Oxidative stress in hypertensive children before and after 1 year of antihypertensive therapy.

BACKGROUND: The relation between primary hypertension (PH), target organ damage (TOD) and oxidative stress (SOX) is not known. METHODS: We assessed SOX in 86 children with PH before and after 12 months of standard non-pharmacological and pharmacological therapy based on renin-angiotensin system blockade. RESULTS: Patients with left ventricular hypertrophy (LVH) and with carotid intima-media thickness (cIMT) >2SDS had higher thiobarbituric acid reactive substances (TBARS) concentrations in comparison to patients without LVH or with normal cIMT. Patients with metabolic syndrome (MS) had lower activity of gluthatione peroxidase, higher asymmetric dimethyloarginine (ADMA) and oxidized LDL cholesterol (oxyLDL) in comparison to patients without MS. TBARS correlated with left ventricular concentric hypertrophy, cIMT, albuminuria and SBP/24 h. ADMA and oxyLDL correlated with CRP and TG/HDL ratio. After 1 year of antihypertensive treatment blood pressure, TOD and prevalence of MS decreased. TBARS decreased and glutathione concentrations increased. The decrease of TBARS concentration correlated with the decrease of body mass index (BMI). Decrease of oxyLDL and ADMA correlated with increased insulin sensitivity, however markers of SOX did not correlate with BP decrease. CONCLUSION: SOX in children with PH correlates with TOD, metabolic abnormalities, changes in fat amount and improvement of insulin sensitivity, but not with BP decrease.

Change in left ventricular geometry during antihypertensive treatment in children with primary hypertension.

The pattern of the left ventricle (LV) has important significance in adults with hypertension. The aim of the present study was to analyze changes and determinants of LV geometry after 1 year of antihypertensive treatment in children with primary hypertension (PH) in relation to metabolic abnormalities and anthropometrical parameters. In 86 children (14.1 ± 2.4 years) with newly diagnosed PH, LV geometry and biochemical parameters before and after 12 months of standard antihypertensive therapy were assessed. At baseline, normal LV geometry (NG) was found in 42 (48.9%), concentric remodeling (CR) in 4 (4.6%), concentric hypertrophy (CH) in 8 (9.3%), and eccentric hypertrophy (EH) in 32 (37.2%) patients. The prevalence of NG in patients with severe hypertension was significantly lower than in patients with ambulatory hypertension. There were no differences in dipping status in relation to LV geometry. Patients with CH and EH were more viscerally obese than patients with NG. Patients with CH had higher diastolic blood pressure in comparison with EH patients (p < 0.05). The main predictor of relative wall thickness (RWT) was the triglycerides to high density lipoprotein cholesterol (TG/HDL) ratio (R(2 ) = 0.319, ß = 0.246, p = 0.004). Patients received 12 months of antihypertensive treatment, either lifestyle modification only (n = 37) or lifestyle modification plus antihypertensive medications (n = 49) if severe ambulatory hypertension or target organ damage were present. After 12 months of treatment the prevalence of EH (37.2% vs 18.6%, p = 0.003) decreased but prevalence of CH did not change. Patients in whom RWT decreased also decreased waist circumference and TG/HDL; the main predictor of RWT decrease was a decrease of the TG/HDL ratio (ß = 0.496, R (2) = 0.329, p = 0.002). In adolescents with PH, LV geometry is related to central obesity and insulin resistance. Decrease of abdominal obesity and insulin resistance are the most important predictors of normalization of LV geometry, however CH has lower potential to normalize LV geometry.

Regression of target organ damage in children and adolescents with primary hypertension.

