[show abstract][hide abstract] 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.
[show abstract][hide abstract] 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; · 2.79 Impact Factor
[show abstract][hide abstract] 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; · 2.79 Impact Factor
[show abstract][hide abstract] 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; · 4.65 Impact Factor
[show abstract][hide abstract] 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
[show abstract][hide abstract] 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. · 2.79 Impact Factor
[show abstract][hide abstract] 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. · 2.85 Impact Factor
[show abstract][hide abstract] 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
[show abstract][hide abstract] 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 (153365 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. · 2.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although diabetic nephropathy (DN) is a major cause of end-stage renal disease, the mechanism of dysfunction has not yet been clarified. We previously reported that in diabetes proinsulin-producing bone marrow-derived cells (BMDCs) fuse with hepatocytes and neurons. Fusion cells are polyploidy and produce tumor necrosis factor (TNF)-α, ultimately causing diabetic complications. In this study, we assessed whether the same mechanism is involved in DN. We performed bone marrow transplantation from male GFP-Tg mice to female C57BL/6J mice and produced diabetes by streptozotocin (STZ) or a high-fat diet. In diabetic kidneys, massive infiltration of BMDCs and tubulointerstitial injury were prominent. BMDCs and damaged tubular epithelial cells were positively stained with proinsulin and TNF-α. Cell fusion between BMDCs and renal tubules was confirmed by the presence of Y chromosome. Of tubular epithelial cells, 15.4% contain Y chromosomes in STZ-diabetic mice, 8.6% in HFD-diabetic mice, but only 1.5% in nondiabetic mice. Fusion cells primarily expressed TNF-α and caspase-3 in diabetic kidney. These in vivo findings were confirmed by in vitro coculture experiments between isolated renal tubular cells and BMDCs. It was concluded that cell fusion between BMDCs and renal tubular epithelial cells plays a crucial role in DN.
The FASEB Journal 12/2011; 26(4):1559-68. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Although the involvement of angiotensin II (Ang II) in insulin resistance and hypertension has been established, the temporal relationships between Ang II receptor activation and changes in insulin sensitivity and blood pressure are not clear. To better understand this issue, we infused rats with Ang II (200 ng kg(-1) min(-1)) or vehicle for 4 weeks and assessed the residual effects after the discontinuation of the infusion on blood pressure, insulin sensitivity and tissue parameters of inflammation. Four weeks after the discontinuation of the Ang II infusion, the blood pressure was higher by 12.8 mm Hg, and insulin sensitivity as determined by a euglycemic hyperinsulinemic glucose clamp was reduced (glucose infusion rate: 11.1±0.7 vs. 17.6±0.5 mg kg(-1) min(-1)) in the Ang II-treated group compared with controls. The persistent hypertension and insulin resistance were associated with greater than two-fold increases in macrophage chemoattractant protein-1, tumor necrosis factor-α and thiobarbituric acid-reactive substrates in the soleus muscle. Furthermore, total and activated forms of Rac-1, a regulatory subunit of the NADPH oxidase complex, were increased by 144±14% and 277±82%, respectively, in the skeletal muscle of Ang II-treated rats. These residual effects after Ang II infusion were all attenuated by the co-administration of tempol, a free radical scavenger, or candesartan with Ang II. The effects of candesartan were not mimicked by hydralazine at an equidepressant dose. These findings suggest that Ang II receptor activation in youth triggers the upregulation of inflammatory cytokines and the production of reactive oxygen species, thereby inducing later insulin resistance and hypertension.
Hypertension Research 12/2011; 35(3):334-40. · 2.79 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess the relationship between metabolic risk factors and the incidence of stroke stratified by obesity, by conducting a meta-analysis using individual participant data from prospective cohort studies.
A total of 19,173 individuals from 10 cohort studies participated at baseline after 1985. Metabolic risk factors were defined using the established criteria in Japan. Participants were subdivided into five categories according to the levels of risk factors and obesity defined by BMI > or = 25 (kg/m2). Multivariate adjusted hazard ratios (HRs) for the incidence of stroke and the population attributable risk (PAR) were estimated by Poisson regression.
