G(13)-mediated signaling pathway is required for pressure overload-induced cardiac remodeling and heart failure.

BACKGROUND: Cardiac remodeling in response to pressure or volume overload plays an important role in the pathogenesis of heart failure. Various mechanisms have been suggested to translate mechanical stress into structural changes, one of them being the release of humoral factors such as angiotensin II and endothelin-1, which in turn promote cardiac hypertrophy and fibrosis. A large body of evidence suggests that the prohypertrophic effects of these factors are mediated by receptors coupled to the G(q/11) family of heterotrimeric G proteins. Most G(q/11)-coupled receptors, however, can also activate G proteins of the G(12/13) family, but the role of G(12/13) in cardiac remodeling is not understood. METHODS AND RESULTS: We use siRNA-mediated knockdown in vitro and conditional gene inactivation in vivo to study the role of the G(12/13) family in pressure overload-induced cardiac remodeling. We show in detail that inducible cardiomyocyte-specific inactivation of the α subunit of G(13), Gα(13), does not affect basal heart function but protects mice from pressure overload-induced hypertrophy and fibrosis as efficiently as inactivation of Gα(q/11). Furthermore, inactivation of Gα(13) prevents the development of heart failure up to 1 year after overloading. On the molecular level, we show that Gα(13), but not Gα(q/11), controls agonist-induced expression of hypertrophy-specific genes through activation of the small GTPase RhoA and consecutive activation of myocardin-related transcription factors. CONCLUSION: Our data show that the G(12/13) family of heterotrimeric G proteins is centrally involved in pressure overload-induced cardiac remodeling and plays a central role in the transition to heart failure.

Uric acid and left ventricular hypertrophy in Japanese men.

BACKGROUND: Experimental studies have reported that allopurinol protects hypertensive rats from left ventricular hypertrophy (LVH) with negligible effects on blood pressure (BP). Uric acid (UA) was thought to induce cardiomyocyte growth and interstitial fibrosis of the heart, partly via activation of the renin-angiotensin system. In the present study, the relationship between serum UA levels and electrocardiographically-diagnosed LVH (ECG-LVH) was examined in Japanese men not taking medication for hypertension (HTN), which could confound the association. METHODS AND RESULTS: A total of 3,305 male workers aged 35-66 years (mean age+/-SD, 48.0+/-7.1) were studied. LVH was defined as meeting the ECG criteria (ie, Sokolow-Lyon voltage and/or Cornell voltage QRS duration product). Subjects were divided into 3 groups by tertile of serum UA level. The highest tertile (UA range 0.39-0.65 mmol/L or 6.6-11.0 mg/dl) had a significantly increased prevalence of LVH compared with the lowest tertile independent of age, body mass index, serum creatinine level, HTN, diabetes and hyperlipidemia (odds ratio 1.58, 95% confidence interval 1.23-2.02, P<0.001). Similar results were obtained in both the normal and high BP subgroups. CONCLUSIONS: UA concentration independently and positively associated with ECG-LVH in Japanese men.

Self-reported medical history was generally accurate among Japanese workplace population.

OBJECTIVE: To assess the validity of self-reported medical history of several diseases among the Japanese population, and to clarify to what extent the self-reported year of diagnosis for chronic diseases is different from the physician's reports. STUDY DESIGN AND SETTING: Subjects were 8,947 persons who responded to questions about medical history in a self-administered questionnaire. Of them, 854 subjects reported one or more medical histories and gave permission to contact their physician. The physicians were then requested to provide information on 809 subjects. Valid responses of 714 subjects were collected. We compared the self-reported medical histories with those reported by the physician. RESULTS: Of 15 persons who reported myocardial infarction, 13 (87%) were confirmed. Angina pectoris was verified in eight out of the 11 (73%). The confirmation proportions of hypertension, diabetes, hyperlipidemia, and hyperuricemia were 97%, 96%, 95%, and 95%, respectively. The self-reported year of diagnosis was 1.70-2.49 years earlier than the physician-reported year for chronic diseases. Agreement between the self-reported and the physician-reported years was higher, the more recent the self-reported year was. CONCLUSION: Self-reported medical histories were generally accurate, especially for diseases with clear diagnostic criteria. However, investigators should be aware of the errors in reporting the year of diagnosis.

