Publications by authors named "Kenjiro Sato"

41 Publications

Discovery of a novel series of GPR119 agonists: Design, synthesis, and biological evaluation of N-(Piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives.

Bioorg Med Chem 2021 Jul 9;41:116208. Epub 2021 May 9.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We undertook an optimization effort involving propan-2-yl 4-({6-[5-(methanesulfonyl)-2,3-dihydro-1H-indol-1-yl]pyrimidin-4-yl}oxy)piperidine-1-carboxylate 1, which we had previously discovered as a novel G protein-coupled receptor 119 (GPR119) agonist. To occupy a presumed hydrophobic space between the pyrimidine and piperidine rings in interaction with GPR119, we replaced the linker oxygen with nitrogen. Subsequently, the introduction of a substituent at the bridging nitrogen atom was explored. We found that the installation of N-trifluoromethyl group 10 not only enhanced GPR119 agonist activity but also considerably improved the human ether-à-go-go-related gene (hERG) inhibition profile. These improvements were not observed for non-fluorinated substituents, such as ethyl analog 8b. The next optimization effort focused on the exploration of a new surrogate structure for the indoline ring and the isosteric replacements of the piperidine N-Boc group to improve solubility, metabolic stability, and oral bioavailability. As a result, N-{1-[3-(2-fluoropropan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}-6-{[1-(methanesulfonyl)piperidin-4-yl]oxy}-N-(trifluoromethyl)pyrimidin-4-amine (27) was identified as a potent and orally bioavailable GPR119 agonist. This compound augmented insulin secretion and effectively lowered plasma glucose excursion in a diabetic animal model after oral administration. In this study, we discuss the designs, syntheses, and biological activities of a novel series of N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine derivatives as GPR119 agonists, and to determine the distinctive effect of the N-trifluoromethyl group on hERG inhibition, we also discuss the conformational preference of representative compounds.
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http://dx.doi.org/10.1016/j.bmc.2021.116208DOI Listing
July 2021

Macrocyclic Peptides that Selectively Inhibit the Proteasome.

J Med Chem 2021 05 5;64(9):6262-6272. Epub 2021 May 5.

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, New York 10065, United States.

Treatment of tuberculosis (TB) currently takes at least 6 months. Latent (Mtb) is phenotypically tolerant to most anti-TB drugs. A key hypothesis is that drugs that kill nonreplicating (NR) Mtb may shorten treatment when used in combination with conventional drugs. The Mtb proteasome (Mtb20S) could be such a target because its pharmacological inhibition kills NR Mtb and its genetic deletion renders Mtb unable to persist in mice. Here, we report a series of macrocyclic peptides that potently and selectively target the Mtb20S over human proteasomes, including macrocycle . The cocrystal structure of macrocycle with Mtb20S revealed structural bases for the species selectivity. Inhibition of 20S within Mtb by dose dependently led to the accumulation of Pup-tagged GFP that is degradable but resistant to depupylation and death of nonreplicating Mtb under nitrosative stress. These results suggest that compounds of this class have the potential to develop as anti-TB therapeutics.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8194371PMC
May 2021

False negative results on PCR for SARS-COV-2 using nasopharyngeal swab.

Infect Dis (Lond) 2021 09 24;53(9):733-735. Epub 2021 Mar 24.

Department of Respiratory Medicine, Ome Municipal General Hospital, Tokyo, Japan.

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http://dx.doi.org/10.1080/23744235.2021.1903075DOI Listing
September 2021

Discovery of a novel series of indolinylpyrimidine-based GPR119 agonists: Elimination of ether-a-go-go-related gene liability using a hydrogen bond acceptor-focused approach.

Bioorg Med Chem 2021 Mar 23;34:116034. Epub 2021 Jan 23.

Cardiovascular & Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

We previously identified a novel series of indolinylpyrimidine derivatives exemplified by 2 in Figure 1, which is an indoline based derivative, as potent GPR119 agonists. Despite the attractive potency of 2, this compound inhibited the human ether-a-go-go-related gene (hERG) K channel. We elucidated crucial roles of the methylsulfonyl group of 2 in its interaction with the hERG channel and the GPR119 receptor, presumably as a hydrogen bond acceptor (HBA). To remove the undesirable hERG inhibitory activity, a strategy was implemented to arrange an HBA on a less conformationally flexible framework at the indoline 5-position instead of the methylsulfonyl group. This successfully led to the discovery of a piperidinone ring as a desirable motif at the indoline 5-position, which could minimize hERG liability as shown by 24b. Further optimization focused on the reduction of lipophilicity in terms of more favorable drug-like properties. Consequently, the introduction of a hydroxy group at the 3-position of the piperidinone ring effectively reduced lipophilicity without compromising GPR119 potency, resulting in the identification of (3S)-3-hydroxy-1-{1-[6-({1-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}oxy)pyrimidin-4-yl]- 2,3-dihydro-1H-indol-5-yl}piperidin-2-one ((S)-29) as a novel, potent, and orally bioavailable GPR119 agonist with a well-balanced profile. The pharmacological effects of this compound were also confirmed after single and chronic oral administration in diabetic animal models.
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http://dx.doi.org/10.1016/j.bmc.2021.116034DOI Listing
March 2021

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

Angew Chem Int Ed Engl 2021 04 11;60(17):9279-9283. Epub 2021 Mar 11.

