Our data suggest that forearm endothelial dysfunction is a marker of future cardiovascular events in patients with essential hypertension.

Abstract-The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the "normal" range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4.0Ϯ2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m 2 in men and 79, 91, 102, and 116 g/m 2 in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4.3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the second (RR 1.6, 95% CI 0.8 to 3.1), third (RR 1.9, 95% CI 1.01 to 4.0), fourth (RR 3.0, 95% CI 1.5 to 5.8), and fifth (RR 3.5, 95% CI 1.8 to 6.8) quintile. For all-cause death, the RR in the fifth quintile compared with the first quintile was 4.3 (95% CI 1.2 to 13.4). In conclusion, the powerful relation between LV mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension is continuous over a wide range of LV mass values, even below the current "upper normal" limits. The relation remains significant after control for traditional risk factors, including ambulatory blood pressure. Key Words: echocardiography Ⅲ hypertension, arterial Ⅲ hypertension, essential Ⅲ hypertrophy Ⅲ morbidity Ⅲ mortality L eft ventricular (LV) hypertrophy detected on echocardiography is a powerful and independent predictor of cardiovascular complications and death in subjects with uncomplicated essential hypertension. 1-3 Furthermore, regression of LV hypertrophy appears to be a favorable prognostic marker independent of the treatment-induced reduction in blood pressure (BP). 4,5 LV mass shows a continuous distribution in the general population, 6 whereas LV hypertrophy is an operational category that defines the upper end of LV mass distribution. 1-3 LV hypertrophy on echocardiography is generally found in 20% to 30% of relatively unselected subjects with mild-tomoderate hypertension, 7,8 and its prevalence varies according to the selected cutoff value. 9 The Framingham Heart Study showed an apparently continuous relation between LV mass and cardiovascular event rate in the general population. 10 However, the important clinical issues regarding the shape of the relation between LV mass and cardiovascular risk in essential hypertension and the prognostic impact of LV mass values below the commonly agreed-on upper normal limits have not been addressed. The present study was specifically designed to establish the link between LV mass and cardiovascular risk in subjects with essential hypertension over a wid...

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Prolongation of the QT interval in the first week of life is strongly associated with SIDS. Neonatal electrocardiographic screening may permit the early identification of a substantial percentage of infants at risk for SIDS, and the institution of preventive measures may therefore be possible.

Endothelial dysfunction has been reported in obese subjects, but its mechanism has not been elucidated. We have therefore investigated 1) the possible relationship among BMI, waist-to-hip ratio (WHR), and endothelium-dependent vasodilation and 2) whether oxidative stress participates in endothelial dysfunction. We recruited 76 healthy subjects (50 men and 26 women aged 21-45 years) and measured their BMI (kg/m 2 ), WHR, and insulin resistance (IR) estimated by the homeostasis model assessment (HOMA). Endothelium-dependent and -independent vasodilation were assessed by increasing doses of acetylcholine (ACh) (7.5, 15, and 30 µg · ml -1 · min -1) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 µg · ml -1 · min 19.8 ± 2.8, 10.8 ± 2.7, and 6.5 ± 1.8 ml · 100 ml -1 tissue · min -1 (P < 0.0001) for groups A, B, and C, respectively. SNP caused comparable increments in FBF in all groups. Regression analysis revealed a significant negative correlation between BMI (r = -0.676, P < 0.0001), WHR (r = -0.631, P < 0.0001), fasting insulin (r = -0.695, P < 0.0001), HOMA-IR (r = -0.633, P < 0.0001), and percent peak increase in FBF during ACh infusion. In obese subjects, both vitamin C and indomethacin increased the impaired vasodilating response to ACh, whereas the SNP effect was unchanged. In conclusion, in obese subjects, ACh-stimulated vasodilation is blunted, and the increase in FBF is inversely related to BMI, WHR, fasting insulin, and HOMA-IR. The effects of both vitamin C and indomethacin on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction in human obesity. O bese subjects are at high risk for developing diabetes, dyslipidemia, hypertension, and cardiovascular diseases, which lead to an increased risk of mortality (1-3). Moreover, it has been demonstrated that obesity is associated with hyperinsulinemia, an independent predictor for coronary artery disease (4). In fact, hyperinsulinemia is linked to insulin resistance (IR) and potentially to atherogenic abnormalities.The normal endothelium plays a key role in the regulation of vascular tone and in preventing the progression of atherosclerosis through the production and release of both contracting and relaxing factors (5). Nitric oxide (NO) represents the major endogenous relaxing factor (6-9), and its production is stimulated by physical stimuli (e.g., shear stress) (9) and by several agonists (e.g., acetylcholine [ACh], bradykinin, substance P, and serotonin) (8). The activation of guanylate cyclase and the subsequent accumulation of cGMP are the main mechanisms of NO-induced vasodilation. In contrast, sodium nitroprusside (SNP) is an endothelium-independent vasodilator capable of inducing vasodilation by providing an inorganic source of NO (10). Major risk factors for atherosclerotic vascular diseases (e.g., hypertension, smoking, diabetes, and hypercholesterolemia) have been associated with endothelial dysfunction due to increased oxidative stress (11-16). Recent reports have also indicated tha...

