Kazuaki Shimamoto

Sapporo Medical University, Sapporo, Hokkaidō, Japan

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Publications (571)1627.48 Total impact

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    ABSTRACT: Objective Fatty acid-binding protein 4 (FABP4) is expressed in adipocytes, and elevated plasma FABP4 level is associated with obesity-mediated metabolic phenotype. Postprandial regulation and secretory signaling of FABP4 has been investigated.Methods Time courses of FABP4 levels were examined during an oral glucose tolerance test (OGTT; n = 53) or a high-fat test meal eating (n = 35). Effects of activators and inhibitors of adenyl cyclase (AC)-protein kinase A (PKA) signaling and guanylyl cyclase (GC)-protein kinase G (PKG) signaling on FABP4 secretion from mouse 3T3-L1 adipocytes were investigated.ResultsFABP4 level significantly declined after the OGTT or a high-fat meal eating, while insulin level was increased. Treatment with low and high glucose concentration or palmitate for 2 h did not affect FABP4 secretion from 3T3-L1 adipocytes. FABP4 secretion was increased by stimulation of lipolysis using isoproterenol, a β3-adrenoceptor agonist (CL316243), forskolin, dibutyryl-cAMP and atrial natriuretic peptide, and the induced FABP4 secretion was suppressed by insulin or an inhibitor of PKA (H-89), PKG (KT5823) or hormone sensitive lipase (CAY10499).ConclusionsFABP4 is secreted from adipocytes in association with lipolysis regulated by AC-PKA- and GC-PKG-mediated signal pathways. Plasma FABP4 level declines postprandially, and suppression of FABP4 secretion by insulin-induced anti-lipolytic signaling may be involved in this decline in FABP4 level.
    Obesity 12/2014; · 4.39 Impact Factor
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    ABSTRACT: The cardiovascular effects of combined therapy with the angiotensin receptor blocker (olmesartan) and a dihydropyridine calcium channel blocker (CCB) or a diuretic were compared in high-risk elderly Japanese hypertensive patients by performing a randomized, open label, blinded-endpoint study of morbidity and mortality (the COLM study). Here we report the results obtained with respect to safety and tolerability. High-risk hypertensive patients aged 65-84 years were enrolled and were randomized to receive olmesartan combined with either a CCB (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years. The primary endpoint was a composite of fatal and non fatal cardiovascular events, whereas adverse events (AEs) and the percentage of patients who discontinued the allocated treatment were evaluated as secondary endpoints. A total of 5141 patients were randomized. Both combination regimens achieved a similar reduction of cardiovascular morbidity and mortality. The incidences of AEs, serious AEs, drug-related serious AEs and discontinuation due to serious AEs were lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group. Serum levels of uric acid and creatinine were significantly higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group. Olmesartan combined with a CCB was significantly superior to olmesartan plus a diuretic with regard to the frequency of AEs and discontinuation of treatment.Hypertension Research advance online publication, 25 September 2014; doi:10.1038/hr.2014.141.
    Hypertension Research 09/2014; · 2.94 Impact Factor
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    ABSTRACT: Combination of OLMesartan and a calcium channel blocker or a diuretic in Japanese elderly hypertensive patients (COLM) trial demonstrated that olmesartan combinations with a CCB or diuretic have similar effects on reducing cardiovascular risk in elderly hypertensive patients. However, the safety profiles suggest that olmesartan combined with CCB may be preferable to olmesartan combined with diuretic. In this subgroup analysis, we further evaluated the effects and safety of these combinations in elderly (65-74 years old (y.o.)) and very elderly (75-84 y.o.) hypertensive patients. In the COLM trial, 5141 patients (2918 elderly and 2223 very elderly) were randomly assigned to receive olmesartan-based therapy with either CCB or diuretic. The hazard ratios and 95% confidence intervals, respectively, in the elderly age group and in the very elderly group were: 1.04 (0.72-1.50; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.85) and 0.71 (0.51-0.99, P=0.045) for the primary composite end point, and 1.07 (0.67-1.72, P=0.77) and 0.64 (0.42-0.98, P=0.036) for the composite of hard end points. The hazard ratios for stroke (fatal and non-fatal) were 1.48 (0.88-2.48; olmesartan plus CCB vs. olmesartan plus diuretic, P=0.13) and 0.63 (0.39-1.02, P=0.059) (interaction-P=0.019). Withdrawal rates from the trial, withdrawal due to serious adverse event and the incidence of any adverse event were higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group in both age groups. In conclusion, angiotensin receptor blocker (ARB) and CCB combination may be preferable to an ARB and diuretic combination in the very elderly hypertensive patients for the reduction of cardiovascular risk, particularly for the reduction in stroke risk.Hypertension Research advance online publication, 25 September 2014; doi:10.1038/hr.2014.144.
