Biomedical subjects

Angela Sciacqua

Publications and source records attributed to Angela Sciacqua.

12 recordsLinked to original sources

PubMed2007

Effects of growth hormone and insulin-like growth factor-1 on cardiac hypertrophy of hypertensive patients.

OBJECTIVES: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) interfere with cardiac mass (left ventricular mass; LVM) development. We investigated the role of the GH/IGF-1 axis on LVM and ventricular geometry in a group of 230 never-treated hypertensive patients. METHODS: Partition values for left ventricular hypertrophy (LVH) were 125 g/m2 for both women and men. Insulin resistance was estimated by the homeostasis model assessment (HOMA) index. RESULTS: A significant inverse correlation was observed between IGF-1 and both fasting insulin (r = -0.249; P < 0.0001) and GH (r = -0.218; P < 0.0001). Systolic blood pressure (157.3 +/- 13.6 versus 149.4 +/- 12.8 mmHg; P < 0.001), fasting insulin (17.4 +/- 8.5 versus 11.4 +/- 6.0 microU/l; P < 0.0001), HOMA (4.4 +/- 2.3 versus 2.9 +/- 1.6; P < 0.0001) and GH (1.0 +/- 1.0 versus 0.4 +/- 0.5 ng/ml; P < 0.0001) were significantly higher in patients with LVH; on the contrary, IGF-1 values (119.1 +/- 47.8 versus 160.1 +/- 75.5 ng/ml; P < 0.0001) were higher in patients without LVH. In a logistic regression analysis, the strongest independent predictors of LVH were GH [relative risk (RR) = 2.078; 95% confidence interval (CI) = 1.364-3.163], HOMA (RR = 1.345; 95% CI = 1.133-1.596), IGF-1 (RR = 0.993; 95% CI = 0.998-0.999) and systolic blood pressure (RR = 1.036; 95% CI = 1.013-1.060). IGF-1 showed an opposite trend in patients with eccentric and concentric hypertrophy. CONCLUSIONS: Present data demonstrate that the increase in LVM prevalent in human essential hypertension is directly associated with serum GH levels and inversely related to circulating IGF-1.

Adult↗

PubMed2006

Effect of interaction between left ventricular dysfunction and endothelial function in hypertension.

Hypertension, one of the most important risk factors for cardiovascular diseases, is associated with both left ventricular hypertrophy and endothelial dysfunction. Both have been recently recognized as independent predictors of clinical events in different groups of patients. In fact, a dysfunctioning endothelium loses its antiatherosclerotic and antithrombotic action, and, therefore, promotes the atherosclerotic process. Similarly, cardiac hypertrophy is recognized as a powerful and independent risk factor for cardiovascular morbidity and mortality because it predisposes to arrhythmias and maximizes the consequences of acute myocardial ischemia. Recently, an evident interaction has been demonstrated between endothelial dysfunction and left ventricular mass. In particular, the coexistence of both left ventricular hypertrophy and endothelial dysfunction almost doubles the risk for future vascular events in hypertensives. Thus, in hypertensive patients, it is clinically useful to choose an aggressive therapeutic strategy--to reduce left ventricular mass and to improve endothelial function.

Coronary Artery Disease↗

PubMed2005

Asymmetric dimethylarginine, L-arginine, and endothelial dysfunction in essential hypertension.

OBJECTIVES: We investigated the relationship between ADMA plasma levels and endothelium-dependent vasodilation in 36 never-treated essential hypertensives and in 8 normotensive healthy subjects. BACKGROUND: It has been demonstrated that endothelium-dependent vasodilatation is impaired in essential hypertension. The potential contribution of asymmetric dimethylarginine (ADMA) to endothelial dysfunction of hypertensive humans has received poor attention. METHODS: Endothelial function was measured during intra-arterial infusion of acetylcholine (ACh), alone and during co-infusion of L-arginine, and sodium nitroprusside at increasing doses. Concentrations of ADMA and L-arginine in plasma were measured by high-performance liquid chromatography. RESULTS: Hypertensive subjects had significantly higher ADMA and L-arginine plasma concentrations than normotensive healthy controls; ACh-stimulated forearm blood flow (FBF) was significantly reduced in hypertensive subjects in comparison to normotensive control subjects (p < 0.0001). Intra-arterial coinfusion of L-arginine induced a further significant enhancement in ACh-stimulated vasodilation in hypertensive patients. In these, ADMA was strongly and inversely associated with the peak increase in FBF. In a multivariate model, only ADMA and L-arginine were independent correlates, accounting for 33.9% and 8.9% of the variability in the peak FBF response to ACh (p < 0.0001), respectively. CONCLUSIONS: 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.

