Language：English   Publishing type：Research paper (scientific journal)  

Elimination of senescent cells (senolysis) was recently reported to improve normal and pathological changes associated with aging in mice1,2. However, most senolytic agents inhibit antiapoptotic pathways3, raising the possibility of off-target effects in normal tissues. Identification of alternative senolytic approaches is therefore warranted. Here we identify glycoprotein nonmetastatic melanoma protein B (GPNMB) as a molecular target for senolytic therapy. Analysis of transcriptome data from senescent vascular endothelial cells revealed that GPNMB was a molecule with a transmembrane domain that was enriched in senescent cells (seno-antigen). GPNMB expression was upregulated in vascular endothelial cells and/or leukocytes of patients and mice with atherosclerosis. Genetic ablation of Gpnmb-positive cells attenuated senescence in adipose tissue and improved systemic metabolic abnormalities in mice fed a high-fat diet, and reduced atherosclerotic burden in apolipoprotein E knockout mice on a high-fat diet. We then immunized mice against Gpnmb and found a reduction in Gpnmb-positive cells. Senolytic vaccination also improved normal and pathological phenotypes associated with aging, and extended the male lifespan of progeroid mice. Our results suggest that vaccination targeting seno-antigens could be a potential strategy for new senolytic therapies.

DOI： 10.1038/s43587-021-00151-2

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Patients with type 2 diabetes treated with Sodium glucose transporter 2 (SGLT2) inhibitors show reduced mortality and hospitalization for heart failure (HF). SGLT2 inhibitors are considered to activate multiple cardioprotective pathways; however, underlying mechanisms are not fully described. This study aimed to elucidate the underlying mechanisms of the beneficial effects of SGLT2 inhibitors on the failing heart. We generated a left ventricular (LV) pressure overload model in C57BL/6NCrSlc mice by transverse aortic constriction (TAC) and examined the effects of empagliflozin (EMPA) in this model. We conducted metabolome and transcriptome analyses and histological and physiological examinations. EMPA administration ameliorated pressure overload-induced systolic dysfunction. Metabolomic studies showed that EMPA increased citrulline levels in cardiac tissue and reduced levels of arginine, indicating enhanced metabolism from arginine to citrulline and nitric oxide (NO). Transcriptome suggested possible involvement of the insulin/AKT pathway that could activate NO production through phosphorylation of endothelial NO synthase (eNOS). Histological examination of the mice showed capillary rarefaction and endothelial apoptosis after TAC, both of which were significantly improved by EMPA treatment. This improvement was associated with enhanced expression phospho-eNOS and NO production in cardiac endothelial cells. NOS inhibition attenuated these cardioprotective effects of EMPA. The in vitro studies showed that catecholamine-induced endothelial apoptosis was inhibited by NO, arginine, or AKT activator. EMPA activates the AKT/eNOS/NO pathway, which helps to suppress endothelial apoptosis, maintain capillarization and improve systolic dysfunction during LV pressure overload.

DOI： 10.1038/s41598-021-97787-2

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[Figure: see text].

DOI： 10.1161/ATVBAHA.120.315612

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Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Treatment for SCAD includes conservative approaches, percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery. Although the success rate of PCI is low, conservative treatment often leads to a good clinical course. Three patients with SCAD who were conservatively treated with intra-aortic balloon pumping without coronary intervention are presented. All three patients continue to do well. <Learning objective: The treatment for spontaneous coronary artery dissection (SCAD) has not yet been established. Intra-aortic balloon pumping (IABP) is a potential conservative treatment for SCAD that increases coronary blood flow. However, IABP could worsen the dissection. In this report, IABP was safely used for SCAD and patients had a good clinical course without worsening the dissection.>.