Department of Microbiology & Immunology, Weill Cornell Medicine, 1300 York Ave, New York, NY, 10065, USA.

Plasmodium falciparum proteasome (Pf20S) inhibitors are active against Plasmodium at multiple stages-erythrocytic, gametocyte, liver, and gamete activation stages-indicating that selective Pf20S inhibitors possess the potential to be therapeutic, prophylactic, and transmission-blocking antimalarials. Starting from a reported compound, we developed a noncovalent, macrocyclic peptide inhibitor of the malarial proteasome with high species selectivity and improved pharmacokinetic properties. The compound demonstrates specific, time-dependent inhibition of the β5 subunit of the Pf20S, kills artemisinin-sensitive and artemisinin-resistant P. falciparum isolates in vitro and reduces parasitemia in humanized, P. falciparum-infected mice.
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http://dx.doi.org/10.1002/anie.202015845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087158PMC
April 2021

Plasma kinetics of mature PCSK9, furin-cleaved PCSK9, and Lp(a) with or without administration of PCSK9 inhibitors in acute myocardial infarction.

J Cardiol 2020 10 18;76(4):395-401. Epub 2020 May 18.

Department of Cardiology, Iwate Prefectural Central Hospital, Morioka, Japan.

Background: There are two types of circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), mature and furin-cleaved. Most types of lipoprotein(a) [Lp(a)], an independent risk factor of cardiovascular events, bind to mature PCSK9.

Objective: This study examined the effects of monoclonal anti-PCSK9 antibody on plasma PCSK9 and Lp(a) levels in acute myocardial infarction (MI).

Methods: Acute MI patients (n=36) were randomly divided into evolocumab (140mg; n=17) and non-evolocumab (n=19) groups. Changes in plasma PCSK9 and Lp(a) levels were monitored before and 1, 3, 5, 10, and 20 days after evolocumab administration.

Results: In the non-evolocumab group, plasma levels of mature PCSK9, furin-cleaved PCSK9, and Lp(a) (236.4±57.3ng/mL, 22.4±5.8ng/mL, and 19.2.±16.5mg/dL, respectively) significantly increased by day 3 (408.8±77.1ng/mL, p<0.001; 47.2±15.7ng/mL, p<0.001; and 39.7±21.3mg/dL, p<0.005, respectively) and returned to the baseline by day 10 or 20. In the evolocumab group, mature PCSK9 significantly increased by >1000ng/mL with a simultaneous decline of furin-cleaved PCSK9 below the measurement sensitivity level after day 3. The incremental area under the curve for plasma Lp(a) levels was significantly smaller in the evolocumab group compared with the non-evolocumab group (p=0.038).

Conclusion: Mature and furin-cleaved PCSK9 are transiently upregulated after MI onset. Evolocumab significantly increases mature PCSK9 and decreases furin-cleaved PCSK9 and might inhibit transient increase of plasma Lp(a) in acute MI.
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http://dx.doi.org/10.1016/j.jjcc.2020.04.006DOI Listing
October 2020

Clinical characteristics and prognostic factors in elderly patients with chronic heart failure -A report from the CHART-2 study.

Int J Cardiol Heart Vasc 2020 Apr 20;27:100497. Epub 2020 Mar 20.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Since most of the randomized clinical trials for heart failure (HF) were designed to exclude elderly patients, limited data are available on their clinical characteristics, prognosis, and prognostic factors.

Methods: We compared clinical characteristics, prognosis, and prognostic factors among Stage C/D HF patients in our CHART-2 Study (N = 4876, mean 69 years, women 32%, 6.3-year follow-up) by age (G1, ≤64 years, N = 1521; G2, 65-74 years, N = 1510; and G3, ≥75 years, N = 1845).

Results: From G1 to G3, the prevalence of women, left ventricular ejection fraction (LVEF) and plasma levels of B-type natriuretic peptide (BNP) increased (all P < 0.001). Similarly, 5-year mortality increased (9.9, 17.3 to 39.9%, P < 0.001) along with a decrease in proportion of cardiovascular death and an increase in non-cardiovascular death in both sexes. While all-cause and cardiovascular mortality was comparable between the sexes, women had significantly lower incidence of non-cardiovascular death than men in G2 and G3, which was attributable to the higher incidence of cancer death and pneumonia death in men than in women. Although NYHA functional class III-IV, chronic kidney disease, cancer, LVEF, and BNP had significant impacts on all-cause death in all groups, their impacts were less evident in G3 as compared with G1.

Conclusions: The elderly HF patients, as compared with younger HF patients, were characterized by more severe clinical background, increased proportion of non-cardiovascular death and worse prognosis with different impacts of prognostic factors across the age groups.
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http://dx.doi.org/10.1016/j.ijcha.2020.100497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090329PMC
April 2020

Inhibition of MGAT2 modulates fat-induced gut peptide release and fat intake in normal mice and ameliorates obesity and diabetes in ob/ob mice fed on a high-fat diet.

FEBS Open Bio 2020 03 5;10(3):316-326. Epub 2020 Feb 5.

Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.

