from existing cardiomyocytes throughout life. To enhance the endogenous cardiac regeneration, we performed chemical screenings to identify compounds that activate pro-proliferative YES-associated protein and transcriptional enhancer factor domain activities in cardiomyocytes. We synthesized a novel fluorine-containing TT-10 (CHFNOS) from the biologically hit compound. TT-10 promoted cardiomyocyte proliferation and simultaneously exerted antioxidant and antiapoptotic effects in vitro. TT-10 treatment in mice ameliorated myocardial infarction-induced cardiac dysfunction at least in part via enhancing clonal expansion of existing cardiomyocytes with nuclear YES-associated protein expression. Stimulating cardiomyocyte proliferation and/or protection with TT-10 might complement current therapies for myocardial infarction.
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http://dx.doi.org/10.1016/j.jacbts.2018.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234526PMC
October 2018

Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.

Nat Commun 2018 10 30;9(1):4435. Epub 2018 Oct 30.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.

Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
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http://dx.doi.org/10.1038/s41467-018-06639-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207673PMC
October 2018

Activated β-catenin in Foxp3 regulatory T cells links inflammatory environments to autoimmunity.

Nat Immunol 2018 12 29;19(12):1391-1402. Epub 2018 Oct 29.

Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, USA.

Foxp3 regulatory T cells (T cells) are the central component of peripheral immune tolerance. Whereas a dysregulated T cytokine signature has been observed in autoimmune diseases, the regulatory mechanisms underlying pro- and anti-inflammatory cytokine production are elusive. Here, we identify an imbalance between the cytokines IFN-γ and IL-10 as a shared T signature present in patients with multiple sclerosis and under high-salt conditions. RNA-sequencing analysis on human T subpopulations revealed β-catenin as a key regulator of IFN-γ and IL-10 expression. The activated β-catenin signature was enriched in human IFN-γ T cells, as confirmed in vivo with T-specific β-catenin-stabilized mice exhibiting lethal autoimmunity with a dysfunctional T phenotype. Moreover, we identified prostaglandin E receptor 2 (PTGER2) as a regulator of IFN-γ and IL-10 production under a high-salt environment, with skewed activation of the β-catenin-SGK1-Foxo axis. Our findings reveal a novel PTGER2-β-catenin loop in T cells linking environmental high-salt conditions to autoimmunity.
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http://dx.doi.org/10.1038/s41590-018-0236-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240373PMC
December 2018

Author Correction: Activation of endothelial β-catenin signaling induces heart failure.

Sci Rep 2018 Oct 29;8(1):15858. Epub 2018 Oct 29.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-34062-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206138PMC
October 2018

MicroRNAs as biomarkers for cardiac sarcoidosis: No matter how small.

J Cardiol 2018 12 1;72(6):449-451. Epub 2018 Sep 1.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jjcc.2018.08.001DOI Listing
December 2018

A Novel Bioabsorbable Sheet That Delivers NF-κB Decoy Oligonucleotide Restrains Abdominal Aortic Aneurysm Development in Rats.

Int Heart J 2018 Sep 11;59(5):1134-1141. Epub 2018 Aug 11.

Department of Cardiovascular Medicine, School of Medicine, The University of Tokyo.

For the suppression of inflammation in the aneurysm development, we focused on inhibition of an important transcription factor, nuclear factor-kappa B (NF-κB), using a decoy strategy. We newly developed a novel bioabsorbable sheet that delivers NF-κB decoy oligodeoxynucleotide (ODN).We treated 5-week-old SD rats that were induced with abdominal aortic aneurysm (AAA) using 0.5 M CaCl with an NF-κB decoy sheet. Four weeks after AAA induction, aortic tissue was excised for further examinations. We showed that this bioabsorbable sheet could deliver the decoy ODN into the target tissues and dissolve within a week. Treatment with the NF-κB decoy sheet reduced the aneurysm size compared with the controls. It also suppressed inflammation due to the effect of NF-κB decoy ODN. Immunohistochemistry revealed that the expression of CD31, CD4, and CD11b in the NF-κB decoy sheet group was significantly lower than in the control sheet group. The NF-κB decoy sheet was absorbed on the target tissue.We have revealed that the bioabsorbable sheet mediated decoy ODN is effective for transfection into target organs. We have also indicated that NF-κB decoy ODN transfection using this sheet has the potential to suppress the dilatation of aneurysm. The bioabsorbable sheet mediated transfection of the decoy ODN can be beneficial for the clinical treatment of AAA and other NF-κB-related cardiovascular diseases.
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http://dx.doi.org/10.1536/ihj.17-632DOI Listing
September 2018

Periodontitis and Diabetes Mellitus: Be true to your teeth.