DOI： 10.1016/j.jccase.2021.01.004

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Language：Japanese   Publisher：(公社)日本透析医会  

近年、心房細動(atrial fibrillation;AF)の治療は直接経口抗凝固薬(direct oral anti-coagulations;DOAC)やカテーテルアブレーションの普及により大きく変化してきた。血液透析患者におけるAF有病率は高いが、特有の病態やリスクから非透析患者とは異なる治療戦略が求められ、至適治療について議論が続いている。ワルファリンによる抗凝固療法は一律的な導入は推奨されず、塞栓症既往や弁膜症の有無を考慮し、必要性が高いと判断される症例のみに限定すべきという意見が強い。抗不整脈治療について心拍数コントロールが第一選択であるが、症状や血行動態から洞調率維持が必要な症例では薬物治療やアブレーションも選択されうる。今後のエビデンスの蓄積が待たれるとともに、個々の患者ごとに病態や塞栓症・出血リスクに基づく治療を行っていくことが求められる。(著者抄録)

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Prognosis of severe heart failure remains poor. Urgent new therapies are required. Some heart failure patients do not respond to established multidisciplinary treatment and are classified as "non-responders". The outcome is especially poor for non-responders, and underlying mechanisms are largely unknown. Mitofusin-1 (Mfn1), a mitochondrial fusion protein, is significantly reduced in non-responding patients. This study aimed to elucidate the role of Mfn1 in the failing heart. Twenty-two idiopathic dilated cardiomyopathy (IDCM) patients who underwent endomyocardial biopsy of intraventricular septum were included. Of the 22 patients, 8 were non-responders (left ventricular (LV) ejection fraction (LVEF) of < 10% improvement at late phase follow-up). Electron microscopy (EM), quantitative PCR, and immunofluorescence studies were performed to explore the biological processes and molecules involved in failure to respond. Studies in cardiac specific Mfn1 knockout mice (c-Mfn1 KO), and in vitro studies with neonatal rat ventricular myocytes (NRVMs) were also conducted. A significant reduction in mitochondrial size in cardiomyocytes, and Mfn1, was observed in non-responders. A LV pressure overload with thoracic aortic constriction (TAC) c-Mfn1 KO mouse model was generated. Systolic function was reduced in c-Mfn1 KO mice, while mitochondria alteration in TAC c-Mfn1 KO mice increased. In vitro studies in NRVMs indicated negative regulation of Mfn1 by the β-AR/cAMP/PKA/miR-140-5p pathway resulting in significant reduction in mitochondrial respiration of NRVMs. The level of miR140-5p was increased in cardiac tissues of non-responders. Mfn1 is a biomarker of heart failure in non-responders. Therapies targeting mitochondrial dynamics and homeostasis are next generation therapy for non-responding heart failure patients.

DOI： 10.1038/s41598-021-86209-y

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Language：English   Publisher：(一社)日本抗加齢医学会  

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p53 is a guardian of the genome that protects against carcinogenesis. There is accumulating evidence that p53 is activated with aging. Such activation has been reported to contribute to various age-associated pathologies, but its role in vascular dysfunction is largely unknown. The aim of this study was to investigate whether activation of endothelial p53 has a pathological effect in relation to endothelial function. We established endothelial p53 loss-of-function and gain-of-function models by breeding endothelial-cell specific Cre mice with floxed Trp53 or floxed Mdm2/Mdm4 mice, respectively. Then we induced diabetes by injection of streptozotocin. In the diabetic state, endothelial p53 expression was markedly up-regulated and endothelium-dependent vasodilatation was significantly impaired. Impairment of vasodilatation was significantly ameliorated in endothelial p53 knockout (EC-p53 KO) mice, and deletion of endothelial p53 also significantly enhanced the induction of angiogenesis by ischemia. Conversely, activation of endothelial p53 by deleting Mdm2/Mdm4 reduced both endothelium-dependent vasodilatation and ischemia-induced angiogenesis. Introduction of p53 into human endothelial cells up-regulated the expression of phosphatase and tensin homolog (PTEN), thereby reducing phospho-eNOS levels. Consistent with these results, the beneficial impact of endothelial p53 deletion on endothelial function was attenuated in EC-p53 KO mice with an eNOS-deficient background. These results show that endothelial p53 negatively regulates endothelium-dependent vasodilatation and ischemia-induced angiogenesis, suggesting that inhibition of endothelial p53 could be a novel therapeutic target in patients with metabolic disorders.