Acetylcholine↗

PubMed2005

Interaction between vascular dysfunction and cardiac mass increases the risk of cardiovascular outcomes in essential hypertension.

AIMS: To investigate the additive prognostic impact of both forearm endothelial dysfunction and left ventricular mass (LVM) for future cardiovascular events. METHODS AND RESULTS: We enrolled 324 Caucasian, never treated, hypertensive outpatients. Endothelial function, by intra-arterial infusion of acetylcholine (ACh), and echocardiographic LVM were investigated. Patients were divided into tertiles on the basis of their increase in ACh-stimulated forearm blood flow (FBF) and LVM indexed by body surface area (LVMI). Cardiovascular events assessed were: fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, transient cerebral ischaemic attack, unstable angina, coronary revascularization procedures, and symptomatic aorto-iliac occlusive disease. During a mean follow-up of 45.2+/-23.6 months, there were 47 new cardiovascular events (3.8 events/100 patient-years). The event rate was 6.8, 2.8, and 1.6% in the tertiles of ACh-stimulated FBF (log-rank test, P=0.0009), and 1.4, 3.4, and 6.6% in the tertiles of LVMI (log-rank test, P=0.0002), respectively. Besides, a significant interaction was documented between FBF and LVMI. In fact, the cardiovascular risk increases up to 11.4% in patients with low FBF and high LVMI. CONCLUSION: For the first time, we demonstrate that the co-existence of LVH and endothelial dysfunction in hypertensive patients increases significantly the risk of subsequent cardiovascular events.

Acetylcholine↗

PubMed2005

Plasma concentration of IGF-I is independently associated with insulin sensitivity in subjects with different degrees of glucose tolerance.

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 < 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 < 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.

Biomarkers↗

PubMed2004

Angiotensin II impairs the insulin signaling pathway promoting production of nitric oxide by inducing phosphorylation of insulin receptor substrate-1 on Ser312 and Ser616 in human umbilical vein endothelial cells.

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 Tyr612 and Tyr632, 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 Ser312 and Ser616, 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 Ser312 and Ser616 via JNK and ERK1/2, respectively, thus impairing the vasodilator effects of insulin mediated by the IRS-1/PI 3-kinase/Akt/eNOS pathway.

Angiotensin II↗

PubMed2004

Impaired endothelial function in never-treated hypertensive subjects carrying the Arg972 polymorphism in the insulin receptor substrate-1 gene.

Some cardiovascular risk factors, such as hypertension and insulin resistance, are associated with endothelial dysfunction. Insulin regulates both in vitro and in vivo expression of endothelial nitric oxide synthase (eNOS) via a pathway involving insulin receptor substrate-1 (IRS-1) and phosphatidylinositol-3 kinase. Recently, we found that human endothelial cells obtained from carriers of the Arg(972) IRS-1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between Arg(972) IRS-1 polymorphism and endothelial dysfunction in vivo, we enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. IRS-1 polymorphism was detected by PCR. The allelic frequency of the Arg(972) IRS-1 variant was 8.0%. Stratifying subjects according to IRS-1 genotype, we observed that acetylcholine-stimulated forearm blood flow was significantly (P < 0.0001) lower in Gly/Arg heterozygous carriers than in Gly/Gly carriers (11.3 +/- 4.4 vs. 14.7 +/- 5.9 ml/100 ml(-1) of tissue per min(-1)). Sodium nitroprusside caused comparable increments in forearm blood flow in both groups (12.9 +/- 2.4 vs. 13.3 +/- 3.5 ml/100 ml(-1) of tissue per min(-1)). Our data strongly suggest that, by inducing endothelial dysfunction, the Arg(972) IRS-1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.