Monoacylglycerol O-acyltransferase 2 (MGAT2) is one of the key enzymes responsible for triglyceride (TG) re-synthesis in the small intestine. We have previously demonstrated that pharmacological inhibition of MGAT2 has beneficial effects on obesity and metabolic disorders in mice. Here, we further investigate the effects of MGAT2 inhibition on (a) fat-induced gut peptide release and fat intake in normal mice and (b) metabolic disorders in high-fat diet (HFD)-fed ob/ob mice, a model of severe obesity and type 2 diabetes mellitus, using an orally bioavailable MGAT2 inhibitor Compound B (CpdB). CpdB inhibited elevation of plasma TG in mice challenged with an oil-supplemented liquid meal. Oil challenge stimulated the secretion of two gut anorectic hormones (peptide tyrosine-tyrosine and glucagon-like peptide-1) into the bloodstream, and these responses were augmented in mice pretreated with CpdB. In a two-choice test using an HFD and a low-fat diet, CpdB selectively inhibited intake of the HFD in normal mice. Administration of CpdB to HFD-fed ob/ob mice for 5 weeks suppressed food intake and body weight gain and inhibited elevation of glycated hemoglobin. These results indicate that pharmacological MGAT2 inhibition modulates fat-induced gut peptide release and fat intake in normal mice and improves obesity and diabetes in HFD-fed ob/ob mice and thus may have potential for development into a treatment of obesity and its related metabolic diseases.
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http://dx.doi.org/10.1002/2211-5463.12778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050258PMC
March 2020

Selective Phenylimidazole-Based Inhibitors of the Proteasome.

J Med Chem 2019 10 15;62(20):9246-9253. Epub 2019 Oct 15.

Department of Microbiology & Immunology , Weill Cornell Medicine , 1300 York Avenue , New York , New York 10065 , United States.

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091493PMC
October 2019

Decline of popliteal artery flow-mediated dilation with aging and possible involvement of asymmetric dimethylarginine in healthy men.

J Med Ultrason (2001) 2019 Oct 23;46(4):503-511. Epub 2019 Apr 23.

Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan.

Purpose: We examined the influences of age and gender on flow-mediated endothelial function and the involvement of the competitive inhibition of L-arginine in endothelial function.

Methods: We measured brachial and popliteal flow-mediated vasodilation (FMD) responses, nitrate/nitrite (NOx) concentrations, and plasma levels of asymmetric dimethylarginine (ADMA) in four healthy, nonsmoking groups: young men (mean 26 ± 2 years, n = 17), middle-aged men (mean 50 ± 3 years, n = 19), young women (mean 27 ± 2 years, n = 16), and middle-aged women (mean 51 ± 2 years, n = 18).

Results: In young men, we found no significant differences between brachial and popliteal artery FMDs (10.6 ± 1.5 vs 8.7 ± 1.6%, p = 0.06). However, the popliteal artery FMD was significantly lower than the brachial artery FMD in middle-aged men (11.4 ± 1.5 vs 6.4 ± 1.0%, p < 0.001). In women, we found no significant differences between brachial and popliteal artery FMDs in young and middle-aged individuals (young, p = 0.17; middle-aged, p = 0.08). Popliteal artery FMD correlated with plasma NOx and ADMA levels as well as with the NOx/ADMA ratio in men but not in women (r = 0.485, - 0.544, and 0.672, respectively).

Conclusion: We concluded that a decrease in flow-mediated endothelial function in arteries of the lower extremities was evident in healthy middle-aged men, but not in middle-aged women. The competitive inhibition of L-arginine may contribute to this decrease in men.
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http://dx.doi.org/10.1007/s10396-019-00946-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765476PMC
October 2019

Impact of decreased insulin resistance by ezetimibe on postprandial lipid profiles and endothelial functions in obese, non-diabetic-metabolic syndrome patients with coronary artery disease.

Heart Vessels 2019 Jun 5;34(6):916-925. Epub 2018 Dec 5.

Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan.

The association between insulin resistance and lipid dysmetabolism after consuming a meal is unclear. We aimed at assessing the effects of ezetimibe on postprandial hyperlipidemia and hyperinsulinemia and to find out whether the medication improves endothelial function in obese metabolic syndrome (MetS) patients with coronary artery disease (CAD). We obtained oral fat loading test results (4 and 6 h after load) and brachial flow-mediated vasodilation (FMD) measurements before and 24 weeks after ezetimibe treatment initiation from 27 MetS patients with CAD and from 68 control patients with CAD alone. Serum triglyceride (TG) and insulin levels (2 h after the loading dose) were significantly higher in MetS patients than in control patients. The incremental areas under the curve (iAUCs) for these levels decreased significantly after ezetimibe treatment in MetS patients but not in control patients. Treatment with ezetimibe resulted in significant FMD changes in MetS patients (from 3.4 to 4.9%, P = 0.002), but not in control patients (from 5.1 to 5.4%, P = 0.216). When MetS patients were divided into two groups based on the median insulin iAUC reduction rate (higher group ≥ 34%, n = 14; lower group < 34%, n = 13), those in the higher group showed a significantly higher rate of change in the iAUCs of TG and FMD than those in the lower group (TG, 31.0% vs. 10.8%; P = 0.033; FMD, 39.2% vs. 9.8%; P = 0.037). These results suggest that ezetimibe may reverse insulin resistance, reducing lipid dysmetabolism after a meal and endothelial dysfunction in MetS patients with CAD.
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http://dx.doi.org/10.1007/s00380-018-1319-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531627PMC
June 2019

Androgen induced cellular proliferation, neurogenesis, and generation of GnRH3 neurons in the brain of mature female Mozambique tilapia.