DOI： 10.1016/j.yjmcc.2019.02.010

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We previously demonstrated that cellular aging signals upregulated a secreted class 3 semaphorin E (Sema3E) and its receptor plexinD1 in the adipose tissue of a murine model of dietary obesity and that Sema3E was a chemoattractant, mediating its biological effects by inducing infiltration of plexinD1-positive inflammatory macrophages into the visceral white adipose tissue. This study was performed to develop a peptide vaccine for Sema3E and test its therapeutic potential in a murine model of dietary obesity. Two antigenic peptides were selected to generate neutralizing antibodies for a vaccine. These peptides were conjugated to keyhole limpet hemocyanin (KLH), and were administered with Freund's adjuvant to obese wild-type male mice. The Sema3E antibody titer was analyzed by ELISA, and the biological effects of the peptides were tested in mice with dietary obesity. Among the two candidate peptides, the Sema3E antibody titer was significantly increased by injection of KLH-conjugated HKEGPEYHWS (Sema3E vaccine). Administration of Sema3E vaccine suppressed the infiltration of plexinD1-positive cells, ameliorated chronic inflammation in visceral white adipose tissue, and improved systemic glucose intolerance in mice with dietary obesity, suggesting that Sema3E vaccine has the potential to become a next generation therapy for obesity and diabetes.

DOI： 10.1038/s41598-019-40325-y

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Pulmonary arterial hypertension (PAH) is characterized by remodeling and narrowing of the pulmonary arteries, which lead to elevation of right ventricular pressure, heart failure, and death. Proliferation of pulmonary artery smooth muscle cells (PASMCs) is thought to be central to the pathogenesis of PAH, although the underlying mechanisms are still being explored. The protein p53 is involved in cell cycle coordination, DNA repair, apoptosis, and cellular senescence, but its role in pulmonary hypertension (PH) is not fully known. We developed a mouse model of hypoxia-induced pulmonary hypertension (PH) and found significant reduction of p53 expression in the lungs. Our in vitro experiments with metabolomic analyses and the Seahorse XF extracellular flux analyzer indicated that suppression of p53 expression in PASMCs led to upregulation of glycolysis and downregulation of mitochondrial respiration, suggesting a proliferative phenotype resembling that of cancer cells. It was previously shown that systemic genetic depletion of p53 in a murine PH model led to more severe lung manifestations. Lack of information about the role of cell-specific p53 signaling promoted us to investigate it in our mouse PH model with the inducible Cre-loxP system. We generated a mouse model with SMC-specific gain or loss of p53 function by crossing Myh11-Cre/ERT2 mice with floxed Mdm4 mice or floxed Trp53 mice. After these animals were exposed to hypoxia for 4 weeks, we conducted hemodynamic and echocardiographic studies. Surprisingly, the severity of PH was similar in both groups of mice and there were no differences between the genotypes. Our findings in these mice indicate that activation or suppression of p53 signaling in SMCs has a minor role in the pathogenesis of PH and suggest that p53 signaling in other cells (endothelial cells, immune cells, or fibroblasts) may be involved in the progression of this condition.

DOI： 10.1371/journal.pone.0212889

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Brown adipose tissue (BAT) is a metabolically active organ that contributes to the maintenance of systemic metabolism. The sympathetic nervous system plays important roles in the homeostasis of BAT and promotes its browning and activation. However, the role of other neurotransmitters in BAT homeostasis remains largely unknown. Our metabolomic analyses reveal that gamma-aminobutyric acid (GABA) levels are increased in the interscapular BAT of mice with dietary obesity. We also found a significant increase in GABA-type B receptor subunit 1 (GABA-BR1) in the cell membranes of brown adipocytes of dietary obese mice. When administered to obese mice, GABA induces BAT dysfunction together with systemic metabolic disorder. Conversely, the genetic inactivation or inhibition of GABA-BR1 leads to the re-browning of BAT under conditions of metabolic stress and ameliorated systemic glucose intolerance. These results indicate that the constitutive activation of GABA/GABA-BR1 signaling in obesity promotes BAT dysfunction and systemic metabolic derangement.