Authors:
Hiroshi Akazawa

Int Heart J 2018 ;59(4):680-682

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

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http://dx.doi.org/10.1536/ihj.18-410DOI Listing
August 2018

Impact of Pathogenic Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome.

Circ Genom Precis Med 2018 06;11(6):e002058

Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.).

Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between genotype and severe aortopathy (aortic root replacement, type A dissections, and related death).

Methods: We evaluated 248 patients with pathogenic or likely pathogenic variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the genotype on severe aortic events (aortic root replacement, type A dissections, and related death).

Results: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; <0.001).

Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.
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http://dx.doi.org/10.1161/CIRCGEN.117.002058DOI Listing
June 2018

Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma.

Eur J Hum Genet 2018 08 30;26(8):1151-1158. Epub 2018 Apr 30.

Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Tokyo, 113-8655, Japan.

Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys-Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG_007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site, which produced an out-of-frame transcript (r.807_882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806_973del, 965_973 del], and produced two functionally inactivated proteins, p.[Asp269_Gln324del, Thr323_Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5' natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant-negative and truncating variants in STK domain induce LDS and MSSE, respectively.
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http://dx.doi.org/10.1038/s41431-018-0127-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057981PMC
August 2018

Coronary Artery Aneurysm Caused by a Stent Fracture.

Int Heart J 2018 ;59(1):203-208

Department of Cardiovascular Medicine, The University of Tokyo Hospital.

Coronary stent fracture (SF) is rare as a complication of percutaneous coronary intervention (PCI), and its adverse events are increasingly being recognized with the development in devices of PCI. The major adverse events caused by SFs are in-stent restenosis due to neointimal overgrowth caused by poor drug delivery. A coronary artery aneurysm (CAA) is a rare complication of SF, but may lead to lethal events such as acute coronary syndrome or rupture of the CAA further leading to cardiac tamponade. However, the management of CAAs is controversial with or without SF. Herein, we report a case of a CAA caused by an SF and discuss the management of CAA complicated with SF, along with a literature review. We suggest that surgical treatment should be considered the higher-priority strategy in the cases of CAA with SF as compared to CAA without SF.
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http://dx.doi.org/10.1536/ihj.17-081DOI Listing
February 2018

[Cardiotoxicity of Cancer Chemotherapy - Mechanisms and Therapeutic Approach].

Authors:
Hiroshi Akazawa

Gan To Kagaku Ryoho 2017 Dec;44(13):2058-2063

Dept. of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

Recent progress in cancer chemotherapy has improved the long-term outcome for cancer patients. Under such circumstances, it is increasingly of clinical importance to manage the cardiovascular complications, which are related to both cancer itself and adverse effects of cancer therapies. Among the most concerning as cardiovascular complications of cancer therapies is chemotherapy-induced cardiotoxicity or chemotherapy-related cardiac dysfunction(CTRCD). CTRCD has been intuitively classified according to the extent of structural abnormalities and degree of reversibility; type 1 is irreversible and dose-dependent with structural abnormalities, and type 2 is reversible after cessation of treatment and dose-independent without structural abnormalities. An example of drugs causing type 1 and 2 CTRCD is anthracyclines and trastuzumab, respectively, although both drugs are likely to induce cardiotoxicity through a combined action. In addition, there is growing awareness that CTRCD is also caused by anti-VEGF inhibitors and tyrosine kinase inhibitors(TKIs), particularly in patients with cardiovascular comorbidities and risk factors. Interdisciplinary collaboration between oncology and cardiology specialists will contribute to the solution of unmet needs to elucidate epidemiologic and pathophysiologic aspects of CTRCD and to establish diagnostic strategies with risk prediction and evidence-based therapeutic strategies against CTRCD in cancer patients and cancer survivors.
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December 2017

Japanese Cardiovascular Disease Patients with Diabetes Mellitus Suffer Increased Tooth Loss in Comparison to Those without Diabetes Mellitus -A Cross-sectional Study.