Sci Rep 2018 11 15;8(1):16855. Epub 2018 Nov 15.

Department of Life Sciences, Toyo University, 1-1-1 Itakura, Oura, Gunma, 374-0193, Japan.

The neuroplastic mechanisms in the fish brain that underlie sex reversal remain unknown. Gonadotropin-releasing hormone 3 (GnRH3) neurons control male reproductive behaviours in Mozambique tilapia and show sexual dimorphism, with males having a greater number of GnRH3 neurons. Treatment with androgens such as 11-ketotestosterone (KT), but not 17β-estradiol, increases the number of GnRH3 neurons in mature females to a level similar to that observed in mature males. Compared with oestrogen, the effect of androgen on neurogenesis remains less clear. The present study examined the effects of 11-KT, a non-aromatizable androgen, on cellular proliferation, neurogenesis, generation of GnRH3 neurons and expression of cell cycle-related genes in mature females. The number of proliferating cell nuclear antigen-positive cells was increased by 11-KT. Simultaneous injection of bromodeoxyuridine and 11-KT significantly increased the number of newly-generated (newly-proliferated) neurons, but did not affect radial glial cells, and also resulted in newly-generated GnRH3 neurons. Transcriptome analysis showed that 11-KT modulates the expression of genes related to the cell cycle process. These findings suggest that tilapia could serve as a good animal model to elucidate the effects of androgen on adult neurogenesis and the mechanisms for sex reversal in the fish brain.
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http://dx.doi.org/10.1038/s41598-018-35303-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237963PMC
November 2018

Antimalarial proteasome inhibitor reveals collateral sensitivity from intersubunit interactions and fitness cost of resistance.

Proc Natl Acad Sci U S A 2018 07 2;115(29):E6863-E6870. Epub 2018 Jul 2.

Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA 94901.

We describe noncovalent, reversible asparagine ethylenediamine (AsnEDA) inhibitors of the proteasome (Pf20S) β5 subunit that spare all active subunits of human constitutive and immuno-proteasomes. The compounds are active against erythrocytic, sexual, and liver-stage parasites, against parasites resistant to current antimalarials, and against strains from patients in Africa. The β5 inhibitors synergize with a β2 inhibitor in vitro and in mice and with artemisinin. selected for resistance to an AsnEDA β5 inhibitor surprisingly harbored a point mutation in the noncatalytic β6 subunit. The β6 mutant was resistant to the species-selective Pf20S β5 inhibitor but remained sensitive to the species-nonselective β5 inhibitors bortezomib and carfilzomib. Moreover, resistance to the Pf20S β5 inhibitor was accompanied by increased sensitivity to a Pf20S β2 inhibitor. Finally, the β5 inhibitor-resistant mutant had a fitness cost that was exacerbated by irradiation. Thus, used in combination, multistage-active inhibitors of the Pf20S β5 and β2 subunits afford synergistic antimalarial activity with a potential to delay the emergence of resistance to artemisinins and each other.
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http://dx.doi.org/10.1073/pnas.1806109115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6055138PMC
July 2018

Sudden failure of ventricular pacing and recovery in a patient with cardiac sarcoidosis.

J Arrhythm 2017 Oct 26;33(5):521-522. Epub 2017 Jul 26.

Department of Cardiology, Iwate Prefectural Central Hospital, Morioka, Iwate 0200066, Japan.

A 76-year-old woman with sarcoidosis who had an implantable pacemaker for complete atrioventricular block was admitted with syncope. Electrocardiogram revealed ventricular pacing failure, and a marked rise in the ventricular pacing threshold. F-Fluorodeoxyglucose positron emission tomography (FDG-PET) indicated increased uptake of FDG in the ventricular septum. Three days after steroid therapy, the ventricular pacing threshold reverted to normal, and FDG-PET showed decreased FDG uptake in the ventricular septum. In this case report, we demonstrate that a sudden deterioration in the ventricular pacing threshold due to worsening cardiac sarcoidosis can be reversed with early steroid therapy.
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http://dx.doi.org/10.1016/j.joa.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5634719PMC
October 2017

Characterisation of human induced pluripotent stem cell-derived endothelial cells under shear stress using an easy-to-use microfluidic cell culture system.

Biomed Microdevices 2017 Oct 9;19(4):91. Epub 2017 Oct 9.

Institute of Microchemical Technology Co., Ltd., 713A West KSP, 3-2-1 Sakado, Takatsu, Kawasaki, 213-0012, Japan.

Induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) can contribute to elucidating the pathogenesis of heart and vascular diseases and developing their treatments. Their precise characteristics in fluid flow however remain unclear. Therefore, the aim of the present study is to characterise these features. We cultured three types of ECs in a microfluidic culture system: commercially available human iPS-ECs, human umbilical vein endothelial cells (HUVECs) and human umbilical artery endothelial cells (HUAECs). We then examined the mRNA expression levels of endothelial marker gene cluster of differentiation 31 (CD31), fit-related receptor tyrosine kinase (Flk-1), and the smooth muscle marker gene smooth muscle alpha-actin, and investigated changes in plasminogen activator inhibitor-1 (PAI-1) secretion and intracellular F-actin arrangement following heat stress. We also compared expressions of the arterial and venous marker genes ephrinB2 and EphB4, and the endothelial gap junction genes connexin (Cx) 37, 40, and 43 under fluidic shear stress to determine their arterial or venous characteristics. We found that iPS-ECs had similar endothelial marker gene expressions and exhibited similar increases in PAI-1 secretion under heat stress as HUVECs and HUAECs. In addition, F-actin arrangement in iPSC-ECs also responded to heat stress, as previously reported. However, they had different expression patterns of arterial and venous marker genes and Cx genes under different fluidic shear stress levels, showing that iPSC-ECs exhibit different characteristics from arterial and venous ECs. This microfluidic culture system equipped with variable shear stress control will provide an easy-to-use assay tool to examine characteristics of iPS-ECs generated by different protocols in various laboratories and contribute to basic and applied biomedical researches on iPS-ECs.
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http://dx.doi.org/10.1007/s10544-017-0229-5DOI Listing
October 2017

Comparison of the measured pre-ejection periods and left ventricular ejection times between echocardiography and impedance cardiography for optimizing cardiac resynchronization therapy.

J Arrhythm 2017 Apr 12;33(2):130-133. Epub 2016 Sep 12.

Department of Cardiology, Iwate Prefectural Central Hospital, Morioka 020-0066, Iwate, Japan.

Background: The pre-ejection period (PEP) and left ventricular ejection time (LVET) are easily measured by impedance cardiography (ICG). We hypothesized that the PEP/LVET measured by ICG would correlate with that measured by echocardiography, and that PEP/LVET measured by ICG would be useful for cardiac resynchronization therapy (CRT) optimization.

Methods: Newly CRT implanted patients were optimized by echocardiography. The PEP/LVET was measured by echocardiography and ICG in two different settings: optimized setting and right ventricle (RV)-only pacing.

Results: The PEP/LVET was significantly decreased in the optimized setting compared with that in RV-only pacing (0.62±0.13 vs 0.75±0.16, <0.05). The PEP/LVET values calculated by ICG and echocardiography were positively correlated (=0.553, =0.003).

Conclusion: ICG was useful for the optimization of CRT.
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http://dx.doi.org/10.1016/j.joa.2016.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388062PMC
April 2017

Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach.

J Med Chem 2017 01 9;60(2):608-626. Epub 2017 Jan 9.

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01007DOI Listing
January 2017

Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors.

Bioorg Med Chem 2016 12 14;24(23):6149-6165. Epub 2016 Sep 14.

Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1' binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.
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http://dx.doi.org/10.1016/j.bmc.2016.09.009DOI Listing
December 2016

Pharmacological characterization of a series of aryl-sulfonamide derivatives that potently and selectively inhibit monoacylglycerol acyltransferase 2.

Eur J Pharmacol 2016 Nov 20;791:569-577. Epub 2016 Sep 20.

Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.

Monoacylglycerol acyltransferase (MGAT) 2 is an endoplasmic reticulum membrane enzyme that catalyzes the synthesis of diacylglycerol (DAG) from fatty acyl-CoA and monoacylglycerol as substrates. It is important for the resynthesis of triacylglycerol in the intestine. We have identified a series of aryl-sulfonamide MGAT2 inhibitors and demonstrated pharmacological inhibition of MGAT2 improved hyperlipidemia, obesity, and diabetes in animal models. However, its mechanism of action has not been elucidated in molecular and cellular levels. In the present study, we have characterized a series of aryl-sulfonamide derivatives that potently and selectively inhibit human MGAT2 and determined their pharmacological profiles. Analyses on the molecular mechanism of a representative aryl-sulfonamide MGAT2 inhibitor revealed a reversible inhibitory activity and a binding activity to MGAT2. The aryl-sulfonamide derivatives exhibited potent inhibitory activities against both human and mouse intestinal MGAT activities, which were correlated to those determined using recombinant human and mouse MGAT enzymes. We have developed a cellular assay using Liquid Chromatography-Mass Spectrometry and confirmed that the aryl-sulfonamide derivatives suppressed DAG synthesis in the cellular context. We have thus elucidated their pharmacological profiles and provided the fundamental clues for understanding the molecular and cellular actions of the aryl-sulfonamide MGAT2 inhibitors.
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http://dx.doi.org/10.1016/j.ejphar.2016.09.021DOI Listing
November 2016

Pharmacological Inhibition of Monoacylglycerol O-Acyltransferase 2 Improves Hyperlipidemia, Obesity, and Diabetes by Change in Intestinal Fat Utilization.

PLoS One 2016 3;11(3):e0150976. Epub 2016 Mar 3.

Cardiovascular and Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.