    Hypertension Research 09/2014; · 2.94 Impact Factor
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    ABSTRACT: Background Fatty acid-binding protein 4 (FABP4) is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, hypertension, and atherosclerosis. However, little is known about role of FABP4 in cardiac function.Methods From the database of the Tanno-Sobetsu Study, data for 190 subjects (male/female: 82/108) who were not treated with any medication and underwent echocardiography in 2011 or 2012 were retrieved for analyses of relationships between serum FABP4 concentration, metabolic markers and parameters of echocardiography.ResultsSerum FABP4 level was positively correlated with age, body mass index (BMI), blood pressure (BP), LDL cholesterol, HOMA-R and mean left ventricular (LV) wall thickness (LVWT, males: r¿=¿0.315, females: r¿=¿0.401, p¿<¿0.01) and was negatively correlated with HDL cholesterol, estimated glomerular filtration rate (eGFR) and peak myocardial velocity during early diastole (e¿; males: r¿=¿¿0.434, females: r¿=¿¿0.353, p¿<¿0.01), an index of LV diastolic function. However, no significant correlation was found between FABP4 level and LV end-diastolic dimension, LV ejection fraction or LV mass index. There were significant correlations of e¿ with age, BMI, BP, eGFR, brain natriuretic peptide (BNP), FABP4, metabolic markers and LVWT. Multivariate regression analysis adjusted by HOMA-R, BMI, eGFR, BNP or LVWT in addition to age, gender and BP revealed that serum FABP4 concentration was independently correlated with e¿.Conclusions Elevation of circulating FABP4 may contribute to LV diastolic dysfunction in a general population.
    Cardiovascular Diabetology 08/2014; 13(1):126. · 3.71 Impact Factor
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    ABSTRACT: The aim of the present study was to compare the cardiovascular effects of olmesartan, an angiotensin II receptor blocker, combined with a calcium channel blocker (CCB) or a diuretic, in a prospective, randomized, open-label, blinded endpoint trial.
    Journal of hypertension. 07/2014;
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    ABSTRACT: Thiazide diuretics are one of the first choice antihypertensives but not optimally utilised because of concerns regarding their adverse effects on glucose metabolism. The Diuretics In the Management of Essential hypertension (DIME) study was designed, for the first time, to assess the risk for type 2 diabetes mellitus in patients with essential hypertension during antihypertensive treatment with low-dose thiazide diuretics compared to those not treated with diuretics.
    BMJ Open 07/2014; 4(7):e004576. · 2.06 Impact Factor
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    ABSTRACT: Angiotensin-converting enzyme 2 (ACE2) is highly expressed in the kidney and converts angiotensin (Ang) II to Ang-(1-7), a renoprotective peptide. Urinary ACE2 has been shown to be elevated in patients with chronic kidney disease. However, the effects of antihypertensive agents on urinary ACE2 remain unclear.
    American Journal of Hypertension 05/2014; · 3.40 Impact Factor
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    ABSTRACT: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2) is expressed in not only adipocytes and macrophages but also peritubular capillaries in the normal kidney. We recently demonstrated that ectopic expression of FABP4, but not FABP1 known as liver FABP (L-FABP), in the glomerulus is associated with progression of proteinuria and renal dysfunction. However, urinary excretion of FABP4 has not been investigated. Subjects who participated in the Tanno-Sobetsu Study, a study with a population-based cohort design, in 2011 (n = 392, male/female: 166/226) were enrolled. Urinary FABP4 (U-FABP4) and urinary albumin-to-creatinine ratio (UACR) were measured. Change in estimated glomerular filtration rate (eGFR) was followed up one year later. In 93 (23.7%) of the 392 subjects, U-FABP4 level was below the sensitivity of the assay. Subjects with undetectable U-FABP4 were younger and had lower UACR and higher eGFR levels than subjects with measurable U-FABP4. U-FABP4 level was positively correlated with age, systolic blood pressure and levels of serum FABP4 (S-FABP4), triglycerides, hemoglobin A1c (HbA1c), urinary FABP1 (U-FABP1) and UACR (r = 0.360, p<0.001). Age, S-FABP4, U-FABP1 and UACR were independent predictors of U-FABP4. On the other hand, systolic blood pressure, HbA1c and U-FABP4 were independently correlated with UACR. Reduction in eGFR after one year was significantly larger in a group with the highest tertile of baseline U-FABP4 than a group with the lowest tertile. Urinary FABP4 level is independently correlated with level of albuminuria and possibly predicts yearly decline of eGFR. U-FABP4 would be a novel biomarker of glomerular damage.