DOI： 10.1016/j.celrep.2018.08.024

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Previous studies have suggested that cellular senescence plays a central role in the progression of pathologic changes in the failing heart. It is well known that the sympathetic nervous system is activated in patients with heart failure, and this change is associated with poor clinical outcomes. Sympathetic activation increases the levels of various catecholamines, such as epinephrine and norepinephrine, but the contribution of these catecholamines to cellular senescence associated with heart failure remains to be determined. We found that catecholamine infusion induced senescence of endothelial cells and bone marrow cells, and promoted cardiac dysfunction in mice. In C57BL/6NCr mice, the continuous infusion of isoproterenol-induced cardiac inflammation and cardiac dysfunction. Expression of p53, a master regulator of cellular senescence, was increased in the cardiac tissue and bone marrow cells of these mice. Suppression of cellular senescence by genetic deletion of p53 in endothelial cells or bone marrow cells led to improvement of isoproterenol-induced cardiac dysfunction. In vitro studies showed that adrenergic signaling increased the expression of p53 and adhesion molecules by endothelial cells and macrophages. Our results indicate that catecholamine-induced senescence of endothelial cells and bone marrow cells plays a pivotal role in the progression of heart failure. Suppression of catecholamine-p53 signaling is crucial for inhibition of remodeling in the failing heart.

DOI： 10.1536/ihj.17-313

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Vascular cells have a finite lifespan and eventually enter irreversible growth arrest called cellular senescence. We have previously suggested that vascular cell senescence contributes to the pathogenesis of human atherosclerosis. Amlodipine is a mixture of two enantiomers, one of which (S- enantiomer) has L-type channel blocking activity, while the other (R+ enantiomer) shows ~1000-fold weaker channel blocking activity than S- enantiomer and has other unknown effects. It has been reported that amlodipine inhibits the progression of atherosclerosis in humans, but the molecular mechanism of this beneficial effect remains unknown. Apolipoprotein E-deficient mice on a high-fat diet were treated with amlodipine, its R+ enantiomer or vehicle for eight weeks. Compared with vehicle treatment, both amlodipine and the R+ enantiomer significantly reduced the number of senescent vascular cells and inhibited plaque formation to a similar extent. Expression of the pro-inflammatory molecule interleukin-1β was markedly upregulated in vehicle-treated mice, but was inhibited to a similar extent by treatment with amlodipine or the R+ enantiomer. Likewise, activation of p53 (a critical inducer of senescence) was markedly suppressed by treatment with amlodipine or the R+ enantiomer. These results suggest that amlodipine inhibits vascular cell senescence and protects against atherogenesis at least partly by a mechanism that is independent of calcium channel blockade.

DOI： 10.1536/ihj.17-265

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Left main coronary compression syndrome rarely occurs in patients with severe pulmonary hypertension. A 65-year-old woman with severe pulmonary hypertension due to an atrial septal defect suffered from angina on effort. Cardiac computed-tomography and coronary angiography revealed considerable stenosis of the left main coronary artery (LMA) caused by compression between the dilated main pulmonary artery trunk and the sinus of valsalva. Stenting of the LMA under intravascular ultrasound imaging was effective for the treatment of angina. We herein report the diagnosis and management of this condition with a brief literature review.

DOI： 10.2169/internalmedicine.9534-17

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Prasugrel, a novel P2Y12 receptor inhibitor, is administered to patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI), but it can increase the risk of bleeding. The Japanese exhibit weaker responses to clopidogrel than other races because of CYP2C19 polymorphisms; thus, it is unclear whether these patients should continue dual antiplatelet therapy (DAPT) using prasugrel or switch to clopidogrel in the chronic phase. Here we evaluated the clinical outcomes of DAPT guided by CYP2C19 polymorphisms after implantation of second-generation drug-eluting stents (DESs) for ACS management. Patients with ACS receiving PCI via DES from November 2011 to March 2015 were divided into two groups: conventional DAPT with clopidogrel (n = 41) and gene-guided DAPT (n = 24). In the gene-guided DAPT group, all patients with ACS were given DAPT using prasugrel as soon as possible; extensive and intermediate metabolizers receiving PCI for the first time were switched to clopidogrel at least 2 weeks after discharge, and intermediate metabolizers with repeated ACS and poor metabolizers continued on DAPT using prasugrel. Notably, gene-guided DAPT significantly reduced major adverse cardiovascular/cerebrovascular events (MACCEs; 22.0% versus 4.2%, hazard ratio [HR]: 0.15, 95% confidence interval [CI]: 0.01-0.81; P = 0.0247). Hemorrhagic complications were observed in 3.1% of patients receiving conventional DAPT and absent in the gene-guided group. Moreover, multivariate analysis showed that gene-guided DAPT significantly decreased MACCE incidence (HR: 0.15, 95% CI: 0.01-0.81; P = 0.033). Collectively, these data suggest that CYP2C19 polymorphism analysis may improve treatment decisions in patients with ACS receiving DES-PCI.