Monoacylglycerol O-acyltransferase 2 (MGAT2) catalyzes the synthesis of diacylglycerol (DG), a triacylglycerol precursor and potential peripheral target for novel anti-obesity therapeutics. High-throughput screening identified lead compounds with MGAT2 inhibitory activity. Through structural modification, a potent, selective, and orally bioavailable MGAT2 inhibitor, compound A (compA), was discovered. CompA dose-dependently inhibited postprandial increases in plasma triglyceride (TG) levels. Metabolic flux analysis revealed that compA inhibited triglyceride/diacylglycerol resynthesis in the small intestine and increased free fatty acid and acyl-carnitine with shorter acyl chains than originally labelled fatty acid. CompA decreased high-fat diet (HFD) intake in C57BL/6J mice. MGAT2-null mice showed a similar phenotype as compA-treated mice and compA did not suppress a food intake in MGAT2 KO mice, indicating that the anorectic effects were dependent on MGAT2 inhibition. Chronic administration of compA significantly prevented body weight gain and fat accumulation in mice fed HFD. MGAT2 inhibition by CompA under severe diabetes ameliorated hyperglycemia and fatty liver in HFD-streptozotocin (STZ)-treated mice. Homeostatic model assessments (HOMA-IR) revealed that compA treatment significantly improved insulin sensitivity. The proximal half of the small intestine displayed weight gain following compA treatment. A similar phenomenon has been observed in Roux-en-Y gastric bypass-treated animals and some studies have reported that this intestinal remodeling is essential to the anti-diabetic effects of bariatric surgery. These results clearly demonstrated that MGAT2 inhibition improved dyslipidemia, obesity, and diabetes, suggesting that compA is an effective therapeutic for obesity-related metabolic disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150976PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777574PMC
August 2016

Prognostic Impact of New-Onset Atrial Fibrillation in Patients With Chronic Heart Failure - A Report From the CHART-2 Study.

Circ J 2016 7;80(1):157-67. Epub 2015 Dec 7.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: The prognostic impact of new-onset atrial fibrillation (AF) is not fully elucidated.

Methods And Results: We examined 4,818 consecutive stage C/D chronic heart failure (CHF) patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). At enrollment, 1,859 (38.6%) of them had AF. Compared with the 2,953 patients without AF, AF patients were characterized by higher age (71 vs. 68 years), lower estimated glomerular filtration rate (58.9 vs. 61.9 ml/min/1.73 m(2)), higher brain natriuretic peptide (152 vs. 74.5 pg/ml), similar left ventricular ejection fraction (56.8 vs. 56.5%), and a similar prescription rate of β-blockers (48.1 vs. 50.6%) and renin-angiotensin system (RAS) inhibitors (72.9 vs. 71.6%). Among the patients without AF at enrollment, 106 (3.6%) developed new AF during the median 3.2-year follow-up, which was associated with increased mortality (adjusted hazard ratio, 1.72; P=0.013). In contrast, neither paroxysmal nor chronic AF at enrollment was associated with increased mortality. The mortality rate was significantly high in the first year after the onset of new AF. On inverse probability of treatment weighting analysis using propensity score, RAS inhibitors and statins were associated with reduced incidence of new AF, and diuretics were associated with increase of new AF.

Conclusions: Onset of new AF, but not a history of AF, is associated with increased mortality in CHF patients, especially in the first year.
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http://dx.doi.org/10.1253/circj.CJ-15-0783DOI Listing
October 2016

Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan -- report from the CHART Studies.

Circ J 2015 10;79(11):2396-407. Epub 2015 Sep 10.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure (HF) remain to be elucidated in Japan.

Methods and results: From the Chronic Heart Failure Analysis and Registry in the Tohoku District-1 (CHART-1; 2000-2005, n=1,278) and CHART-2 (2006-present, n=10,219) Studies, we enrolled 1,006 and 3,676 consecutive symptomatic stage C/D HF patients, respectively. As compared with the patients in the CHART-1 Study, those in the CHART-2 Study had similar age and sex prevalence, and were characterized by lower brain natriuretic peptide, higher prevalence of preserved left ventricular ejection fraction (LVEF) and higher prevalence of hypertension, diabetes mellitus and ischemic heart disease (IHD), particularly IHD with LVEF ≥50%. From CHART-1 to CHART-2, use of renin-angiotensin system inhibitors, β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was decreased. Three-year incidences of all-cause death (24 vs. 15%; adjusted hazard ratio [adjHR], 0.73; P<0.001), cardiovascular death (17 vs. 7%; adjHR, 0.38; P<0.001) and hospitalization for HF (30 vs. 17%; adjHR, 0.51; P<0.001) were all significantly decreased from CHART-1 to CHART-2. In the CHART-2 Study, use of β-blockers was associated with improved prognosis in patients with LVEF <50%, while that of statins was associated with improved prognosis in those with LVEF ≥50%.

Conclusions: Along with implementation of evidence-based medications, the prognosis of HF patients has been improved in Japan. (

Trial Registration: clinicaltrials.gov identifier: NCT00418041)
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http://dx.doi.org/10.1253/circj.CJ-15-0514DOI Listing
August 2016

Optimization of a novel series of N-phenylindoline-5-sulfonamide-based acyl CoA:monoacylglycerol acyltransferase-2 inhibitors: Mitigation of CYP3A4 time-dependent inhibition and phototoxic liabilities.

