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Articles by K Okumura
Total Records ( 3 ) for K Okumura
  R Sofat , A. D Hingorani , L Smeeth , S. E Humphries , P. J Talmud , J Cooper , T Shah , M. S Sandhu , S. L Ricketts , S. M Boekholdt , N Wareham , K. T Khaw , M Kumari , M Kivimaki , M Marmot , F. W Asselbergs , P van der Harst , R. P.F Dullaart , G Navis , D. J van Veldhuisen , W. H Van Gilst , J. F Thompson , P McCaskie , L. J Palmer , M Arca , F Quagliarini , C Gaudio , F Cambien , V Nicaud , O Poirer , V Gudnason , A Isaacs , J. C.M Witteman , C. M van Duijn , M Pencina , R. S Vasan , R. B D'Agostino , J Ordovas , T. Y Li , S Kakko , H Kauma , M. J Savolainen , Y. A Kesaniemi , A Sandhofer , B Paulweber , J. V Sorli , A Goto , S Yokoyama , K Okumura , B. D Horne , C Packard , D Freeman , I Ford , N Sattar , V McCormack , D. A Lawlor , S Ebrahim , G. D Smith , J. J.P Kastelein , J Deanfield and J. P. Casas
 

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.

Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.

Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

  S Kamakura , T Ohe , K Nakazawa , Y Aizawa , A Shimizu , M Horie , S Ogawa , K Okumura , K Tsuchihashi , K Sugi , N Makita , N Hagiwara , H Inoue , H Atarashi , N Aihara , W Shimizu , T Kurita , K Suyama , T Noda , K Satomi , H Okamura , H Tomoike and for the Brugada Syndrome Investigators in Japan
 

Background— The prognosis of patients with saddleback or noncoved type (non–type 1) ST-elevation in Brugada syndrome is unknown. The purpose of this study was to clarify the long-term prognosis of probands with non–type 1 ECG and those with coved (type 1) Brugada-pattern ECG.

Methods and Results— A total of 330 (123 symptomatic, 207 asymptomatic) probands with a coved or saddleback ST-elevation ≥1 mm in leads V1–V3 were divided into 2 ECG groups—type 1 (245 probands) and non–type 1 (85 probands)—and were prospectively followed for 48.7±15.0 months. The absence of type 1 ECG was confirmed by drug provocation test and multiple recordings. The ratio of individuals with a family history of sudden cardiac death (14%) was lower than previous studies. Clinical profiles and outcomes were not notably different between the 2 groups (annual arrhythmic event rate of probands with ventricular fibrillation; type 1: 10.2%, non–type 1: 10.6%, probands with syncope; type 1: 0.6%, non–type 1: 1.2%, and asymptomatic probands; type 1: 0.5%, non–type 1: 0%). Family history of sudden cardiac death at age <45 years and coexistence of inferolateral early repolarization with Brugada-pattern ECG were independent predictors of fatal arrhythmic events (hazard ratio, 3.28; 95% confidence interval, 1.42 to 7.60; P=0.005; hazard ratio, 2.66; 95% confidence interval, 1.06 to 6.71; P=0.03, respectively, by multivariate analysis), although spontaneous type 1 ECG and ventricular fibrillation inducibility by electrophysiological study were not reliable parameters.

Conclusions— The long-term prognosis of probands in non–type 1 group was similar to that of type 1 group. Family history of sudden cardiac death and the presence of early repolarization were predictors of poor outcome in this study, which included only probands with Brugada-pattern ST-elevation.

  Y Yamanishi , J Kitaura , K Izawa , A Kaitani , Y Komeno , M Nakamura , S Yamazaki , Y Enomoto , T Oki , H Akiba , T Abe , T Komori , Y Morikawa , H Kiyonari , T Takai , K Okumura and T. Kitamura
 

Leukocyte mono-immunoglobulin (Ig)–like receptor 5 (LMIR5)/CD300b is a DAP12-coupled activating receptor predominantly expressed in myeloid cells. The ligands for LMIR have not been reported. We have identified T cell Ig mucin 1 (TIM1) as a possible ligand for LMIR5 by retrovirus-mediated expression cloning. TIM1 interacted only with LMIR5 among the LMIR family, whereas LMIR5 interacted with TIM4 as well as TIM1. The Ig-like domain of LMIR5 bound to TIM1 in the vicinity of the phosphatidylserine (PS)-binding site within the Ig-like domain of TIM1. Unlike its binding to TIM1 or TIM4, LMIR5 failed to bind to PS. LMIR5 binding did not affect TIM1- or TIM4-mediated phagocytosis of apoptotic cells, and stimulation with TIM1 or TIM4 induced LMIR5-mediated activation of mast cells. Notably, LMIR5 deficiency suppressed TIM1-Fc–induced recruitment of neutrophils in the dorsal air pouch, and LMIR5 deficiency attenuated neutrophil accumulation in a model of ischemia/reperfusion injury in the kidneys in which TIM1 expression is up-regulated. In that model, LMIR5 deficiency resulted in ameliorated tubular necrosis and cast formation in the acute phase. Collectively, our results indicate that TIM1 is an endogenous ligand for LMIR5 and that the TIM1–LMIR5 interaction plays a physiological role in immune regulation by myeloid cells.

 
 
 
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