    PLoS ONE 01/2014; 9(12):e115429. · 3.53 Impact Factor
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    ABSTRACT: Background: Patients with mild-to-moderate essential hypertension in the HOMED-BP trial were randomly allocated to first-line treatment with a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB). Methods: We recruited 265 (93 for CCB, 71 for ACEI and 101 for ARB) patients who completed the genomic study. Home blood pressure was measured for 5 days off-treatment before randomization and for 5 days after 2-4 weeks of randomized drug treatment. Genotyping was performed by 500K DNA microarray chips. The blood pressure responses to the three drugs were analyzed separately as a quantitative trait. For replication of SNPs with p < 10(-4), we used the multicenter GEANE study, in which patients were randomized to valsartan or amlodipine. Results: SNPs in PICALM, TANC2, NUMA1 and APCDD1 were found to be associated with CCB responses and those in ABCC9 and YIPF1 were found to be associated with ARB response with replication. Conclusion: Our approach, the first based on high-fidelity phenotyping by home blood pressure measurement, might be a step in moving towards the personalized treatment of hypertension. Original submitted 29 April 2013; Revision submitted 14 August 2013.
    Pharmacogenomics 11/2013; 14(14):1709-21. · 3.43 Impact Factor
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    ABSTRACT: The aim of this study was to determine the efficacies of valsartan and telmisartan as add-on agents for the control of morning blood pressure (BP) in patients already on amlodipine monotherapy. A total of 414 hypertensive patients were prospectively enrolled in a 4-week run-in period when they were treated with amlodipine (5 mg/day), and home BP was measured in the morning and evening. Patients with home systolic BP (SBP) being 135-159 mm Hg in the morning at the end of the run-in period were randomized to additional treatment with valsartan (80 mg/day) or with telmisartan (40 mg/day) for 8 weeks. The primary endpoint was the change in morning home BP, and secondary endpoints included variability of morning home BP. Of the 282 patients randomized, 262 patients (n=131, in each treatment) completed the protocols. Demographic parameters and baseline morning SBP/diastolic BP (DBP) (146.3±7.1/84.8±9.3 vs. 146.0±7.1/84.2±9.1 mm Hg) were comparable in the valsartan group and telmisartan group, and changes in SBP/DBP after 8-week treatment were not significantly different between the two groups (-7.4±10.6/-3.9±6.1 vs. -8.3±9.9/-5.0±5.9 mm Hg). Valsartan significantly increased individual standard deviation and variation coefficient of morning SBP, but telmisartan did not change either of these indices of SBP variation. In subgroups with baseline SBP being above the median (145.2 mm Hg), change in DBP was significantly larger by telmisartan than by valsartan (-6.3±5.6 vs. -3.9±6.7 mm Hg, P<0.05). These results suggest that telmisartan is more useful than valsartan as an add-on agent for reducing the level and variability of morning BP in patients on amlodipine monotherapy.Hypertension Research advance online publication, 10 October 2013; doi:10.1038/hr.2013.141.
    Hypertension Research 10/2013; · 2.94 Impact Factor
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    ABSTRACT: This phase III, multicenter, randomized, double-blind, parallel-group study compared the efficacy and safety of nifedipine controlled-release (CR) 40 mg twice daily (b.i.d.) and once daily (q.d.) in 325 Japanese patients with essential hypertension uncontrolled with nifedipine CR 40 mg q.d. (ClinicalTrials.gov record: NCT01287260). The primary endpoint was the change from baseline in trough seated diastolic blood pressure (DBP) after 8 weeks. Nifedipine CR 40 mg b.i.d. showed significantly greater reductions in trough seated DBP (-7.7±0.6 mm Hg vs. -3.6±0.6 mm Hg) and trough seated systolic blood pressure (BP) (-11.1±0.9 mm Hg vs. -3.7±0.9 mm Hg) after 8 weeks of treatment compared with nifedipine CR 40 mg q.d. (both P<0.0001). At week 8, BP target achievement and responder rates were higher with nifedipine CR 40 mg b.i.d. (21.5% and 42.4% vs. 10.3% and 19.5%, respectively). Adverse events considered related to the study drug were reported in 9.0 and 9.7% of patients receiving nifedipine CR 40 mg b.i.d. and q.d., respectively. The frequency of drug-related adverse events commonly reported with nifedipine CR (headache, hot flush, palpitations, peripheral edema, hypotension, dizziness, tachycardia) was low and the results were similar between the treatment groups. In conclusion, a higher dose of nifedipine CR was associated with greater efficacy and a safety profile similar to that of the currently approved dose (40 mg q.d.) in Japanese patients with essential hypertension, and it may offer a valuable treatment choice for patients who do not achieve target BP levels with standard treatment.Hypertension Research advance online publication, 15 August 2013; doi:10.1038/hr.2013.80.