During an average 7.1-year follow-up period, 374 stroke events occurred. Hypertension was highest among the risk factors not concerned with BMI stratification. The HR for stroke was 2.48 (95% CI: 1.75-3.5) for BMI < 25 with 1 other risk factor and 3.75 (2.58-5.45) with 2 or more, 2.38 while it was (1.58-3.59) for BMI > or = 25 with 0 or 1 factor and 3.26 (2.11-5.02) with 2 or more. The HR was significantly elevated in all categories with one or more risk factors. The PAR was highest in the category of BMI < 25 with 1 risk factor (23.3%) and second highest in the category of BMI < 25 with 2 or more. The respective PARs for BMI > or = 25 with 0 or 1 and 2 or more risk factors were 8.1% and 8.0%. Similar results were found from the analyses of different stroke subtypes.
The HR was found to be significantly elevated with the number of risk factors both with and without obesity. The attributable risk for stroke was larger in the non-obese group. Therefore, public health intervention based only on obesity may miss many of those at high risk of stroke so the focus should not only be on obesity but also cardiovascular risk factors.
[Nippon kōshū eisei zasshi] Japanese journal of public health 12/2011; 58(12):1007-15.
[show abstract][hide abstract] ABSTRACT: Two-dimensional speckle tracking imaging (2DS) enables quantitative measurement of left ventricular strain. However, application of 2DS for measurement of circumferential carotid arterial strain (CAS) is not fully elucidated. We investigated the feasibility and reproducibility of measuring CAS by 2DS and determinants of CAS in healthy subjects.
Fifty-one healthy subjects (20 men and 31 women) with a mean age of 29 ± 11 years were enrolled. Ultrasound examination of bilateral common carotid arteries (CCAs) was performed and short axial views were recorded. The mean intima-media thickness (IMT) of bilateral CCAs was measured using semiautomated edge-detection software. Bilateral peak CAS at systole and time to peak CAS in each region were measured by 2DS. Stiffness parameter β of bilateral CCAs was measured and bilateral cardio-ankle vascular index (CAVI) was recorded. Intraobserver and interobserver variabilities for mean CAS were calculated in 15 subjects.
Of the 612 regions, 577 (94%) had adequate waveforms for measurement of CAS. The mean value of CAS was 6.7 ± 2.1%. Required time for CAS analysis was 128 ± 12 seconds per subject. Multiple regression analysis identified age (P < 0.001) and pulse pressure (P < 0.05) as independent significant determinants of mean CAS. Corrected CAS, which was calculated as mean CAS/pulse pressure, correlated with age, mean IMT, and stiffness parameter β and systolic pressure (P < 0.001), age (P < 0.01), and stiffness parameter β (P = 0.02) were identified as independent significant determinants of corrected CAS. Coefficient of variance (CV) of intraobserver and interobserver variabilities for mean CAS were 8.8% and 5.9%, respectively.
2DS in the CCAs is simply and quickly performed with high feasibility and excellent reproducibility. In healthy subjects, age and pulse pressure are the most important determinants of mean CAS.
[show abstract][hide abstract] ABSTRACT: In the plasma kallikrein-kinin system, it has been shown that when plasma prekallikrein (PK) and high molecular weight kininogen (HK) assemble on endothelial cells, plasma kallikrein (huPK) becomes available to cleave HK, releasing bradykinin, a potent mediator of the inflammatory response. Because the formation of soluble glycosaminoglycans occurs concomitantly during the inflammatory processes, the effect of these polysaccharides on the interaction of HK on the cell surface or extracellular matrix (ECM) of two endothelial cell lines (ECV304 and RAEC) was investigated. In the presence of Zn(+2), HK binding to the surface or ECM of RAEC was abolished by heparin; reduced by heparan sulfate, keratan sulfate, chondroitin 4-sulfate or dermatan sulfate; and not affected by chondroitin 6-sulfate. By contrast, only heparin reduced HK binding to the ECV304 cell surface or ECM. Using heparin-correlated molecules such as low molecular weight dextran sulfate, low molecular weight heparin and N-desulfated heparin, we suggest that these effects were mainly dependent on the charge density and on the N-sulfated glucosamine present in heparin. Surprisingly, PK binding to cell- or ECM-bound-HK and PK activation was not modified by heparin. However, the hydrolysis of HK by huPK, releasing BK in the fluid phase, was augmented by this glycosaminoglycan in the presence of Zn(2+). Thus, a functional dichotomy exists in which soluble glycosaminoglycans may possibly either increase or decrease the formation of BK. In conclusion, glycosaminoglycans that accumulated in inflammatory fluids or used as a therapeutic drug (e.g., heparin) could act as pro- or anti-inflammatory mediators depending on different factors within the cell environment.