Intern Med 2018 Mar 20;57(6):777-782. Epub 2017 Nov 20.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Japan.

Objective Tooth loss is an irreversible condition that reflects the end-stage of oral diseases, including periodontitis. Although periodontitis is a major factor in the progression of diabetes mellitus (DM) and cardiovascular disease (CVD), no previous studies have compared tooth loss in CVD patients with and without DM. Methods The subjects included CVD patients with (n=94) and without (n=145) DM who attended Tokyo Medical and Dental University Hospital. Blood examinations and periodontal measurements were performed. Results The oral and periodontal examinations revealed that the numbers of missing teeth in the DM group were increased in comparison to the non-DM group. There was no significant difference between the groups with regard to the incidence of edentulism, the probing pocket depth, the clinical attachment level or the incidence of bleeding on probing. Conclusion We showed that the numbers of missing teeth among CVD patients with DM was significantly higher than that among CVD patients without DM.
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http://dx.doi.org/10.2169/internalmedicine.9578-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891513PMC
March 2018

Cost-Effectiveness Analysis of Cardiovascular Disease Treatment in Japan.

Int Heart J 2017 Dec 17;58(6):847-852. Epub 2017 Nov 17.

Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo.

The quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER) are important concepts in cost-effectiveness analysis, which is becoming increasingly important in Japan. QALY is used to estimate quality of life (QOL) and life years, and can be used to compare the efficacies of cancer and cardiovascular treatments. ICER is defined as the difference in cost between treatments divided by the difference in their effects, with a smaller ICER indicating better cost-effectiveness. Here, we present a review of cost-effectiveness analyses in Japan as well other countries. A number of treatments were shown to be cost-effective, e.g., statin for secondary prevention of cardiovascular disease, aspirin for primary prevention of cardiovascular disease, DOAC for high-risk atrial fibrillation, beta blockers, ACE inhibitors, and ARB for heart failure, sildenafil and bosentan for pulmonary hypertension, CABG for multi-vessel coronary disease, ICD for ventricular tachycardia, and CRT for heart failure with low ejection fraction, while others were not cost-effective, e.g., epoprostenol for pulmonary hypertension and LVAD for end-stage heart failure. Further investigations are required regarding some treatments, e.g., PCSK-9 inhibitors for familial hypercholesterolemia, PCI for multi-vessel coronary disease, catheter ablation for atrial fibrillation, and TAVI for severe aortic stenosis. Ethical aspects should be taken into consideration when utilizing the results of cost-effectiveness analysis in medical policy.
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http://dx.doi.org/10.1536/ihj.17-365DOI Listing
December 2017

Detrimental effects of specific Periodontopathic bacterial infection on tachyarrhythmia compared to Bradyarrhythmia.

BMC Cardiovasc Disord 2017 Oct 17;17(1):267. Epub 2017 Oct 17.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8549, Japan.

Background: Tachyarrhythmia (TA) and bradyarrhythmia (BA) are cardiac rhythm disorders that result in the decline of quality of life. While patients with periodontitis are at a high risk of cardiovascular disease (CVD), little causal information between TA and BA has been provided to date. To assess the relationship, periodontal bacterial infection in patients with TA or BA was evaluated.

Methods: The subjects were patients with TA (n = 98) or BA (n = 40) who attended Tokyo Medical and Dental University hospital. Periodontal and blood examinations were performed. Periodontopathic bacterial existence in saliva was evaluated.

Results: We found that specific periodontopathic bacteria, Porphyromonas gingivalis and Prevotella intermedia, were highly detected in saliva from TA patients compared to BA subjects. The rates of hypertension and dyslipidemia were comparable between the two groups.

Conclusion: Specific periodontal bacterial infection might affect TA progression.
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http://dx.doi.org/10.1186/s12872-017-0703-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645863PMC
October 2017