    Hypertension Research 08/2013; · 2.94 Impact Factor
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    ABSTRACT: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial was a multicenter, randomized, three-arm comparative study (N=3293) undertaken to determine the optimal combination therapy, based on the occurrence of cardiovascular events in patients treated with an angiotensin II receptor blocker (ARB), a β-blocker (BB) or a thiazide diuretic (TD) in addition to the calcium antagonist benidipine as baseline medication. This subanalysis was conducted to compare the efficacy of three combination therapies in a subset of 834 patients with chronic kidney disease (CKD) (287 patients treated with benidpine-ARB, 283 patients treated with benidipine-BB and 264 patients treated with benidipine-TD). The incidence of composite cardiovascular events as the primary end point did not differ among these three groups. The incidence of hard end points and cerebrovascular events among these groups did not differ either, although the incidence among all patients in the COPE trial was lower in the benidipine-TD group than in the benidipine-BB group. The incidence of new-onset diabetes mellitus was higher in the benidipine-TD group than in the benidipine-ARB group among patients with CKD. The estimated glomerular filtration rate (eGFR) was maintained even after 12 months of treatment in patients with a baseline eGFR <60 ml min(-1) per 1.73 m(2) regardless of the treatment group, although the eGFR decreased over time in all patients in the three groups. In conclusion, in patients with CKD, all of the tested combination therapies demonstrated comparable efficacy in terms of prevention of cardiovascular events as well as maintenance of eGFR.Hypertension Research advance online publication, 18 July 2013; doi:10.1038/hr.2013.63.
    Hypertension Research 07/2013; · 2.94 Impact Factor
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    ABSTRACT: Cardiomyopathy is the main cause of death in Duchenne muscular dystrophy. Here we show that oral administration of resveratrol, which leads to activation of an NAD+-dependent protein deacetylase SIRT1, suppresses cardiac hypertrophy and fibrosis, and restores cardiac diastolic function in dystrophin-deficient mdx mice. The pro-hypertrophic co-activator p300 protein but not p300 mRNA was upregulated in the mdx heart and resveratrol administration downregulated the p300 protein level. In cultured cardiomyocytes, cardiomyocyte hypertrophy induced by an α1 agonist phenylephrine was inhibited by the overexpression of SIRT1 as well as resveratrol, both of which downregulated p300 protein level but not p300 mRNA level. In addition, activation of atrial natriuretic peptide promoter by p300 was inhibited by SIRT1. We found that SIRT1 induced p300 downregulation via the ubiquitin/proteasome pathway by deacetylation of lysine residues for ubiquitination. These findings indicate the pathological significance of p300 upregulation in the dystrophic heart and that SIRT1 activation has the therapeutic potential for dystrophic cardiomyopathy.
    Journal of Biological Chemistry 01/2013; · 4.60 Impact Factor
  • Hiroshi Akasaka, Tetsuji Miura, Kazuaki Shimamoto
    Nippon rinsho. Japanese journal of clinical medicine 11/2012; 70 Suppl 8:593-6.
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    ABSTRACT: Background Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, and atherosclerosis. However, little is known about the role of FABP4 in essential hypertension.Methods We first examined serum FABP4 concentrations in 18 normotensives (NT) and 30 nontreated essential hypertensives (EHT). The EHT were divided into 18 insulin-sensitive EHT (EHT-S) and 12 insulin-resistant EHT (EHT-R) based on their insulin-sensitivity index, the M value, determined by the hyperinsulinemic-euglycemic clamp technique. In the second study, we determined FABP4 levels in 30 young NT men with or without a family history of hypertension (FH(+) and FH(-), respectively; n = 15 each).ResultsSerum FABP4 level was significantly higher in the EHT-R than in the NT, whereas elevation of FABP4 level in the EHT-S was not statistically significant. FABP4 level was positively correlated with age, body mass index (BMI), blood pressure, and triglycerides and negatively correlated with the M value. FABP4 level was an independent predictor of mean arterial pressure after adjustment of age, gender, and adiposity. The FH(+) group had a significantly lower level of M value and higher level of FABP4 than did the FH(-) group, and FABP4 concentration was an independent determinant of the M value.ConclusionsFABP4 contributes to blood pressure elevation and atherogenic metabolic phenotype in hypertensives, and the elevation of FABP4 is predisposed by a family history of hypertension.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.88.