[show abstract][hide abstract] ABSTRACT: Muscular dystrophies are inherited myogenic disorders accompanied by progressive skeletal muscle weakness and degeneration. We previously showed that resveratrol (3,5,4'-trihydroxy-trans-stilbene), an antioxidant and activator of the NAD(+)-dependent protein deacetylase SIRT1, delays the progression of heart failure and prolongs the lifespan of δ-sarcoglycan-deficient hamsters. Because a defect of dystroglycan complex causes muscular dystrophies, and δ-sarcoglycan is a component of this complex, we hypothesized that resveratrol might be a new therapeutic tool for muscular dystrophies. Here, we examined resveratrol's effect in mdx mice, an animal model of Duchenne muscular dystrophy. mdx mice that received resveratrol in the diet for 32 weeks (4 g/kg diet) showed significantly less muscle mass loss and nonmuscle interstitial tissue in the biceps femoris compared with mdx mice fed a control diet. In the muscles of these mice, resveratrol significantly decreased oxidative damage shown by the immunostaining of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine and suppressed the up-regulation of NADPH oxidase subunits Nox4, Duox1, and p47(phox). Resveratrol also reduced the number of α-smooth muscle actin (α-SMA)(+) myofibroblast cells and endomysial fibrosis in the biceps femoris, although the infiltration of CD45(+) inflammatory cells and increase in transforming growth factor-β1 (TGF-β1) were still observed. In C2C12 myoblast cells, resveratrol pretreatment suppressed the TGF-β1-induced increase in reactive oxygen species, fibronectin production, and expression of α-SMA, and SIRT1 knockdown blocked these inhibitory effects. SIRT1 small interfering RNA also increased the expression of Nox4, p47(phox), and α-SMA in C2C12 cells. Taken together, these findings indicate that SIRT1 activation may be a useful strategy for treating muscular dystrophies.
Journal of Pharmacology and Experimental Therapeutics 06/2011; 338(3):784-94. · 3.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Here we examined whether the Matsuda-DeFronzo insulin sensitivity index (ISI-M) is more efficient than the homeostasis model assessment of insulin resistance (HOMA-IR) for assessing risk of hypertension. Cross-sectional and longitudinal analyses were conducted using normotensive subjects who were selected among 1399 subjects in the Tanno-Sobetsu cohort. In the cross-sectional analysis (n=740), blood pressure (BP) level was correlated with HOMA-IR and with ISI-M, but correlation coefficients indicate a tighter correlation with ISI-M. Multiple linear regression analysis adjusted by age, sex, body mass index (BMI) and serum triglyceride level (TG) showed contribution of ISI-M and fasting plasma glucose, but not of HOMA-IR. In the longitudinal analysis (n=607), 241 subjects (39.7%) developed hypertension during a 10-year follow-up period, and multiple logistic regression indicated that age, TG, systolic BP and ISI-M, but not HOMA-IR, were associated with development of hypertension. In subjects <60 years old, odds ratio of new-onset hypertension was higher in the low ISI-M group (ISI-M, less than the median) than in the high ISI-M group for any tertile of BMI. In conclusion, ISI-M is a better predictor of hypertension than is HOMA-IR. Non-hepatic IR may be a determinant, which is independent of TG, BP level and BMI, of the development of hypertension.
Journal of human hypertension 03/2011; 26(5):325-33. · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: Systolic reserve is an important compensatory mechanism against increasing afterload. Although longitudinal systolic dysfunction with preserved ejection fraction has been reported in hypertensive hearts, radial and circumferential function has not been fully examined. The aim of this study was to investigate three-directional systolic function and its relationships with left ventricular geometry in asymptomatic hypertensive patients using two-dimensional speckle-tracking imaging.