Having more healthy practice was associated with low white blood cell counts in middle-aged Japanese male and female workers.

White blood cell (WBC) count is well known to be an independent risk marker for cardiovascular disease. The aim of this study is to examine the relationships of WBC counts to seven health practices including obesity, eating habits, smoking, alcohol intake, sleeping, physical activity, and perceived mental stress, and then clustering the relevant healthy practices. The subjects were 1,492 male and 316 female Japanese workers aged 40 yr and over in 2002. Each of seven health practices from a self-administered questionnaire was categorized as a 'healthy' or 'unhealthy' practice, and WBC counts from fasting blood samples were determined by automated particle counters. The means of age and WBC counts were 49.5 yr and 5,375 cells/microl in men, and 48.6 yr and 4,890 cells/microl in women, respectively. After multivariate adjustments for all health practices and age, the estimated WBC counts were significantly lower in normal weight subjects and never or former smokers (p<0.01). Age-adjusted WBC counts decreased significantly by 204.9+/-23.7 cells/microl (means+/-SE) and 117.6+/-53.2 cells/microl for each increase in one healthy practice (p<0.05), respectively, suggesting that cultivating healthier practices would lead to lower WBC counts. This study recommends modifying unhealthy practice one by one and maintaining healthy practices as an effective strategy for the prevention of atherosclerotic diseases, in addition, to quit smoking or abstain from heavy smoking especially in men is important to prevent the low-grade inflammation.

Low leptin but high insulin resistance of smokers in Japanese men.

AIMS: To investigate the association between smoking and leptin, and to discuss their influence on diabetes in a large-scale study of Japanese men. METHODS: A cross-sectional study was carried out in 2002. The subjects were 2836 men aged 35-66. Smoking history was investigated in a self-administered questionnaire. Blood leptin, glucose and insulin were measured. RESULTS: Significant differences in leptin levels and homeostasis model assessment of insulin resistance (HOMA-IR) related to smoking status were observed (P=0.001 and P=0.008, respectively). The multivariate-adjusted geometric means of leptin in current, past and never smokers were 3.88, 4.08 and 4.12 ng/ml, respectively, while the means of HOMA-IR were 1.64, 1.61 and 1.49, respectively. The age-, body mass index-, and other lifestyle-adjusted prevalences of diabetes in current and never smokers were 9.2 and 4.7%, respectively. That of current smokers was significantly higher than in never smokers (P<0.001). The dose-dependent association found between the intensity of smoking and leptin levels in current smokers was statistically significant (P=0.030). CONCLUSIONS: The present finding may explain in part an association among smoking, leptin levels and diabetes. Smoking is one of the important modifiable risk factors for the prevention of diabetes.

Association between low birth weight and elevated white blood cell count in adulthood within a Japanese population.

BACKGROUND: Epidemiological studies have demonstrated the association between low birth weight and increased adulthood risk for cardiovascular and metabolic diseases. However, the precise mechanism underlying the association remains poorly understood. We investigated the association between birth weight and adult white blood cell (WBC) count in a Japanese population. METHODS AND RESULTS: The subjects were 779 men and 209 women aged 35-64 years. The mean WBC count was 5,283 /microl (SD: 1,326). Birth weight was divided to 6 categories: <2,500, 2,500-<2,800, 2,800-<3,000, 3,000-<3,200, 3,200-<3,500, and >3,500 g. Estimated WBC counts were 5,729, 5,341, 5,301, 5,212, 5,013 and 5,372 for the subjects with birth weights of the above respective categories (p=0.015, trend p=0.016) by one-way analysis of covariance after adjustments for sex, age, height, body mass index (BMI), lifestyles, and chronic diseases. This association was pronounced among the subjects with a BMI <25.0 kg/m2 rather than those with a higher BMI. CONCLUSIONS: These findings support the idea that part of the association of low birth weight with elevated risk for vascular and metabolic diseases in later life could be mediated by an inflammatory pathway.