    American Journal of Hypertension 06/2012; 25(10):1124-30. · 3.67 Impact Factor
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    ABSTRACT: High serum uric acid level (SUA) and chronic kidney disease (CKD) are risk factors for cardiovascular events (CVEs). However, their interactions as cardiovascular risk factors remain unknown. This subanalysis of the Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study included 7629 patients, in whom the serum creatinine level was measured at least twice. The study examined the impact of hyperuricemia (SUA ≥7 mg dl(-1)) on CVE according to the level of renal dysfunction and whether early changes in SUA predicted future glomerular filtration rates (GFRs). The mean follow-up period was 3.1 years. The patients were divided into three groups according to the baseline estimated GFR (eGFR): groups A, B and C with eGFR <45, 45-59 and ≥60 ml min(-1) per 1.73 m(2), respectively. eGFR increased from 38.1 to 57.6, from 52.8 to 67.5 and from 74.7 to 80.7 ml min(-1) per 1.73 m(2) in groups A, B and C, respectively. In non-hyperuricemic patients, the CVE rate was 10.83, 4.98 and 4.21/1000 person-years in groups A, B and C, respectively, while in hyperuricemic patients, the corresponding values were 14.18, 17.02 and 5.93. Thus, hyperuricemia increased the risk of CVE only in group B (relative risk (RR) 3.43 (95% confidence interval (CI) 1.55 to 7.60); P<0.002). The final change in the eGFR was negatively correlated with the change in SUA from baseline to year 1 (P<0.001). CVEs were more frequent in those with a decrease in eGFR. Hyperuricemia may be a major determinant of increased cardiovascular risk in CKD stage 3A, and SUA may be involved in the progression of CKD. Changes in the GFR influence the rate of CVE.
    Hypertension Research 05/2012; 35(8):867-73. · 2.94 Impact Factor
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    ABSTRACT: Although the myocardial gated single photon emission computed tomography (SPECT) technique makes it possible to assess concurrent myocardial perfusion and function, quantitative methods for analyzing and displaying gated SPECT data in 2- and 3-dimensional presentations for regional and global cardiac assessment have not been established. We have developed an automated quantitative method for assessing perfusion and function by means of technetium-99m sestamibi gated SPECT with a computerized technique combining count-based and image-based methods. We have examined its validity in 91 patients by comparing its results with those of conventional techniques: contrast left ventriculography and radionuclide angiocardiography. In addition to color-scale displays of regional function, simultaneous 3-dimensional presentations of regional wall motion and perfusion have been produced. High reproducibility of gated SPECT analysis with this algorithm was demonstrated; interoperator errors (%CV) were 2.6% to 5.5%, and good intraobserver reproducibility was confirmed by means of high correlation coefficients (0.954 to 0.989). Left ventricular volumes assessed by means of contrast left ventriculography and by means of the gated SPECT technique showed significant correlations (left ventricular end-diastolic volume, y = 1.01x - 9.7, r = 0.845, P<.001, standard errors of the estimate [SEE] = 14 mL; left ventricular end-systolic volume, y = 1.03x - 1.4, r = 0.902, P<.001, SEE = 6 mL). Left ventricular ejection fraction determined by means of gated SPECT with the new algorithm closely correlated with that determined by means of radionuclide ventriculography (y = 1.05x - 0.6, r = 0.891, P<.001, SEE = 3 %). These parameters quantified by means of the present method correlated closely with those derived from the QGS program (r = 0.926 to 0.987). In comparison with conventional techniques, myocardial gated SPECT with automated quantitative analysis provides accurate and reproducible data for global and regional function. Quantitative concurrent assessment of myocardial perfusion and function by using 2-and 3-dimensional representations appears to be superior to other modalities and to contribute to nuclear cardiology practice.