We assessed the effects of 12 months of non-pharmacological and pharmacological therapy on 24-h ambulatory blood pressure, regression of target organ damage (TOD) and metabolic abnormalities in 86 children (14.1 ± 2.4 years) with primary hypertension. Twenty-four hour systolic and diastolic blood pressure (BP) decreased (130 ± 8 vs 126 ± 8, 73 ± 7 vs 70 ± 7, p = 0.0001 and 0.004 respectively). Body mass index (BMI) did not change, but waist-to-hip (0.85 ± 0.07 vs 0.83 ± 0.05, p = 0.01) and waist-to-height ratio (WHtR; 0.49 ± 0.07 vs 0.48 ± 0.05, p = 0.008) decreased. Left ventricular mass index (LVMi; 38.5 ± 10.7 vs 35.2 ± 7.5 g/m(2.7), p = 0.0001), prevalence of left ventricular hypertrophy (46.5% vs 31.4%; p = 0.0001), carotid intima-media thickness (cIMT; 0.44 ± 0.05 vs 0.42 ± 0.04 mm, p = 0.0001), wall cross sectional area (WCSA; 7.5 ± 1.3 vs 6.9 ± 1.2 mm(2), p = 0.002), hsCRP (1.1 ± 1.0 vs 0.7 ± 0.7 mg/l, p = 0.002), and LDL-cholesterol (115 ± 33 vs 107 ± 26 mg/dl, p = 0.001) decreased. Patients who had lowered BP had a lower cIMT at the second examination (0.41 ± 0.04 vs 0.43 ± 0.04 mm, p = 0.04) and lower initial hsCRP values (0.9 ± 0.7 vs 1.5 ± 1.3 mg/l, p = 0.04) in comparison to non-responders. Regression analysis revealed that the main predictor of LVMi decrease was a decrease in abdominal fat expressed as a decrease in waist circumference (WC) (R (2) = 0.280, ß = 0.558, p = 0.005), for WCSA-SDS a decrease in WC (R (2) = 0.332, ß = 0.611, p = 0.009) and for a cIMT-SDS decrease the main predictor was a decrease in hsCRP concentrations (R (2) = 0.137, ß = 0.412, p = 0.03). Standard antihypertensive treatment lowered BP and led to regression of TOD in hypertensive children. Lean body mass increase and decrease in abdominal obesity correlated with TOD regression.

Inflammatory activation in children with primary hypertension.

Low-grade inflammation plays a role in the pathogenesis of primary hypertension (PH) and target organ damage (TOD). We evaluated the profile of inflammatory mediators (CRP, RANTES, MIP-1beta, MIP-1alpha, MCP-1, IL-6, angiogenin, adiponectin) in 30 healthy children (12.7 +/- 3.3 years) and 44 patients with untreated PH (13.7 +/- 2.7 years; n.s). Patients had greater concentrations of CRP, MIP-1beta, and RANTES than controls (all p < 0.05). Children with metabolic syndrome (MS) had greater CRP than children without MS (p = 0.007) and CRP correlated with number of MS criteria, body mass index (BMI), visceral fat, deep subcutaneous fat assessed by magnetic resonance imaging, carotid intima-media thickness (cIMT), left ventricular mass index, and markers of oxidative stress. RANTES correlated with cholesterol, LDL cholesterol, ApoB, and ApoB/ApoA1. Angiogenin correlated with BMI, waist circumference, visceral fat, uric acid, and patients with cIMT>2SD had greater concentration of angiogenin than those with normal cIMT (p = 0.03). Adiponectin was lower in patients with cIMT>2SD than in those with normal cIMT (p = 0.02). No model explaining variability of TOD has been built. Elevated RANTES and MIP-1beta and normal IL-6 and TNF-alpha levels indicate a vascular inflammatory process. Lack of correlation between CRP and chemokines suggests that vascular inflammation in PH precedes the systemic inflammatory changes.

Evolution of large-vessel arteriopathy in paediatric patients with chronic kidney disease.