Further inflammatory information on metabolic syndrome by adiponectin evaluation.

BACKGROUND: Despite a close association of adiponectin with metabolic syndrome (MetS), its usefulness as an additional MetS factor has not been well investigated. METHODS: We studied 2327 apparently healthy Japanese male office workers aged 35 to 66 years old and investigated cross-sectionally whether categorization by serum adiponectin distinguished participants' levels of high-sensitivity C-reactive protein (CRP) beyond the conventional MetS. RESULTS: In a linear regression analysis, adiponectin was associated with CRP independently of all MetS factors (beta=-0.192, P<0.001). Furthermore, a graded decrease in CRP level was observed with elevation of adiponectin in every stratum characterized by the presence or absence of each MetS component (trend P<0.05 in all strata except those of decreased high-density lipoprotein cholesterol or hyperglycemia). Similarly, geometric means of CRP levels (mg/l) decreased as adiponectin increased from the lowest to the highest tertile in all strata classified by the number of MetS components, though a P value did not reach statistical significance in those with 3 MetS components (the stratum of 0 MetS component: 0.41 [95% confidence interval, 0.34-0.49], 0.32 [0.28-0.37] and 0.26 [0.23-0.30], trend P<0.001; 1 component: 0.45 [0.39-0.52], 0.38 [0.34-0.43], and 0.32 [0.28-0.36], trend P<0.001; 2 components: 0.58 [0.50-0.67], 0.51 [0.44-0.60], and 0.46 [0.38-0.55], trend P=0.043; 3 components: 0.80 [0.66-0.96], 0.69 [0.55-0.87], and 0.58 [0.39-0.85], trend P=0.139). CONCLUSIONS: Adiponectin evaluation provides additional inflammatory information on conventional MetS, supporting the potential of hypoadiponectinemia as an additional MetS component for identifying high-risk individuals for cardiovascular disease.

Eating fast leads to insulin resistance: findings in middle-aged Japanese men and women.

OBJECTIVE: To examine relationships between speed of eating and insulin resistance. METHODS: Cross-sectional study of 2704 male (mean age and BMI: 48.2 y and 23.3 kg/m(2)) and 761 female (46.3 y and 21.8 kg/m(2)) non-diabetic Japanese civil servants, 75% clerical, and 25% manual laborers, using a two-part questionnaire on life-style factors and diet history with self-assessment of categorical speed of eating and energy intake over a 1-month period. We measured BMI, blood glucose and insulin concentrations and calculated insulin resistance using the homeostasis model assessment of insulin resistance: (HOMA-IR). RESULTS: BMI correlated with eating rate in both sexes, and with daily energy intake in men. Multiple regression analysis of log HOMA-IR by categorical speed of eating, adjusting for age, energy intake and lifestyle factors showed a statistically significant gradual increase in HOMA-IR with increases in relative eating rate in men (p<0.001, for trend) and in women (p<0.01). Adjusting for BMI, this positive relationship appeared only in men (p=0.03). CONCLUSIONS: Our results suggest that eating fast is independently associated with insulin resistance in middle-aged Japanese men and women.

Smoking status and adiponectin in healthy Japanese men and women.

BACKGROUND: Recent studies promisingly indicate that adiponectin plays an important and fundamental role in the development and progression of metabolic and atherosclerosis disorders. Smoking is known as one of the most important risk factors of atherosclerosis, and its relation with metabolic disorders has also been reported. We therefore investigated the association between cigarette smoking and adiponectin concentration in a large sample of Japanese men and women. METHOD: The cross-sectional study was carried out in 2002. The subjects were 3260 men and 953 women local government workers aged 35 to 59 in Japan. Lifestyle-related variables including detailed smoking history were inquired in a self-administered questionnaire. RESULTS: Significant differences in adiponectin levels related to smoking status were observed in both men and women (p=0.001). A dose-dependent association was found between the intensity of smoking and adiponectin levels in current smokers, and was statistically significant in men (p for trend=0.006 in the multivariate-adjusted model). Men who quit smoking for more than 20 years and women for more than 10 years had an adiponectin concentration similar to that observed in non-smokers. CONCLUSION: We not only revealed that current smoking habit was associated with low adiponectin level but also found a dose-dependent association between smoking intensity and adiponectin level in current smokers. The present finding may provide further evidence of the importance of a causal relationship between smoking status and adiponectin concentrations.