DOI： 10.1536/ihj.17-005

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Endothelial cells have an important role in maintaining vascular homeostasis. Age-related disorders (including obesity, diabetes, and hypertension) or aging per se induce endothelial dysfunction that predisposes to the development of atherosclerosis. Polyphenols have been reported to suppress age-related endothelial cell disorders, but their role in vascular function is yet to be determined. We investigated the influence of boysenberry polyphenol on vascular health under metabolic stress in a murine model of dietary obesity. We found that administration of boysenberry polyphenol suppressed production of reactive oxygen species (ROS) and increased production of nitric oxide (NO) in the aorta. It has been reported that p53 induces cellular senescence and has a crucial role in age-related disorders, including heart failure and diabetes. Administration of boysenberry polyphenol significantly reduced the endothelial p53 level in the aorta and ameliorated endothelial cell dysfunction in iliac arteries under metabolic stress. Boysenberry polyphenol also reduced ROS and p53 levels in cultured human umbilical vein endothelial cells (HUVECs), while increasing NO production. Uncoupled endothelial nitric oxide synthase (eNOS monomer) is known to promote ROS production. We found that boysenberry polyphenol reduced eNOS monomer levels both in vivo and in vitro, along with an increase of eNOS dimerization. To investigate the components of boysenberry polyphenol mediating these favorable biological effects, we extracted the anthocyanin fractions. We found that anthocyanins contributed to suppression of ROS and p53, in association with increased NO production and eNOS dimerization. In an ex vivo study, anthocyanins promoted relaxation of iliac arteries from mice with dietary obesity. These findings indicate that boysenberry polyphenol and anthocyanins, a major component of this polyphenol, inhibit endothelial dysfunction and contribute to maintenance of vascular homeostasis.

DOI： 10.1371/journal.pone.0202051

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It is thought that at least 6,500 low-molecular-weight metabolites exist in humans, and these metabolites have various important roles in biological systems in addition to proteins and genes. Comprehensive assessment of endogenous metabolites is called metabolomics, and recent advances in this field have enabled us to understand the critical role of previously unknown metabolites or metabolic pathways in the cardiovascular system. In this review, we will focus on heart failure and how metabolomic analysis has contributed to improving our understanding of the pathogenesis of this critical condition.

DOI： 10.1253/circj.CJ-17-1184

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Dipeptidyl peptidase 4 inhibitors are used worldwide in the management of diabetes, but their role in the prevention or treatment of cardiovascular disorders has yet to be defined. We found that linagliptin, a DPP-4 inhibitor, suppressed capillary rarefaction in the hearts of mice with dietary obesity. Metabolomic analysis performed with capillary electrophoresis/mass spectrometry (LC-MS/MS) showed that linagliptin promoted favorable metabolic remodeling in cardiac tissue, which was characterized by high levels of citrulline and creatine. DNA microarray analysis revealed that the cardiac tissue level of early growth response protein 1 (EGR-1), which activates angiogenesis, was significantly reduced in untreated mice with dietary obesity, while this decrease was inhibited by administration of linagliptin. Mature fibroblast growth factor 2 (FGF-2) has a putative truncation site for DPP-4 at the NH2-terminal, and LC-MS/MS showed that recombinant DPP-4 protein cleaved the NH2-terminal dipeptides of mature FGF-2. Incubation of cultured neonatal rat cardiomyocytes with FGF-2 increased Egr1 expression, while it was suppressed by recombinant DPP-4 protein. Furthermore, vascular endothelial growth factor-A had a critical role in mediating FGF-2/EGR-1 signaling. In conclusion, pharmacological inhibition of DPP-4 suppressed capillary rarefaction and contributed to favorable remodeling of cardiac metabolism in mice with dietary obesity.