Bioorg Med Chem 2015 Aug 9;23(15):4544-4560. Epub 2015 Jun 9.

Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has emerged as a potential peripheral target for the treatment of obesity and metabolic disorders. We previously identified a novel series of N-phenylindoline-5-sulfonamide derivatives exemplified by 2 as potent and orally bioavailable MGAT2 inhibitors. Despite its attractive potency, further assessment revealed that this compound exhibited time-dependent inhibition (TDI) of cytochrome P450 3A4 (CYP3A4). To remove the undesirable CYP3A4 TDI activity, structural modification was focused on the 2,4-difluoroaniline moiety on the basis of the assumption that this moiety would be involved in mechanism-based inhibition of CYP3A4 via oxidative metabolism. This led to the finding that the introduction of 4-chloro-2,6-difluoroaniline significantly improved CYP3A4 TDI risk. Further optimization resulted in the discovery of N-(4-chloro-2,6-difluorophenyl)-1-{5-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyrimidin-2-yl}-7-(2-oxopyrrolidin-1-yl)-2,3-dihydro-1H-indole-5-sulfonamide (27c) with potent MGAT2 inhibitory activity (IC50=7.8 nM) and excellent ADME-Tox profiles including metabolic stability, oral bioavailability, and CYP3A4 TDI. In a mouse oral fat tolerance test, compound 27c effectively and dose-dependently suppressed the elevation of plasma triacylglycerol levels after oral administration at doses of 1 and 3mg/kg. We also discuss mitigation of the phototoxic liability of biaryl derivatives on the basis of the HOMO-LUMO gap hypothesis during the course of optimization efforts.
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http://dx.doi.org/10.1016/j.bmc.2015.06.003DOI Listing
August 2015

Prognostic Impact of Anemia in Patients With Chronic Heart Failure- With Special Reference to Clinical Background: Report From the CHART-2 Study.

Circ J 2015 5;79(9):1984-93. Epub 2015 Jun 5.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF).

Methods and results: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with β-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease.

Conclusions: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology.
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http://dx.doi.org/10.1253/circj.CJ-15-0174DOI Listing
May 2016

A microfluidic cell culture system for monitoring of sequential changes in endothelial cells after heat stress.

Thromb Res 2015 Aug 17;136(2):328-34. Epub 2015 May 17.

Department of Life Sciences, Toyo University, 1-1-1 Itakura, Oura, Gunma 374-0193, Japan; Bio-Nano Electronic Research Centre, Toyo University, 2100 Kujirai, Kawagoe, Saitama 350-8585, Japan. Electronic address:

Endothelial damage induced by a highly elevated body temperature is crucial in some diseases including viral hemorrhagic fevers. Here, we report the heat-induced sequential changes of endothelial cells under shear stress, which were determined with a microfluidic culture system. Although live cell imaging showed only minor changes in the appearance of heat-treated cells, Hsp70 mRNA expression analysis demonstrated that the endothelial cells in channels of the system responded well to heat treatment. F-actin staining also revealed clear changes in the bundles of actin filaments after heat treatment. Well-organized bundles of actin filaments in control cells disappeared in heat-treated cells cultured in the channel. Furthermore, the system enabled detection of sequential changes in plasminogen activator inhibitor-1 (PAI-1) secretion from endothelial cells. PAI-1 concentration in the effluent solution was significantly elevated for the first 15min after initiation of heat treatment, and then decreased subsequently. This study provides fundamental information on heat-induced endothelial changes under shear stress and introduces a potent tool for analyzing endothelial secretions.
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http://dx.doi.org/10.1016/j.thromres.2015.05.008DOI Listing
August 2015

Prognostic Impact of Diabetes Mellitus in Chronic Heart Failure According to Presence of Ischemic Heart Disease – With Special Reference to Nephropathy.

Circ J 2015 22;79(8):1764-72. Epub 2015 May 22.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: It is unclear whether the prognostic impact of diabetes mellitus (DM) in chronic heart failure (CHF) is influenced by ischemic heart disease (IHD) and/or nephropathy.

Methods And Results: We enrolled 4,065 consecutive patients with stage C/D CHF (mean age, 69.0 years; 68.7% male) in the CHART-2 Study (n=10,219). We defined DM as current history of DM treatment or HbA1c ≥6.5% (National Glycohemoglobin Standardization Program [NGSP]), and nephropathy as urine albumin:creatinine ratio ≥30 mg/g or urine dipstick test ≥(±) at enrollment. Impacts of DM and nephropathy on the composite of death, myocardial infarction, stroke, and HF admission were examined. Among the 4,065 patients, 1,448 (35.6%) had DM, while IHD and nephropathy were also noted in 1,644 (40.4%) and in 1,549 (38.1%), respectively. During the median follow-up of 2.88 years, 1,025 (25.2%) reached the composite endpoint. On multivariate Cox regression, DM was significantly associated with the composite endpoint in all patients (HR, 1.17; P=0.02), and in those with IHD (HR, 1.38; P=0.004), but not in those without IHD (HR, 1.12; P=0.22; P for interaction=0.12). Furthermore, when the patients were stratified by nephropathy, DM was associated with worse prognosis only in the IHD patients with nephropathy.