    Journal of Nuclear Cardiology 04/2012; 7(6):623-32. · 2.65 Impact Factor
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    ABSTRACT: A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P=1.6 × 10(-34)), HLA-DQB1 on 6p21 (P=4.7 × 10(-7)), and CDKN2A/B on 9p21 (P=6.1 × 10(-16)). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P=1.4 × 10(-40)). On 6p21, an HLA allele, DQB1(*)0604, could show one of the most prominent association signals in an ∼8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects - population specific and common - on susceptibility to CAD.
    European journal of human genetics: EJHG 03/2012; 20(3):333-40. · 3.56 Impact Factor
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    ABSTRACT: The Combination Therapy of Hypertension to Prevent Cardiovascular Events (COPE) trial demonstrated that the calcium-channel blocker benidipine-based combination therapies with an angiotensin-receptor blocker (ARB), a β-blocker, or a thiazide diuretic (thiazide) were similarly effective in preventing cardiovascular events and achieving the target blood pressure (BP; <140/90 mm Hg). We further evaluated the efficacy and safety of these combination therapies in older (65 years) and younger (<65 years) hypertensive patients. In this sub-analysis of the COPE trial 3293 patients (153365 years old and 1760 <65 years old) were randomly assigned to receive benidipine-based therapy with an ARB, a β-blocker or a thiazide. In each group, the average BP did not differ among the three treatment groups. The incidence of the primary cardiovascular composite end point in the older group was higher than in the younger group (12.7 vs. 8.3 per 1000 person-years, P=0.023). The primary composite cardiovascular end point, achievement (%) of target BP, and cardiovascular hard composite end points were similar among the three treatment groups. However, the hazard ratios and 95% confidence intervals in older patients were 2.74 (1.08-6.96; β-blocker vs. thiazide, P=0.022) for fatal and non-fatal stroke, and 2.47 (1.03-5.91; β-blocker vs. ARB, P=0.043) for new-onset diabetes. Thus, benidipine combined with an ARB, a β-blocker, or a thiazide was similarly effective in preventing cardiovascular events and achieving the target BP in both older and younger hypertensive patients. Further studies will be necessary to evaluate the usefulness of benidipine combined with a β-blocker in terms of the incidence of stroke and new-onset diabetes in older patients.
    Hypertension Research 01/2012; 35(4):441-8. · 2.94 Impact Factor

Publication Stats

8k Citations
1,627.48 Total Impact Points


  • 1993–2014
    • Sapporo Medical University
      • • Division of Internal Medicine II
      • • School of Medicine
      • • Department of Public Health
      • • Division of Urology
      Sapporo, Hokkaidō, Japan
  • 2002–2013
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
    • Yamaguchi University
      Yamaguti, Yamaguchi, Japan
    • Kanazawa University
      Kanazawa, Ishikawa, Japan
  • 2012
    • Tohoku University
      • Department of Nephrology, Endocrinology and Vascular Medicine
      Sendai-shi, Miyagi-ken, Japan
  • 2010
    • Muroran City General Hospital
      Муроран, Hokkaidō, Japan
    • Chiba University
      Tiba, Chiba, Japan
  • 2008–2009
    • Osaka University
      • Division of Gene Therapy Science
      Suika, Ōsaka, Japan
    • Osaka General Medical Center
      Ōsaka, Ōsaka, Japan
    • Ibaraki University
      Mito-shi, Ibaraki, Japan
    • National Cerebral and Cardiovascular Center
      Ōsaka, Ōsaka, Japan
    • Jichi Medical University
      Totigi, Tochigi, Japan
  • 2007
    • Nippon Medical School
      • Nippon Medical School Hospital
      Tokyo, Tokyo-to, Japan
  • 2006
    • Fourth Military Medical University
      Xi’an, Liaoning, China
  • 2005
    • University of the Ryukyus
      Okinawa, Okinawa, Japan
  • 2003
    • Beijing Hospital
      Peping, Beijing, China
  • 2001
    • Kushiro City General Hospital
      Kusiro, Hokkaidō, Japan
  • 1999
    • Kyushu University
      • Faculty of Medical Sciences
      Fukuoka-shi, Fukuoka-ken, Japan
  • 1997
    • Sapporo Gakuin University
      Sapporo, Hokkaidō, Japan
    • Tokyo Junshin Women's College
      • Department of Cardiology
      Edo, Tōkyō, Japan
  • 1989–1992
    • Steel Memorial Muroran Hospital
      Hokodate, Hokkaidō, Japan
  • 1990
    • Oji General Hospital
      Томакомай, Hokkaidō, Japan
  • 1987
    • Fukuyama University
      Hukuyama, Hiroshima, Japan