UNLABELLED: This observational study was designed to verify the hypothesis that the treatment modality significantly affects the evolution of CKD-associated arteriopathy. PATIENTS: Paediatric patients (mean age 13.8 +/- 4.2 years) with chronic kidney disease (CKD) stages 3-5, including 24 patients with mean GFR 54 +/- 21 ml/min/1.73 m(2) (CKD group) and 32 patients in end-stage renal disease, of whom 19 received a renal allograft (D-Rtx) and 13 remained on dialysis (D-D). METHODS: Sonography of the common carotid artery was performed at baseline and after 12 months. Intima-media thickness (IMT) and the cross-sectional areas of the vessel wall (WCSA) and lumen (LCSA) were measured and normalized to age (SDS). RESULTS: At baseline IMT-SDS and WCSA-SDS were increased above normal, and were significantly higher in D than in CKD patients (P < 0.001). IMT-SDS increased over time in CKD and D-D patients (1.4 +/- 1.7 to 2.1 +/- 1.2, P = 0.05). In contrast, IMT-SDS (2.8 +/- 0.6 to 2.0 +/- 0.6, P < 0.005) decreased in those D-Rtx patients who had elevated values prior to transplantation. The total number of patients with elevated cIMT-SDS changed from 7 to 13 in the 24 CKD, from 8 to 11 in the 13 D-D and from 11 to 12 in the 19 D-Rtx patients. While IMT-SDS was independently correlated with blood pressure and serum phosphate in the CKD and D patients, only total dialysis vintage (r = 0.50; P < 0.05) and the IMT-SDS attained at the time of grafting (r = 0.46, P < 0.05) correlated with IMT-SDS 1 year post-Rtx. CONCLUSION: While vascular lesions rapidly progress in CKD and D patients, abolition of the uraemic state by Rtx leads to stabilization or partial regression of CKD-associated arteriopathy. Cumulative dialysis duration and the degree of arterial damage prevalent at the time of grafting are the main determinants of persistent arteriopathy 1 year after Rtx.

Metabolic abnormalities, insulin resistance, and metabolic syndrome in children with primary hypertension.

BACKGROUND: We sought to describe the prevalence of metabolic abnormalities and of metabolic syndrome (MS) and its relationship to target-organ damage in children with primary hypertension (PH). METHODS: Patients included 113 children with untreated PH at a mean age of 14.6 years (range, 5 to 18 years). The control group consisted of 134 healthy children at a mean age of 13.5 years (range, 5 to 20 years). We performed a cross-sectional assessment of anthropometric and biochemical cardiovascular risk factors, homeostatic metabolic assessment (HOMA-IR), the insulin sensitivity index (ISI[0,120]), and adiponectin. RESULTS: Metabolic syndrome, as defined by classic criteria, was present in 4 of 134 (3%) of controls versus 23 of 113 (20.4%) patients (P=.0001), but when PH was not taken as a criterion of MS, MS was diagnosed in 6.2% of patients (no significance). Left-ventricular hypertrophy (LVH) was found in 46 of 113 patients (40.7%), and severe LVH was found in 14 of 113 patients (12.5%). Patients with LVH had a greater body mass index, greater waist-to-hip-ratio, and greater number of parameters of metabolic syndrome (overall P<.05). Carotid (cIMT) and femoral superficial artery intima-media thicknesses correlated positively with HOMA-IR and negatively with ISI[0.120] and serum adiponectin (P<.05). The main predictor for cIMT was adiponectin (R2=0.178, beta=-0.466, P=.002). Left-ventricular hypertrophy was predicted (R2=0.332) by body mass index-standard deviation score (beta=0.551, P=.005) and HOMA-IR (beta=0.380, P=.04). CONCLUSIONS: Metabolic syndrome, as defined by classic criteria, was diagnosed in 20% of children with PH, but when PH was not a criterion, MS was present in 6.2% of patients. Irrespective of the definition of MS, the applied markers of MS and insulin resistance were the main predictors of target-organ damage.

[Fat tissue distribution and metabolic alterations in boys with primary hypertension]. / Rozklad tkanki tluszczowej a uszkodzenie narzadowe u chlopców z nadcisnieniem tetniczym pierwotnym (NTP).