Acetylcholine↗

PubMed2004

The -866A/A genotype in the promoter of the human uncoupling protein 2 gene is associated with insulin resistance and increased risk of type 2 diabetes.

Uncoupling protein (UCP)-2 is a member of the mitochondrial inner membrane carriers that uncouple pro-ton entry in the mitochondrial matrix from ATP synthesis. The -866G/A polymorphism in the UCP2 gene, which enhances its transcriptional activity, was associated with enhanced risk for type 2 diabetes in obese subjects. We addressed the question of whether the -866G/A polymorphism contributes to variation in insulin sensitivity by genotyping 181 nondiabetic offspring of type 2 diabetic patients. Insulin sensitivity, assessed by the hyperinsulinemic-euglycemic clamp, was reduced in -866A/A carriers compared with -866A/G or -866G/G carriers (P = 0.01). To directly investigate the correlation between UCP2 expression and insulin resistance, UCP2 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from 100 obese subjects who underwent laparoscopic adjustable gastric banding. UCP2 mRNA expression was significantly correlated with insulin resistance as assessed by the homeostasis model assessment index (r = 0.27, P = 0.007). We examined the association of the -866A/A genotype in a case-control study including 483 type 2 diabetic subjects and 565 control subjects. The -866A/A genotype was associated with diabetes in women (odds ratio 1.84, 95% CI 1.03-3.28; P = 0.037), but not in men. These results indicate that the -866A/A genotype of the UCP2 gene may contribute to diabetes susceptibility by affecting insulin sensitivity.

Adipose Tissue↗

PubMed2004

The Arg972 variant in insulin receptor substrate-1 is associated with an increased risk of secondary failure to sulfonylurea in patients with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate whether diabetic patients carrying the Arg(972) insulin receptor substrate-1 (IRS-1) variant are at increased risk for secondary failure to sulfonylurea. RESEARCH DESIGN AND METHODS: A total of 477 unrelated Caucasian type 2 diabetic patients were recruited according to the following criteria: onset of diabetes after age 35 years, absence of ketonuria at diagnosis, and anti-GAD(-) antibody. Type 2 diabetes was diagnosed according to the American Diabetes Association criteria. Patients with secondary sulfonylurea failure were defined as those requiring insulin due to uncontrolled hyperglycemia (fasting plasma glucose >300 mg/dl) despite sulfonylurea-metformin combined therapy, appropriate diet, and absence of any conditions causing hyperglycemia. RESULTS: Of the total patients, 53 (11.1%) were heterozygous for the Arg(972) IRS-1 variant, 1 (0.2%) was homozygous, and the remainder (88.7%) were homozygous for the wild-type allele. The genotype frequency of the Arg(972) IRS-1 variant was 8.7% among diabetic patients well controlled with oral therapy and 16.7% among patients with secondary failure to sulfonylurea (odds ratio 2.1 [95% CI 1.18-3.70], P = 0.01). Adjustment for age, sex, BMI, metabolic control, age at diagnosis, duration of diabetes, and Pro12Ala polymorphism of peroxisome proliferator-activated receptor-gamma2 gene in a logistic regression analysis with secondary failure to sulfonylurea as a dependent variable did not change this association (2.0 [1.38-3.86], P = 0.038). CONCLUSIONS: These data demonstrate that the Arg(972) IRS-1 variant is associated with increased risk for secondary failure to sulfonylurea, thus representing a potential example of pharmacogenetics in type 2 diabetes.

Adult↗

PubMed2003

Relation of fasting insulin related to insertion/deletion polymorphism of angiotensin-converting enzyme-gene and cardiac mass in never-treated patients with systemic hypertension.