The main finding in this study is that in essential hypertensives the L-arginine and endogenous inhibitor of nitric oxide synthase, ADMA, are inversely related to endothelial function.

Abstract-It has been suggested that serine (Ser) phosphorylation of insulin receptor substrate-1 (IRS-1) decreases the ability of IRS-1 to be phosphorylated on tyrosine, thereby attenuating insulin signaling. There is evidence that angiotensin II (AII) may impair insulin signaling to the IRS-1/phosphatydilinositol 3-kinase (PI 3-kinase) pathway by enhancing Ser phosphorylation. Insulin stimulates NO production by a pathway involving IRS-1/PI3-kinase/Akt/endothelial NO synthase (eNOS). We addressed the question of whether AII affects insulin signaling involved in NO production in human umbilical vein endothelial cells and tested the hypothesis that the inhibitory effect of AII on insulin signaling was caused by increased site-specific Ser phosphorylation in IRS-1. Exposure of human umbilical vein endothelial cells to AII resulted in inhibition of insulin-stimulated production of NO. This event was associated with impaired IRS-1 phosphorylation at Tyr 612 and Tyr 632 , two sites essential for engaging the p85 subunit of PI3-kinase, resulting in defective activation of PI 3-kinase, Akt, and eNOS. This inhibitory effect of AII was reversed by the type 1 receptor antagonist losartan. AII increased c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) 1/2 activity, which was associated with a concomitant increase in IRS-1 phosphorylation at Ser 312 and Ser 616 , respectively. Inhibition of JNK and ERK1/2 activity reversed the negative effects of AII on insulin-stimulated NO production. Our data suggest that AII, acting via the type 1 receptor, increases IRS-1 phosphorylation at Ser 312 and Ser 616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway. Key Words: endothelium Ⅲ angiotensin II Ⅲ nitric oxide Ⅲ insulin E ndothelial dysfunction is an early event in the pathogenesis of atherosclerosis and a feature of insulin-resistant conditions, including type 2 diabetes, obesity, and hypertension. 1-4 Several preclinical and clinical studies have established the involvement of angiotensin II (AII) and its type 1 receptor (AT 1 ) in endothelial dysfunction. [5][6][7] Insulin promotes vasodilatation by activation of the signaling pathway involving the insulin receptor/insulin receptor substrate-1 (IRS-1)/ phosphatidylinositol 3-kinase (PI 3-kinase)/Akt that leads to activation of endothelial NO synthase (eNOS) in endothelium. 8 Cross-talk between the renin-angiotensin system (RAS) and insulin signaling has been demonstrated. 9 Inhibition of RAS by angiotensin-converting enzyme inhibitors or AT 1 antagonists has been shown to both increase insulin sensitivity and improve endothelial function. 10 -12 Evidence has been provided that AII interferes with insulin signaling in vascular cells mainly by affecting insulin-induced tyrosine phosphorylation of IRS-1 and impairing its interaction with the p85 regulatory subunit of PI 3-kinase. 9 However, it is still unclear whether AII adversely affects the downstream signaling path...

OBJECTIVE -We studied the relationships between plasma IGF-I concentrations and insulin sensitivity in subjects with various degrees of glucose tolerance.RESEARCH DESIGN AND METHODS -A total of 357 nondiabetic subjects, 54 subjects with impaired glucose tolerance and 98 newly diagnosed type 2 diabetic subjects, were consecutively recruited, and anthropometric and biochemical characteristics were collected.RESULTS -IGF-I concentrations were negatively correlated with age, BMI, waist-to-hip ratio, triglyceride levels, and systolic and diastolic blood pressure. IGF-I concentrations were positively correlated with HDL cholesterol and homeostasis model assessment of insulin sensitivity (HOMA-S). The correlations remained significant after adjusting for sex, age, and BMI. Correlations for HOMA-S with these metabolic and anthropometric variables were of a similar degree and direction to those for IGF-I concentrations. Stepwise linear regression analysis in a model, which included well-known modulators of insulin sensitivity such as sex, age, BMI, glucose tolerance status, family history of diabetes, waist-to-hip ratio, systolic and diastolic blood pressure, HDL cholesterol, and triglyceride levels, revealed that IGF-I concentrations were independently associated with insulin sensitivity accounting for 10.8% of its variation (P Ͻ 0.0001). IGF-I concentrations were significantly lower in subjects with World Health Organization (WHO)-defined metabolic syndrome compared with subjects without metabolic syndrome (P Ͻ 0.0001). Logistic regression analysis showed that each unit increase in log-transformed IGF-I concentrations was associated with a 90.5% reduction in the risk of WHO-defined metabolic syndrome.CONCLUSIONS -These data indicate that IGF-I has the characteristics to be a marker for the insulin resistance syndrome. This suggests that low IGF-I levels may be a useful marker for identifying subjects at risk for cardiovascular disease. Diabetes Care 28:132-137, 2005