DOI： 10.1371/journal.pone.0182422

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Language：Japanese   Publisher：(一社)日本内科学会  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J01159&link_issn=&doc_id=20170822110016&doc_link_id=10.2169%2Fnaika.106.1652&url=https%3A%2F%2Fdoi.org%2F10.2169%2Fnaika.106.1652&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Data of long-term efficacy and safety including bleeding risk associated with antithrombotic regimens after primary percutaneous coronary intervention (PCI) using first-generation drug-eluting stent (1st DES) are scarce. Consecutive 422 patients with ST-elevation myocardial infarction (STEMI) underwent primary PCI with DES (285 patients), bare metal stent (BMS, 58 patients) or balloon angioplasty (BA 79 patients). At a median follow-up of 44 months, major cardiovascular events were significantly lower for 1st DES compared with BMS and BA (11.9 vs. 25.9 vs. 16.5 %, p = 0.027). Cardiac death, recurrent myocardial infarction and target lesion revascularization (TLR), differed among the groups (DES 8.8 %; BMS 13.8 %; BA 17.7 %; p = 0.019), although the superiority of DES subsided beyond 1 year by increased late TLRs. Major bleedings were not higher in DES than in BMS and BA (4.6 vs. 6.9 vs. 1.5 %, p = 0.252). Multivariate logistic regression analysis revealed that both dual antiplatelet therapy (DAPT)[ 24 months and indefinite oral anticoagulation (OAC) were associated with a major bleeding. The risk was even greater with triple antithrombotic therapy (odds ratio 19.5; 95 % confidence interval 3.73-102.07; p < 0.0001). 1st DES showed favorable overall long-term clinical outcome in STEMI, with an inherent limitation of an increased risk of late TLR. Prolonged DAPT and OAC synergistically increase the risk of major bleeding after primary PCI.

DOI： 10.1007/s12928-014-0306-0

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Language：English   Publisher：CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS  

DOI： 10.1016/j.cardfail.2014.07.102

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：新潟市民病院  

症例は突然死と肥大型心筋症の家族歴がある45歳の男性。8年前に閉塞性肥大型心筋症と診断された。薬物治療(β遮断薬、カルシウム拮抗薬、抗不整脈薬Ia群)が行われたが、左室流出路圧較差及び労作時息切れの改善は認められなかった。今回、心房細動から心室細動になり、自動体外式除細動器で蘇生された。心臓カテーテル検査で左室流出路圧較差が130mmHgあり、ICD(implantable cardioverter defibrillator)植え込みを行った後に経皮的心筋中隔焼灼術(percutaneous transluminal septal myocardial ablation:PTSMA)を施行され、左室流出路圧較差は110mmHgから26mmHgへ改善した。その後息切れ等なく経過し、6ヵ月後の心臓カテーテル検査で左室流出路圧較差を認められなかった。本症例はPTSMAが奏効した経過良好な症例である。また、PTSMAを施行した後であっても頻脈性不整脈による心停止のリスクはあると報告されており、閉塞性肥大型心筋症で心停止をきたした症例に対してはPTSMAに加えてICDを植え込む必要があると考える。(著者抄録)

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Language：Japanese   Publisher：新潟市民病院  

