Sadayoshi Ito

Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

In this study, we defined the role of peroxisome proliferator-activated receptor β/δ (PPARδ) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARδ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARδ controls fatty acid oxidation by regulating genes involved in fatty acid transport, β-oxidation, and mitochondrial respiration. Similar PPARδ-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid β-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid β-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARδ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Home blood pressure measurement has a stronger predictive power for mortality than does screening blood pressure measurement: a population-based observation in Ohasama, Japan.

Objective To compare the predictive powers of self-measurement of blood pressure at home (home blood pressure measurement) and casual (screening) blood pressure measurement for mortality. Design A prospective cohort study. Subjects and methods We obtained home and screening blood pressure measurements for 1789 subjects aged ≥ 40 years who were followed up for a mean of 6.6 years. The prognostic significance of blood pressure for mortality was determined by the Cox proportional hazards regression model adjusted for age, sex, smoking status, past history of cardiovascular disease, and the use of antihypertensive medication. Results When the home blood pressure values and the screening blood pressure values were simultaneously incorporated into the Cox model as continuous variables, only the average of multiple (taken more than three times) home systolic blood pressure values was significantly and strongly related to the cardiovascular mortality risk. The average of the two initial home blood pressure values was also better related to the mortality risk than were the screening blood pressure values. Conclusions Home blood pressure measurement had a stronger predictive power for mortality than did screening blood pressure measurement for a general population. This appears to be the first study in which the prognostic significances of home and screening blood pressure measurements have been compared.

Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes

BACKGROUND Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria. METHODS In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points. RESULTS The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139); the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77; 95% confidence interval, 0.63 to 0.94; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events--81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)--but a greater number had fatal cardiovascular events--15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs. 1 of 540 [0.2%], P=0.02). CONCLUSIONS Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo; ClinicalTrials.gov number, NCT00185159.).

Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study

To investigate the association between cardiovascular mortality and short-term variabilities in blood pressure and heart rate, we performed a long-term prospective study of ambulatory blood pressure monitoring in Ohasama, Japan, starting in 1987. We obtained ambulatory blood pressure and heart rate in 1542 subjects ≥40 years of age. Blood pressure and heart rate variabilities were estimated as a standard deviation measured every 30 minutes by ambulatory monitoring. There were 67 cardiovascular deaths during the follow-up period (mean=8.5 years). The Cox proportional hazards model, adjusted for possible confounding factors, demonstrated a significant increase in cardiovascular mortality, with an increase in daytime systolic ambulatory blood pressure variability. A similar trend was observed in daytime diastolic and nighttime ambulatory blood pressures. Cardiovascular mortality rate increased linearly, with a decrease in daytime heart rate variability. Subjects in whom the daytime systolic ambulatory blood pressure variability was larger than third quintile and the daytime heart rate variability was lower than the mean−SD were at extremely high risk of cardiovascular mortality. The blood pressure and heart rate variabilities obtained every 30 minutes by ambulatory blood pressure monitoring were independent predictors for cardiovascular mortality in the general population.

Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease

BackgroundAccurate estimation of the glomerular filtration rate (GFR) is crucial for the detection of chronic kidney disease (CKD). In clinical practice, GFR is estimated from serum creatinine using the Modification of Diet in Renal Disease (MDRD) study equation or the Cockcroft-Gault (CG) equation instead of the time-consuming method of measured clearance for exogenous markers such as inulin. In the present study, the equations originally developed for a Caucasian population were tested in Japanese CKD patients, and modified with the Japanese coefficient determined by the data.MethodsThe abbreviated MDRD study and CG equations were tested in 248 Japanese CKD patients and compared with measured inulin clearance (Cin) and estimated GFR (eGFR). The Japanese coefficient was determined by minimizing the sum of squared errors between eGFR and Cin. Serum creatinine values of the enzyme method in the present study were calibrated to values of the noncompensated Jaffé method by adding 0.207 mg/dl, because the original MDRD study equation was determined by the data for serum creatinine values measured by the noncompensated Jaffé method. The abbreviated MDRD study equation modified with the Japanese coefficient was validated in another set of 269 CKD patients.ResultsThere was a significant discrepancy between measured Cin and eGFR by the 1.0 × MDRD or CG equations. The MDRD study equation modified with the Japanese coefficient (0.881 × MDRD) determined for Japanese CKD patients yielded lower mean difference and higher accuracy for GFR estimation. In particular, in Cin 30–59 ml/min per 1.73 m2, the mean difference was significantly smaller with the 0.881 × MDRD equation than that with the 1.0 × MDRD study equation (1.9 vs 7.9 ml/min per 1.73 m2; P <?0.01), and the accuracy was significantly higher, with 60% vs 39% of the points deviating within 15%, and 97% vs 87% of points within 50%, respectively (both P <?0.01). Validation with the different data set showed the correlation between eGFR and Cin was better with the 0.881 × MDRD equation than with the 1.0 × MDRD study equation. In Cin less than 60 ml/min per 1.73 m2, the accuracy was significantly higher, with 85% vs 69% of the points deviating within 50% (P <?0.01), respectively. The mean difference was also significantly smaller (P <?0.01). However, GFR values calculated by the 0.881 × MDRD equation were still underestimated in the range of Cin over 60 ml/min per 1.73 m2.ConclusionsAlthough the Japanese coefficient improves the accuracy of GFR estimation of the original MDRD study equation, a new equation is needed for more accurate estimation of GFR in Japanese patients with CKD stages 3 and 4.

Rationale, study design and implementation of the COLM study : the combination of OLMesartan and calcium channel blocker or diuretic in high-risk elderly hypertensive patients

The COLM study is an investigator-initiated trial comparing the combination therapy using an angiotensin II receptor blocker (ARB), olmesartan, and a calcium channel blocker (CCB) with that using an ARB and a diuretic in high-risk elderly hypertensive patients. Here we describe the rationale and study design. Olmesartan was administered concomitantly with a long-acting dihydropyridine CCB (ARB/CCB group) or with a low-dose diuretic (ARB/diuretic group) to elderly hypertensive patients with a history of or risk factors for cardiovascular disease. Cardiovascular morbidity and mortality as a primary end point were compared between the two groups, with the target blood pressure (BP) being <140 mm Hg for systolic BP and <90 mm Hg for diastolic BP. Safety and tolerability will also be investigated. A total of more than 4000 patients were recruited and will be followed up for at least 3 years.

Target Blood Pressure for Treatment of Isolated Systolic Hypertension in the Elderly: Valsartan in Elderly Isolated Systolic Hypertension Study

In this prospective, randomized, open-label, blinded end point study, we aimed to establish whether strict blood pressure control (<140 mm Hg) is superior to moderate blood pressure control (≥140 mm Hg to <150 mm Hg) in reducing cardiovascular mortality and morbidity in elderly patients with isolated systolic hypertension. We divided 3260 patients aged 70 to 84 years with isolated systolic hypertension (sitting blood pressure 160 to 199 mm Hg) into 2 groups, according to strict or moderate blood pressure treatment. A composite of cardiovascular events was evaluated for ≥2 years. The strict control (1545 patients) and moderate control (1534 patients) groups were well matched (mean age: 76.1 years; mean blood pressure: 169.5/81.5 mm Hg). Median follow-up was 3.07 years. At 3 years, blood pressure reached 136.6/74.8 mm Hg and 142.0/76.5 mm Hg, respectively. The blood pressure difference between the 2 groups was 5.4/1.7 mm Hg. The overall rate of the primary composite end point was 10.6 per 1000 patient-years in the strict control group and 12.0 per 1000 patient-years in the moderate control group (hazard ratio: 0.89; [95% CI: 0.60 to 1.34]; P=0.38). In summary, blood pressure targets of <140 mm Hg are safely achievable in relatively healthy patients ≥70 years of age with isolated systolic hypertension, although our trial was underpowered to definitively determine whether strict control was superior to less stringent blood pressure targets.