Echocardiographic evaluations were performed in 74 hypertensive patients and 55 age-matched control subjects.
Longitudinal strain was significantly reduced in the hypertrophy groups compared with that in control subjects (concentric, -15.1 ± 4.0%; eccentric, -15.9 ± 4.4%; control, -18.9 ± 3.3%; P < .05). Conversely, radial strain was significantly higher in the normal geometry group than in control subjects (53.8 ± 19.4% vs 40.3 ± 15.1%, P < .05). However, this augmentation was attenuated in the other geometries.
Hypertrophic remodeling attenuates compensatory augmentation of radial systolic function and is associated with latent longitudinal systolic dysfunction.
Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography 02/2011; 24(2):192-9. · 2.98 Impact Factor
[show abstract][hide abstract] ABSTRACT: We investigated the effect of abdominal obesity (AO) on new onset of type 2 diabetes (NODM) in a general Japanese elderly population compared with that in a non-elderly population.
The subjects were 827 people aged 29-84 who underwent medical examinations in the towns of Tanno and Sobetsu in Hokkaido, first in 1994 and subsequently in either 2003 or 2004, after the exclusion of individuals with preexisting type 2 diabetes at baseline. The subjects were divided into 2 groups according to waist circumference (WC) at baseline: an AO (WC ≥85 cm for men and ≥90 cm for women) group and a non-AO group. The percentages of subjects with NODM recorded in either in 2003 or 2004 were compared between these 2 groups, and the AO odds ratio in NODM was calculated separately for elderly (≥65 years) and non-elderly (<65 years) subjects, using multiple logistic regression analysis.
The percentage of non-elderly subjects with NODM was significantly higher in the AO group than in the non-AO group (16.9% vs. 5.4%, p<0.0001), but there was no statistically significant difference in the elderly subjects. Multiple logistic regression analysis showed that there was a significant relationship between AO and NODM (AO odds ratio in NODM=2.68, 95% confidence interval (CI): 1.05-6.90) in the non-elderly subjects, but not in the elderly subjects.
Consideration of the different effects of AO on NODM in elderly and non-elderly people may be important for the prevention of type 2 diabetes.
Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics 01/2011; 48(1):71-7.
[show abstract][hide abstract] ABSTRACT: Fatty acid-binding protein 4 (FABP4/A-FABP/aP2), a lipid chaperone, is expressed in both adipocytes and macrophages. Recent studies have shown that FABP4 is secreted from adipocytes and that FABP4 level is associated with obesity, insulin resistance, and atherosclerosis. However, little is known about the impact of FABP4 concentrations on prognosis. We tested the hypothesis that FABP4 level predicts prognosis of patients with end-stage renal disease (ESRD), a group at high risk for atherosclerosis-associated morbidity and mortality.
Biochemical markers including FABP4 were determined in 61 ESRD patients on chronic hemodialysis (HD). Serum FABP4 level in females (404.2±30.5 ng/ml) was significantly higher than that in males (315.8±30.0 ng/ml), and the levels in ESRD patients were about 20-times higher than those in age-, gender- and body mass index (BMI)-matched control subjects with normal renal function. FABP4 level was decreased by 57.2% after HD and was positively correlated with blood pressure, BMI, and levels of lipids and insulin. Multiple regression analysis indicated that HD duration, BMI, and triglycerides level were independent determinants for FABP4 level. ESRD patients with high FABP4 levels had higher cardiovascular mortality during the 7-year follow-up period. Cox proportional hazard regression analysis showed that logarithmically transformed FABP4 level was an independent predictor of cardiovascular death adjusted for age, gender, HD duration, BMI, and triglycerides level (hazard ratio, 7.75; 95% CI, 1.05-25.31).
These findings suggest that FABP4 level, being related to adiposity and metabolic disorders, is a novel predictor of cardiovascular mortality in ESRD.
PLoS ONE 01/2011; 6(11):e27356. · 3.73 Impact Factor