症例は45歳男性。仕事中に胸痛の出現とともに意識消失し救急要請となった。救急車内で心室細動を繰り返し電気的除細動および心肺蘇生を受けながら当院へ搬送された。当院到着後も心室細動とPEA(無脈性電気活動)が持続し、救急外来で気管挿管、経皮的心肺補助装置(PCPS)を導入した。急性心筋梗塞を疑い緊急冠動脈造影を施行したところ、左冠動脈主幹部の完全閉塞を認め緊急経皮的冠動脈形成術(PCI)を施行し再灌流を得た。Max CPK 29779IU/L、Max CK-MB 2500IU/Lと非常に大きな心筋梗塞で、術直後の心エコーではEF 5%に低下していた。術後、低体温療法、PCPSとIABP(大動脈内バルーンパンピング)による機械的循環補助、薬物加療(カテコラミン、PDEIII阻害薬、カルペリチド、硝酸イソソルビド、利尿剤)を併用しながら左室収縮能の回復を待つと、下壁領域の壁運動が徐々に改善した。第7病日にPCPSを離脱、第19病日にIABPを抜去することができた。機械的循環補助離脱後も重篤な左心不全の薬物治療に難渋したが、第30病日に人工呼吸器を離脱、心臓リハビリテーションを行い第93病日に独歩退院となった。左冠動脈主幹部閉塞による急性心筋梗塞で心原性ショックを来した際の院内死亡率は55～80%と報告される。PCI手技が成熟した現在も極めて予後不良な疾患であり、いまだ確実な治療方法は確立していない。救命例は貴重であると考え報告する。(著者抄録)

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：新潟市民病院  

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73歳男性。診断は徐脈頻脈症候群であり、心房細動停止時に症状を伴う心停止が認められた。心房細動に対するアブレーション治療を施行することにより、心房細動発作が消失し、ペースメーカ埋込みを回避することができた。当院ではこれまでに11例の心房細動に対してアブレーション治療を行っている。11症例中10例において心房細動発作の減少、消失を認めており、BNP値、左房径の改善を認めている。心房細動アブレーション治療は、洞調律維持により、抗不整脈薬からの離脱、QOLの向上をもたらすと考えられる。(著者抄録)

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：新潟医学会  

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：新潟医学会  

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症例は50歳代、男性。既往歴は高血圧症、高尿酸血症。自宅にて突然の意識消失から心肺停止となり、家人により直ちに心肺蘇生を行われた。救急隊到着後に自己心拍再開し、当院搬送されたが、循環動態が安定せず、造影CTにて急性肺塞栓症と左膝窩静脈嚢状瘤と診断した。大量肺動脈血栓に対して、経皮的カテーテル治療を施行し、術直後より循環動態は安定した。血行動態が不安定な重症肺動脈塞栓症に対しては、速やかな血栓除去が必要であり、カテーテル治療は極めて有効であった。又、肺塞栓症の原因である膝窩静脈嚢状瘤に対しては、待機的に瘤の切開縫縮術を施行し、術後も抗凝固療法を併用した。しかし、外科的治療の長期有効性には、更なる検討が必要であると思われた。(著者抄録)

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：医歯薬出版  

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Other Link： https://search.jamas.or.jp/link/ui/2019280915

Language：English   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(NPO)日本冠疾患学会  

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Language：Japanese   Publisher：(NPO)日本冠疾患学会  

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Language：Japanese   Publisher：(株)羊土社  

加齢や肥満に伴い体内の脂肪は質的・量的変容を示し、メタボリックシンドロームや糖尿病を発症する基盤が形成される。高齢者や肥満者の脂肪組織には老化細胞が蓄積し、脂肪が機能不全に陥る主要なメカニズムを担うことが明らかになってきた。細胞老化の抑制、および老化細胞の除去を標的としたアプローチは、加齢や肥満に伴う脂肪機能不全を抑制し、全身の代謝障害に対する新しい治療法となる可能性がある。(著者抄録)

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：English   Publisher：(一社)日本肥満学会  

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Language：Japanese   Publisher：科学評論社  

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Other Link： https://search.jamas.or.jp/link/ui/2018137488

Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：(一社)日本肥満学会  

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Language：English   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：(一社)日本抗加齢医学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(株)羊土社  

種々の栄養関連シグナルは老化のプロセスと密接な関係があり、老化・寿命の制御にかかわっている。カロリー制限やインスリンシグナルの抑制が寿命を延長することは、さまざまな種で報告されてきた。反対に、過剰なインスリンシグナルの亢進は、老化のプロセスを促進する可能性が示唆されている。また最近、細胞レベルでの老化が内臓脂肪や血管内皮細胞で生じることで、全身のインスリン抵抗性(高インスリン血症)が増悪することもわかってきた。細胞老化を病態基盤として発症、進展する全身の代謝不全は、さまざまな老化関連疾患にとって病的意義をもつことが明らかとなった。(著者抄録)