Adiponectin level and left ventricular hypertrophy in Japanese men.

A recent study has demonstrated that adiponectin inhibited hypertrophic signaling in the myocardium of mice, implying that a decrease in the blood adiponectin level could cause cardiac muscle hypertrophy. We hypothesized that a relationship might exist between the serum adiponectin level and electrocardiographically diagnosed left ventricular hypertrophy (ECG-LVH), and we examined this hypothesis by epidemiological study of 2839 Japanese male workers who were not taking medications for hypertension. ECG-LVH was defined as meeting Sokolow-Lyon voltage criteria and/or Cornell voltage-duration product. The subjects were categorized by tertiles of serum adiponectin level, and a multivariate logistic regression analysis was conducted relating left ventricular hypertrophy to adiponectin tertiles adjusting for potential confounding factors. Prevalence of ECG-LVH in the studied sample was 16.7%. Adiponectin ranged from 1.0 to 5.0 microg/mL in the lowest category and from 7.4 to 30.6 microg/mL in the highest. Compared with subjects in the highest adiponectin category, those in the lowest one had a significantly higher prevalence of ECG-LVH independent of age, body mass index, and systolic blood pressure with an odds ratio of 1.50 and a 95% CI of 1.16 to 1.94. Further adjustment for high-density lipoprotein cholesterol, triglyceride, and insulin resistance did not change the association (odds ratio: 1.68; 95% CI: 1.28 to 2.21; P<0.001). Similar results were obtained when different criteria for ECG-LVH were used or when subjects were stratified by blood pressure or body mass index. Adiponectin concentration was inversely and independently associated with ECG-LVH in Japanese men.

The transition to menopause reinforces adiponectin production and its contribution to improvement of insulin-resistant state.

OBJECTIVE: To evaluate the influence of menopausal status on the serum adiponectin concentration and investigate whether the contribution of adiponectin to insulin resistance is modified by menopausal status. SUBJECTS: We conducted a population-based, cross-sectional study of 207 premenopausal and 206 postmenopausal Japanese women. MEASUREMENTS: Data on anthropometric characteristics, fasting serum adiponectin, glucose and insulin concentrations were used. Insulin resistance (homeostasis model assessment of insulin resistance: HOMA-IR) was calculated. RESULTS: Postmenopausal women had significantly higher HOMA-IRs than premenopausal women [1.50 (1.42, 1.59) vs 1.18 (1.12, 1.24), geometric mean (1 standard error range), P = 0.005]. Paradoxically, adiponectin levels in postmenopausal women were also significantly higher than those in premenopausal women [10.3 (9.95, 10.7) vs 9.04 (8.71, 9.39), P = 0.028]. Multiple regression analysis showed that body mass index (BMI) was the only significantly independent predictor [standardized partial regression coefficients (sbeta) = 0.319, P < 0.001] for HOMA-IR among premenopausal women, whereas both BMI and adiponectin were the significant predictors among postmenopausal (sbeta = 0.334 and -0.141, P < 0.001 and < 0.05, respectively). When the subjects were restricted to those without metabolic disorders including high blood pressure, hypertriglyceridaemia, hypo-HDL cholesterolaemia and high fasting glucose, adiponectin (sbeta = -0.249, P < 0.05) was the only significant predictor for HOMA-IR among postmenopausal women but BMI was not significant (sbeta = 0.223, P = 0.075). CONCLUSIONS: The transition to menopause increases serum adiponectin concentrations. And the significant and negative association between adiponectin and HOMA-IR was observed only after menopause. Therefore, adiponectin may play a role in the improvement of an incipient insulin-resistant state after, rather than before, menopause.

Role of microglia in the pathogenesis of osmotic-induced demyelination.