Left ventricular (LV) mass that develops as cardiac adaptive remodeling represents a powerful independent predictor of cardiovascular morbidity and mortality in the general population and in several clinical conditions, including essential hypertension. However, many studies have shown that blood pressure explains only 10% to 25% of the variation in LV mass, supporting the hypothesis that other factors, such as genetics or metabolics (insulin-resistance/hyperinsulinemia), are involved in the cardiac growth in human hypertension. Essential hypertension is also characterized by insulin-resistance/hyperinsulinemia, which may directly induce LV hypertrophy through the stimulation of insulin-like growth factor-1 receptors, abundantly expressed in myocardium. Taken together, we investigated the growth effect of fasting insulin, associated with angiotensin-converting enzyme-gene polymorphism, on cardiac mass in a group of previously untreated hypertensive patients.

Adult↗

PubMed2003

Pulse pressure and endothelial dysfunction in never-treated hypertensive patients.

OBJECTIVES: This study sought to investigate whether pulse pressure (PP) is associated with endothelium-dependent vasodilation in a group of never-treated hypertensives. BACKGROUND: Pulse pressure represents a well-established independent predictor for cardiovascular morbidity and mortality. Forearm endothelial dysfunction, defined as impaired vasodilating response to acetylcholine (ACh), may be associated with several cardiovascular risk factors. Recently, the prognostic value of coronary and forearm endothelial dysfunction has been demonstrated. METHODS: All patients underwent measurement of blood pressure (BP) both clinically and in an ambulatory setting. Endothelium-dependent and -independent vasodilation was investigated by strain-gauge plethysmography in 262 hypertensive patients (age 30 to 55 years) during intra-arterial infusion of increasing doses of ACh and sodium nitroprusside. RESULTS: We observed that systolic BP rather than diastolic BP significantly induces the PP increase. Linear regression analysis revealed a significant inverse correlation between ACh-stimulated forearm blood flow (FBF) and age, body mass index, clinic and monitored systolic BP, and clinic and monitored PP. However, stepwise multivariate analysis showed that monitored PP was the strongest independent predictor of ACh-stimulated FBF, accounting for 33.6% of the variation. After adjustment for other covariates, ACh-stimulated FBF decreases by 8.7% for each mm Hg increment in monitored PP. CONCLUSIONS: Our data indicate that monitored PP is inversely correlated with ACh-stimulated vasodilation. It is possible to hypothesize that elevation in PP reduces FBF by increasing oxidative stress and reducing production of nitric oxide caused by reduced shear stress. In addition, the present findings demonstrate the accuracy of ambulatory BP as a prognostic predictor of hypertension-associated endothelial dysfunction.

Acetylcholine↗

PubMed2003

Weight loss in combination with physical activity improves endothelial dysfunction in human obesity.

OBJECTIVE: To test whether weight loss may improve endothelial dysfunction in human obesity, we recruited 28 healthy obese subjects, aged 30-46 years, with BMI 30-43 kg/m(2). RESEARCH DESIGN AND METHODS: Endothelium-dependent and -independent vasodilation were investigated by intra-arterial infusion of increasing doses of acetylcholine (ACh; 7.5, 15, and 30 microg x ml(-1) x min(-1)) and sodium nitroprusside (0.8, 1.6, and 3.2 microg x ml(-1) x min(-1)). Insulin resistance was estimated by homeostasis model assessment (HOMA). Weight loss was obtained by caloric restriction and physical activity. RESULTS: We observed a significant reduction in BMI (from 33.1 +/- 4.2 to 27.5 +/- 4.5 kg/m(2), -16.9%, P < 0.0001) and in waist circumference (from 108.2 +/- 12.1 to 96.8 +/- 12.9 cm, -10.5%, P < 0.0001). Weight loss was also associated with a significant increase in ACh-stimulated forearm blood flow (FBF), from 7.4 +/- 2.8 to 12.9 +/- 3.4 ml. 100 ml(-1) of tissue x min(-1) kg/m(2) (P < 0.0001). Multivariate regression analysis demonstrated that the only independent predictor of FBF was HOMA, accounting for 44.5% of the variation, whereas the addition of BMI explained another 2.3% of the variation. CONCLUSIONS: Our data demonstrate that energy-restricted diet associated with physical activity induce a significant and clinically relevant improvement in ACh-stimulated vasodilation in obese healthy subjects.

Acetylcholine↗