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Language：Japanese   Publisher：(公財)臨床薬理研究振興財団  

骨粗鬆症を合併した冠動脈疾患患者12例(全女、平均75.7歳)を対象に、RANKL阻害薬であるデノスマブを投与し、6～12ヵ月後の冠動脈石灰化(CAC)スコアを冠動脈CTを用いて評価した。デノスマブ投与により骨密度は平均0.662g/cm2から0.679g/cm2に改善し、その改善率は2.5%であった。CACスコアは平均366.5から362.9に低下し、その改善率は1.8%であったが、CACスコアはばらつきが大きく治療前後で有意差はなかった。心血管事故の出現はなく、副作用としての低カルシウム血症もみられず、冠動脈疾患患者に対するデノスマブの安全性に問題はなかった。骨密度改善率とCACスコア改善率には相関関係を認め、骨粗鬆症治療薬デノスマブが冠動脈石灰化に対して抑制効果を示す可能性があることが示された。

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Language：English   Publisher：(一社)日本抗加齢医学会  

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Language：Japanese   Publisher：メディカルレビュー社  

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Language：Japanese   Publisher：新潟市民病院  

<目的>非保護左冠動脈主幹部(ULM)病変への血行再建では冠動脈バイパス術(CABG)もしくは経皮的冠動脈インターベンション(PCI)が選択される。ガイドラインではCABGがクラスI、症例によってPCIがクラスIIaとされるが、近年の臨床成績の向上と手技の普及に伴い、PCIが選択されることも増えている。当院での中期的な治療成績に基づき、ULM病変の治療方針の妥当性について検証を行う。<対象と方法>2005年1月～2012年3月に、ST上昇型心筋梗塞を除くULM病変へ血行再建が行われた124名(CABG群:66名、PCI群58名)の検討を行った。複合1次エンドポイントは、MACCE(総死亡・心筋梗塞(MI)・脳梗塞・標的血管再血行再建(TVR))とし、複合2次エンドポイントはcardiac event(心臓死・MI・TVR)とした。<結果>CABG群で慢性腎不全が有意に多かったが、それ以外の患者背景では両群に有意差を認めなかった。平均追跡期間はCABG群で3.41年、PCI群で3.29年であった。1次エンドポイントでは両群に有意差は認めず(CABG vs.PCI:57% vs 66%;logrank p=0.74)、2次エンドポイントでも有意差は認めなかった(CABG vs.PCI:83% vs 69%;logrank p=0.31)。SYNTAX scoreで階層化した両群の比較では予後に有意差は認めなかったが、ULM分岐部病変に対するPCIを1-stenting crossover法と2-stenting法で分けて比較すると、CABGに比べ有意に2-stenting法の成績が不良であった。<結語>当院におけるULM病変へのCABGとPCIの中期的な治療成績の比較検討では、PCIにおいても良好な治療成績が得られていた。(著者抄録)

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Language：Japanese   Publisher：Japan Heart Foundation  

DOI： 10.11281/shinzo.46.1114

DOI： 10.2169/internalmedicine.0886-18_references_DOI_aRsiniUvsOe14yOJaukETTAUWP9

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Language：Japanese   Publisher：(一社)日本不整脈心電学会  

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Language：Japanese   Publisher：新潟市民病院  

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Language：Japanese   Publisher：新潟市民病院  

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Other Link： http://hdl.handle.net/10191/36071

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J00990&link_issn=&doc_id=20131128040025&doc_link_id=%2Fdg3nigta%2F2013%2Fs12707%2F019%2F0393-0393%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg3nigta%2F2013%2Fs12707%2F019%2F0393-0393%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Other Link： http://hdl.handle.net/10191/36059

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Other Link： http://hdl.handle.net/10191/36022

Language：Japanese   Publisher：新潟市民病院  

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Other Link： http://hdl.handle.net/10191/35346

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Other Link： http://hdl.handle.net/10191/31495

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Other Link： http://hdl.handle.net/10191/31441

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Other Link： http://hdl.handle.net/10191/29130