UNLABELLED: Metabolic alterations related to obesity are regarded as significant risk factor for target organ damage in hypertensive patients. Fat tissue distribution seems to play significant role in metabolic alterations related to cardiovascular damage. The aim of the study was to test hypothesis that fat tissue distribution and excess of visceral fat is related to cardiovascular damage and metabolic cardiovascular risk factors in obese boys with yet untreated, primary hypertension. PATIENTS: 40 boys (14.8 +/- 3.0 yrs) with untreated essential hypertensions. METHODS: amount of visceral (VAT), intraperitoneal visceral (ipVAT), extraperitoneal visceral (epVAT) and subcutaneous fat (SAT) was measured by nuclear magnetic imaging (NMR). Carotic intima media thickness (cIMT), fenoral intima media thickness (fIMT) and left ventricular mass index (LVMi) were evaluated by sonography. Oral glucose loading test was done, lipids, homocysteine, CRP, uric acid, microalbuminuria, adipocytokines, IGF-1 and IGF binding proteins (IGFBP) were determined. RESULTS: The ratio of VAT to epVAT (V/Ve) correlated with carotid IMT (p=0.0001; r=0.561), standard deviation from median of the norm of cIMT (cIMT-SDS) (p=0.0001; r=0.681), femoral IMT (p=0.015; r=0.480) and fIMT-SDS (p=0.002; r=0.579). SAT correlated negatively with cIMT (p=0.0016; r=-0.355) and cIMT-SDS (p=0.01; r=-0.391). Waist to hip ratio (WHR) correlated with cIMT-SDS (p=0.03; r=0.401). VAT correlated positively and SAT negatively with HDL, apoA1, uric acid concentration and HOMA-IR value. VAT/epVAT correlated with HOMA-IR (p=0.02; r=0.402), free IGF-1 (p=0.001; r=0.478). epVAT also correlated with free IGF-1 (p=0.006; r=-0.494) and IGFBP3 (p=0.02; r=-0.471). Step-wise regression analysis revealed that relative excess of intraperitoneal visceral fat (VAT/epVAT) and WHR were independent predictors of cIMT-SDS(p=0.022, R2=0.755). CONCLUSIONS: Fat tissue distribution correlates with early vascular injury and metabolic alterations in boys with primary hypertension. Relative excess of visceral fat assessed by NMR and truncal obesity expressed as WHR are independent risk factors for early vascular damage in overweight boys with primary hypertension.

Different BMI cardiovascular risk thresholds as markers of organ damage and metabolic syndrome in primary hypertension.

Obesity is the main intermediate phenotype of primary hypertension (PH), and increased fat mass is directly related to target organ damage (TOD) and metabolic syndrome (MS). The aim of the study was to assess the sensitivity and specificity of body mass index (BMI), percentile-based, definitions of obesity [BMI > 95th percentile (pc)], and overweight (BMI > 85th pc), and BMI thresholds for cardiovascular (cv) complications (BMIcv) described by Katzmarzyk et al. (Pediatrics 114:198-205, 2004) in predicting risk of TOD and MS in 122 adolescents with PH. Our results indicated that the prevalence of left ventricular hypertrophy (LVH) and carotid intima-media thickness (cIMT) above 2 standard deviations (SDS) was the same, irrespective of the criteria used. BMIcv was more sensitive as a marker of LVH than were the cut-off values of the 85th pc and 95th pc of BMI (87.5%, 75%, 62.5%, respectively; P < 0.0001). BMIcv thresholds and cut-off values of the 85th pc of BMI were of the same sensitivity in predicting the presence of MS (95.8% and 95.8%, respectively) and were more sensitive than the cut-off values of the BMI 95th pc (87.5%; P = 0.02). Metabolic abnormalities, including insulin resistance, were more marked in patients with greater BMI, irrespective of cut-off value. However, only when a stratification system using the 85th pc of BMI was used, were the differences significant for a homoeostasis model assessment for insulin resistance (HOMA-IR) and for serum concentrations of high-density lipoprotein (HDL)-cholesterol, triglycerides and adiponectin. We concluded that BMIcv is more sensitive for diagnosing the presence of LVH and that the cut-off value of the 85th pc of BMI is more sensitive for predicting presence of MS in children with PH.