Conclusions: The prognostic impact of DM was more evident in patients with IHD than in those without IHD, particularly when complicated with nephropathy.
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http://dx.doi.org/10.1253/circj.CJ-15-0096DOI Listing
April 2016

Comprehensive Risk Stratification of Japanese Patients With Aortic Stenosis--A Proposal of a New Risk Score From the CHART-2 Study.

Circ J 2015 1;79(7):1631-8. Epub 2015 May 1.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: The risk of patients with aortic stenosis (AS) should be stratified not only by AS severity but also by comorbidities.

Methods And Results: We aimed to develop a risk score for mortality in 412 patients with AS (pressure gradient ≥30 mmHg, mean age 74.9 years, male 52.4%) in the CHART-2 Study (n=10,219). During a 3-year follow-up, 73 (17.7%) patients died. Crude 3-year mortality of patients in New York Heart Association (NYHA) classes I, II, and III/IV was 9.5%, 16.5%, and 49.7%, respectively (P<0.001). Stepwise Cox regression analysis showed that the combination of 7 factors was the best model to predict the mortality of AS patients, who were scored according to their hazard ratios, including NYHA class III-IV (score 6), male sex (3), serum albumin level ≤4 g/dl (2), aortic peak flow ≥4.5 m/s (2), age ≥75 years (2), chronic kidney disease (2), and anemia (1). Receiver-operating characteristic analysis showed excellent association between the sum of the scores and 3-year mortality (area under the curve, 0.78). The multivariate Cox proportional hazard model demonstrated that the present risk score also well stratified the mortality risk.

Conclusions: The present study demonstrates that, in addition to the classical prognostic factors related to symptoms and AS severity, various comorbidities are associated with mortality. Thus, the present comprehensive risk score may be useful for risk stratification of AS patients.
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http://dx.doi.org/10.1253/circj.CJ-15-0062DOI Listing
April 2016

Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors.

J Med Chem 2015 May 30;58(9):3892-909. Epub 2015 Apr 30.

Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from N-phenylbenzenesulfonamide derivative 1 with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced N-phenylindoline-5-sulfonamide derivative 10b, which displayed much improved potency, with an IC50 value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1H-indole-1-carboxamide (24d) endowed with potent MGAT2 inhibitory activity (IC50 = 3.4 nM) and high oral bioavailability (F = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00178DOI Listing
May 2015

Improved Long-Term Prognosis of Dilated Cardiomyopathy With Implementation of Evidenced-Based Medication - Report From the CHART Studies - .

Circ J 2015 2;79(6):1332-41. Epub 2015 Apr 2.

Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: Recent trends in the clinical characteristics, management and prognosis of dilated cardiomyopathy (DCM) remain to be examined in Japan.

Methods And Results: We compared 306 and 710 DCM patients in the Chronic Heart Failure Analysis and Registry in the Tohoku District (CHART)-1 (2000-2005, n=1,278) and the CHART-2 (2006-present, n=10,219) Studies, respectively. Between the 2 groups of DCM patients, there were no significant differences in baseline characteristics. The prevalence of hypertension, dyslipidemia and diabetes mellitus were all significantly increased from the CHART-1 to the CHART-2 Study. The use of β-blockers and aldosterone antagonists was significantly increased, while that of loop diuretics and digitalis was significantly decreased in the CHART-2 Study. The 3-year mortality rate was significantly improved from 14% in the CHART-1 to 9% in the CHART-2 Study (adjusted HR, 0.60; 95% CI: 0.49-0.81; P=0.001). In particular, 3-year incidence of cardiovascular death was significantly decreased (adjusted HR, 0.26; 95% CI: 0.14-0.50, P<0.001), while that of HF admission was not (adjusted HR, 0.90; 95% CI: 0.59-1.37, P=0.632). The prognostic improvement was noted in patients with BNP <220 pg/ml, LVEF>40%, β-blocker use and aldosterone antagonist use.

Conclusions: Long-term prognosis of DCM patients has been improved, along with the implementation of evidence-based medication in Japan.
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http://dx.doi.org/10.1253/circj.CJ-14-0939DOI Listing
March 2016

Predictors and prognostic impact of post-traumatic stress disorder after the great East Japan earthquake in patients with cardiovascular disease.

Circ J 2015 13;79(3):664-7. Epub 2015 Feb 13.

Departments of Cardiovascular Medicine and Evidence-based Cardiovascular Medicine, Tohoku University Graduate School of Medicine.

Background: We examined the prevalence, predictors and prognostic impact of post-traumatic stress disorder (PTSD) after the Great East Japan Earthquake in patients with cardiovascular disease (CVD) in the CHART-2 study. METHODS AND RESULTS: The prevalence of PTSD was 14.7% at 6 months after the Earthquake. Female sex, experiencing the Tsunami, property loss, poverty, and insomnia medication use were associated with PTSD. The patients with PTSD more frequently experienced a composite of death, acute myocardial infarction, stroke and heart failure (18.5% vs. 15.0%, P=0.035).

Conclusions: PTSD was frequent in CVD patients after the Earthquake and had an adverse prognostic impact.
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http://dx.doi.org/10.1253/circj.CJ-14-1403DOI Listing
November 2015
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