Prevalence of chronic kidney disease (CKD) in the Japanese general population predicted by the MDRD equation modified by a Japanese coefficient

BackgroundThe number of patients with end-stage renal disease (ESRD) in Japan has continuously increased in the past three decades. In 2005, 36 063 patients whose average age was 66 years entered a new dialysis program. This large number of ESRD patients could be just the tip of the iceberg of an increasing number of patients with chronic kidney disease (CKD). However, to date, a nationwide epidemiological study has not been conducted yet to survey the CKD population.MethodsData for 527 594 (male, 211 034; female, 316 560) participants were obtained from the general adult population aged over 20 years who received annual health check programs in 2000–2004, from seven different prefectures in Japan: Hokkaido, Fukushima, Ibaraki, Tokyo, Osaka, Fukuoka, and Okinawa prefectures. The glomerular filtration rate (GFR) for each participant was estimated from the serum creatinine values, using the abbreviated Modification of Diet in Renal Disease (MDRD) study equation modified by the Japanese coefficient.ResultsThe prevalences of CKD stage 3 in the study population, stratified by age groups of 20–29, 30–39, 40–49, 50–59, 60–69, 70–79, and 80–89 years, were 1.4%, 3.6%, 10.8%, 15.9%, 31.8%, 44.0%, and 59.1%, respectively, predicting 19.1 million patients with stage 3 CKD in the Japanese general adult population of 103.2 million in 2004. CKD stage 4 + 5 was predicted in 200 000 patients in the Japanese general adult population. Comorbidity of hypertension, diabetes, and proteinuria increased as the estimated GFR (eGFR) decreased. The prevalence of concurrent CKD was significantly higher in hypertensive and diabetic populations than in the study population overall when CKD was defined as being present with an eGFR of less than 40 ml/min per 1.73 m2 instead of less than 60 ml/min per 1.73 m2.ConclusionsAbout 20% of the Japanese adult population (i.e., approximately 19 million people) are predicted to have stage 3 to 5 CKD, as defined by a GFR of less than 60 ml/min per 1.73 m2.

Modulation of angiotensin II-induced vasoconstriction by endothelium-derived relaxing factor in the isolated microperfused rabbit afferent arteriole.

Although endothelium-derived relaxing factor (EDRF) has been studied extensively in large vessels, little is known about its role in the preglomerular afferent arteriole (Af-Art). We tested the hypothesis that EDRF, which is produced locally in the Af-Art, modulates arteriolar responses to angiotensin II (AII). A single rabbit Af-Art with its glomerulus intact was microperfused in vitro at 60 mmHg. When 0.1 microM AII was first applied, luminal diameter decreased by 49 +/- 7.0% (n = 9; P less than 0.0001); however, constriction waned, with the decrease becoming 15 +/- 3.5% at 1 min. After washing the Af-Art, repeated AII caused less constriction (13 +/- 4.0%; P less than 0.0002 vs. first application), showing tachyphylaxis. Pretreatment with Nw-nitro-L-arginine (N-Arg), which inhibits synthesis of nitric oxide (an EDRF), decreased basal diameter by 18 +/- 3.0% (n = 14; P less than 0.0001). N-Arg also augmented AII-induced constriction (86 +/- 6.8%; P less than 0.02 vs. nontreated Af-Art) and rendered it persistent (82 +/- 6.9% at 1 min). Even after pretreatment with N-Arg, repeated AII caused a weaker response, which was restored by washing with kidney homogenate rich in angiotensinase. In conclusion, this study provides evidence that local production of EDRF is an important determinant of the tone of the Af-Art. Our results suggest that the transient nature of AII-induced constriction of the Af-Art may be due to production of EDRF, while tachyphylaxis may be the result of long lasting receptor occupancy.

Role of urotensin II in patients on dialysis.

Urotensin II is a potent vasoconstrictor, which also has some vasodilatory properties. We investigated its expression in various tissues and in the plasma of patients with renal dysfunction. Plasma concentrations of urotensin II-like immunoreactivity were 2-fold higher in patients not on dialysis and 3-fold higher in those on haemodialysis thanin healthy individuals. Messenger RNA encoding theurotensin II precursor and the urotensin II receptor precursor were expressed in various human tissues. The peptidemight act as an important regulator in the cardiovascularand renal systems. Urotensin II antagonists could, therefore, be useful in the treatment of diseases affecting theseorgans.