Left ventricular hypertrophy and arterial wall thickening in children with essential hypertension.

OBJECTIVE: Our aim was to determine the prevalence of left ventricular hypertrophy (LVH) and increased intima-media thickness (IMT) in Caucasian children with newly diagnosed, untreated essential hypertension (EH). PARTICIPANTS: Our study cohort consisted of 72 children with EH (mean age: 14.5 years; range: 5-18 years). The control groups consisted of 103 age-matched, healthy children. METHODS: We evaluated the left ventricular mass (LVM), intima-media thickness in the carotid (cIMT) and superficial femoral (fIMT) arteries, 24-h ambulatory blood pressure, and biochemical cardiovascular risk factors. RESULTS: Of the hypertensive children examined, 41.6% had LVM above the 95th percentile, and 13.2% had LVM above 51 g/m2.7. Of the hypertensive subjects, the cIMT was above 2 SDS of normal values in 38.8%, and the flMT was above 2 SDS of normal values in 17.5%. Patients with LVM above 51 g/m2.7 had a higher birth weight than other patients. LVM, cIMT, and fIMT correlated with 24-h SBP and pulse pressure; LVM also correlated with homocysteine and serum uric acid concentrations. fIMT correlated with low Aprotein A1 (ApoA1), higher ApoB and C reactive protein, and daily sodium excretion. Step-wise regression analysis revealed that serum uric acid and higher birth weight were predictors for LVM, pulse pressure was a predictor for cIMT, and ApoB was a predictor for fIMT. CONCLUSIONS: A significant number of adolescents with EH already had cardiovascular damage at diagnosis. LVM and markers of arterial injury correlate with SBP, biochemical, and perinatal cardiovascular risk factors. Serum uric acid and higher birth weight are predictors of LVM.

Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation.

Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD (GFR 51 +/- 31 ml/min per 1.73 m2), 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.

In vivo effect of 5- and 8-methoxypsoralens and cimetidine on R,S-warfarin metabolism in rat.

Several forms of cytochrome P-450 (CYP) metabolize R,S-warfarin in a regio- and enantioselective manner, therefore R,S-warfarin can be recognized as a metabolic probe for a number of CYP isoforms. We have applied a warfarin model in vivo in order to estimate the inhibitory properties of 5- and 8-methoxypsoralens on the activity of rat CYP isoforms. The area under the serum concentration versus time curve (AUC) values from time zero to 5 h for R- and S-warfarin and their metabolites were calculated. R,S-Warfarin kinetics measurements were made three times on each rat: a week before the 7-days inhibitor treatment, 3 h after the last dose of inhibitor and 3-7 days after the inhibitor was withdrawn. The inhibitory effect of cimetidine on CYP 2C11 and CYP 2C6 activities was confirmed in this approach and can be recognized as a positive control in validation of the in vivo experiment. Both 5- and 8-methoxypsoralen inhibited CYP 2C6 activity as the respective AUC for metabolite/warfarin enantiomer ratio decreased significantly. The activity of CYP 2C6 in 5- and 8-methoxypsoralen-treated rats increased over control values after the inhibitor was withdrawn. It was also observed that cimetidine additionally inhibits the absorption of R,S-warfarin and a decrease in the sum of AUC for R- and S-enantiomers became evident in spite of inhibition of the activity of both CYPs. 5-Methoxypsoralen modified the serum R-warfarin/S-warfarin ratio and a selective increase in AUC(S-warfarin) was observed, the most pronounced being after the inhibitor was withdrawn. This effect is not likely to be mediated by P-glycoprotein (P-gp) because quinidine--, a P-gp inhibitor at a dose of 15 mg kg(-1) body wt.--did not influence the AUC for either enantiomer.