Osmotic demyelination is a serious disease caused by rapid correction of hyponatremia. In humans, demyelinative lesions occur preferentially in the central pons, and thus are termed central pontine myelinolysis. Although accumulation of microglia has been reported in such demyelinative lesions, their role in the pathogenesis of osmotic demyelination remains unclear. We examined the expression of cytokines in microglia that accumulated in the demyelinative lesions in a rat model of osmotic demyelination. Hyponatremia was induced in rats by a combination of dDAVP infusion and liquid diet feeding. After 7 days, serum sodium levels were rapidly corrected by hypertonic saline injection. The rats developed severe motor deficits, and marked demyelinative lesions were found in the midbrain and cerebral cortex. In the area of the demyelinative lesions, massive accumulations of microglia were observed that expressed the proinflammatory cytokines TNF-alpha and IFN-gamma as well as iNOS. In contrast, in hyponatremia corrected rats treated with lovastatin, which is known to inhibit microglial infiltration in various animal models of CNS disease, neurological impairments and the degree of demyelination were significantly ameliorated. Lovastatin also reduced the accumulation of microglia and decreased the expression of TNF-alpha in the demyelinative lesions. These results indicate that microglia play a detrimental role in the pathogenesis of osmotic demyelination by producing proinflammatory cytokines, and further suggest that lovastatin may be useful in repressing the demyelination.

Mechanisms and therapy of osmotic demyelination.

Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.

Eating fast leads to obesity: findings based on self-administered questionnaires among middle-aged Japanese men and women.

BACKGROUND: Few epidemiologic studies have examined the association between the rate of eating and obesity. In this study, we cross-sectionally examined the association of the self-reported rate of eating with current Body Mass Index (BMI), and BMI-change from 20 years of age to the current age. METHODS: Subjects were 3737 male (mean age +/- standard deviation and mean BMI +/- standard deviation: 48.2 +/- 7.1 years and 23.3 +/- 2.7 kg/m(2)) and 1005 female (46.3 +/- 7.0 years and 21.8 +/- 2.8 kg/m(2)) Japanese civil servants. We measured self-reported categorical rate of eating, current BMI, BMI at age 20, and BMI-change from age 20. Energy intake was assessed over a 1-month period with a brief-type diet history questionnaire. RESULTS: The multiple regression analysis in which the current BMI was regressed by categorical rate of eating, energy intake, age, and lifestyle factors showed that current BMI steadily increased by -0.99, -0.67, 0.81, and 1.47 kg/m(2) along with the progress of categorical rate of eating from the 'medium' group to 'very slow', 'relatively slow', 'relatively fast', and 'very fast' groups, respectively, in men. In women, the corresponding values were -1.06, -0.35, 0.50, and 1.34 kg/m(2). When the BMI increment from age 20 to current age was regressed in the same manner, the increment was -0.63, -0.34, 0.57, and 1.05 kg/m(2) in men and -0.71, -0.32, 0.34, and 1.14 kg/m(2) in women, respectively. Additionally, both BMI at age 20 and current height were positively associated with rate of eating. CONCLUSIONS: Our results among middle-aged men and women suggest that eating fast would lead to obesity.

Association between parental histories of hypertension, diabetes and dyslipidemia and the clustering of these disorders in offspring.

BACKGROUND: Familial aggregation of hypertension, diabetes and dyslipidemia has been well reported. However, only a few studies have assessed to what extent parental histories were involved in the clustering of these diseases. METHOD: In 2002, associations between parental histories of hypertension, diabetes and dyslipidemia and the clustering of high blood pressure, hyperglycemia and dyslipidemia in individuals were assessed on the basis of 5010 Japanese men and women aged 33-66 years. Risk factor clusters were defined as those having at least two of the three clinical disorders. RESULTS: Compared with persons with no parental history of the three diseases, those who had 1, 2 and 3 or more parental histories had risk factor clusters, 1.25 (95% CI: 1.07, 1.47), 1.46 (95% CI: 1.16, 1.84) and 1.41 (95% CI: 0.95, 2.11) times higher, respectively, after adjusting for confounding factors. ORs by 1, 2 and 3 of maternal history were 1.33 (95% CI: 1.12, 1.58), 1.65 (95% CI: 1.16, 2.35) and 1.69 (95% CI: 0.64, 4.42), respectively (trend P < 0.001). However, the number of paternal history was not associated with risk factor clusters. CONCLUSION: We conclude that familial history, particularly maternal history, is an important aid to prevention strategy and public health practice for metabolic disorders.

Comparison of circulating adiponectin and proinflammatory markers regarding their association with metabolic syndrome in Japanese men.

BACKGROUND: Anti-inflammatory and proinflammatory molecules purportedly play an important role in developing metabolic syndrome (MetS). However, little is known as to the relative importance of these molecules in the association with MetS. METHODS AND RESULTS: We studied 624 middle-aged Japanese men without medical history of cardiovascular disease or cancer and investigated the associations of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), C-reactive protein (CRP), and adiponectin with MetS. We used the respective definitions proposed by the National Cholesterol Education Program Adult Treatment Panel III (ATP-III), the International Diabetes Federation, and the Japanese Society of Internal Medicine. Decreased serum adiponectin was observed in those with any of the ATP-III-MetS components, whereas this was not the case with increased TNF-alpha, IL-6, or CRP. Adiponectin and CRP levels linearly deteriorated with an increasing number of ATP-III-MetS components (trend P<0.001, respectively). Significantly higher CRP and lower adiponectin levels were observed in those who met any MetS criteria, whereas increased TNF-alpha was observed in only those with ATP-III-MetS. Finally, odds ratios (ORs) for MetS prevalence of a 1-SD increase/decrease in log-transformed 4 markers were calculated with multivariate logistic regression analyses. Consequently, decreased adiponectin was associated most strongly with ATP-III-MetS (adiponectin: OR, 1.90 [95% CI, 1.44 to 2.51]; P<0.001; CRP: OR, 1.33 [95% CI, 1.01 to 1.74]; P=0.03; TNF-alpha: OR, 1.25 [95% CI, 0.94 to 1.67]; P=0.12; and IL-6: OR, 0.87 [95% CI, 0.63 to 1.19]; P=0.37). This result was not altered by using the other 2 criteria. CONCLUSIONS: The present results raise the possibility that decreased serum adiponectin might be fundamentally involved in the development of MetS.

Protective effect of dexamethasone on osmotic-induced demyelination in rats.

Central pontine myelinolysis (CPM) is a serious demyelination disease commonly associated with the rapid correction of hyponatremia. Although its pathogenesis remains unclear, the disruption of the blood-brain barrier (BBB) as a consequence of a rapid increase in serum sodium concentration is considered to play a critical role. Since glucocorticoids are known to influence BBB permeability and prevent its disruption as a result of hypertension or hyperosmolarity, we investigated whether dexamethasone (DEX) could protect against osmotic demyelination in an animal model of CPM. Hyponatremia was induced in rats by liquid diet feeding and dDAVP infusion. Seven days later, the animals' hyponatremia was rapidly corrected by injecting a bolus of hypertonic saline intraperitoneally. Rats subjected to this treatment displayed serious neurological impairment and 77% died within 5 days of rapid correction of their hyponatremia; demyelinative lesions were observed in various brain regions in these animals. On the other hand, rats that were treated with DEX (2 mg/kg, 0 and 6 h after hypertonic saline injection) exhibited minimal neurological impairment and all were alive after 5 days. Demyelinative lesions were rarely seen in the brains of DEX-treated rats. A marked extravasation of endogenous IgG was observed in the demyelinative lesions in the brains of rats that did not receive DEX, indicating disruption of the BBB, but was not observed in DEX-treated rats. Furthermore, Evans blue injection revealed a significant reduction in staining in the brains of DEX-treated rats (P < 0.05). These results indicate that early DEX treatment can prevent the BBB disruption that is caused by the rapid correction of hyponatremia and its associative demyelinative changes, and suggest that DEX might be effective in preventing CPM.