Anti-vascular endothelial growth factor therapy for diabetic macular edema.

Diabetes mellitus is a serious health problem that affects over 350 million individuals worldwide. Diabetic retinopathy (DR), which is the most common microvascular complication of diabetes, is the leading cause of new cases of blindness in working-aged adults. Diabetic macular edema (DME) is an advanced, vision-limiting complication of DR that affects nearly 30% of patients who have had diabetes for at least 20 years and is responsible for much of the vision loss due to DR. The historic standard of care for DME has been macular laser photocoagulation, which has been shown to stabilize vision and reduce the rate of further vision loss by 50%; however, macular laser leads to significant vision recovery in only 15% of treated patients. Mechanisms contributing to the microvascular damage in DR and DME include the direct toxic effects of hyperglycemia, sustained alterations in cell signaling pathways, and chronic microvascular inflammation with leukocyte-mediated injury. Chronic retinal microvascular damage results in elevation of intraocular levels of vascular endothelial growth factor A (VEGF), a potent, diffusible, endothelial-specific mitogen that mediates many important physiologic processes, including but not limited to the development and permeability of the vasculature. The identification of VEGF as an important pathophysiologic mediator of DME suggested that anti-VEGF therapy delivered to the eye might lead to improved visual outcomes in this disease. To date, four different inhibitors of VEGF, each administered by intraocular injection, have been tested in prospective, randomized phase II or phase III clinical trials in patients with DME. The results from these trials demonstrate that treatment with anti-VEGF agents results in substantially improved visual and anatomic outcomes compared with laser photocoagulation, and avoid the ocular side effects associated with laser treatment. Thus, anti-VEGF therapy has become the preferred treatment option for the management of DME in many patients.

Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age.

BACKGROUND: Few antihypertensive drugs are available in appropriate formulations for infants. METHOD: We investigated candesartan cilexetil liquid suspension in a 4-week, randomized double-blind dose-ranging study followed by a 1-year open-label treatment phase (NCT00244621). The drug was administered at 0.05, 0.2 or 0.4 mg/kg per day in 93 hypertensive children aged 1-5 years, of whom 74 had underlying renal disorders. RESULTS: A single-dose pharmacokinetic profile was obtained in 10 patients. At 4 weeks, SBP declined dose dependently by 6, 9 and 12 mmHg in the three dose groups (P = 0.01), and DBP by 5, 8 and 11 mmHg (P = 0.03). During the 1-year follow-up, responder rates (both SBP and DBP < 95th percentile) ranged from 48.2 to 54.1%. Candesartan lowered the blood pressure regardless of age, sex, BMI or cause of hypertension. The pharmacokinetic profile was independent of age, sex and weight, and was similar to that in older children and adults. In participants with proteinuric renal disease (urinary albumin/creatinine ratio >30 mg/g), a 57% median decline in albumin/creatinine ratio was observed at 4 weeks, which was dose related (P = 0.007) and persisted with long-term administration. There were no notable electrocardiographic or laboratory abnormalities. A mild decline in estimated glomerular filtration rate observed at 4 weeks was not progressive with long-term dosing. Candesartan was generally well tolerated; two patients withdrew for adverse events (fatigue and worsening glomerulopathy). One patient died, probably from acute-on-chronic renal failure. CONCLUSION: Candesartan cilexetil dose-dependently decreases blood pressure and albuminuria in hypertensive infants and is generally well tolerated.

Efficacy, safety, and pharmacokinetics of candesartan cilexetil in hypertensive children aged 6 to 17 years.

This 4-week randomized, double blind, placebo-controlled study (N=240), 1-year open label trial (N=233), and single-dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy-one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8-11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo-corrected 4.9/3.0-7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6- to 12- and 12- to 17-year-olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well-tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

Left ventricular hypertrophy in hypertensive adolescents: analysis of risk by 2004 National High Blood Pressure Education Program Working Group staging criteria.

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents recently recommended staging hypertension (HTN) in children and adolescents based on blood pressure severity. The use of blood pressure staging and its corresponding therapeutic approach was examined in this pooled analysis assessing the risk for end-organ damage, specifically left ventricular hypertrophy among hypertensive adolescents stratified by working group criteria. Newly diagnosed hypertensive adolescents and normotensive control subjects similar in age, race/ethnicity, gender, and body mass index completed casual and 24-hour ambulatory blood pressure measurements, M-mode echocardiography, and fasting serum laboratories. Hypertensive subjects had higher insulin and cholesterol but similar glucose levels as compared with control subjects. Among subjects with stage 1 HTN by casual blood pressure, 34% had white-coat HTN as opposed to 15% of stage 2 hypertensive subjects. Of the subjects with normal casual measurements, 20% had HTN by ambulatory monitoring. Subjects with stage 2 HTN by casual measurement alone (odds ratio: 4.13; 95% CI: 1.04 to 16.48) and after 24-hour ambulatory confirmation (odds ratio: 7.23; 95% CI: 1.28 to 40.68) had increased odds for left ventricular hypertrophy. In addition, the risk for left ventricular hypertrophy was similar for subjects with masked and confirmed stage 1 HTN, whereas subjects with white-coat HTN had a risk comparable to normotensive subjects. Thus, recommendations that adolescents with stage 2 HTN by casual measurements alone receive medication initially along with therapeutic lifestyle counseling are reasonable, though ambulatory blood pressure monitoring remains a valuable tool for evaluating children with stage 2 HTN, because >10% have white-coat HTN.

Prevalence of hypertension and pre-hypertension among adolescents.

OBJECTIVE: To determine the prevalence of hypertension and pre-hypertension on the basis of the 2004 National High Blood Pressure Education Program Working Group guidelines in an adolescent school-screening population. STUDY DESIGN: Cross-sectional assessment of blood pressure (BP) in 6790 adolescents (11-17 years) in Houston schools was conducted from 2003 to 2005. Initial measurements included height, weight, and 4 oscillometric BP readings. Repeat measurements were obtained on 2 subsequent occasions in students with persistently elevated BP. Final prevalence was adjusted for loss to follow-up and logistic regression used to assess risk factors. RESULTS: BP distribution at initial screen was 81.1% normal, 9.5% pre-hypertension, and 9.4% hypertension (8.4% Stage 1; 1% Stage 2). Prevalence after 3 screenings was 81.1% normal, 15.7% pre-hypertension, and 3.2% hypertension (2.6% Stage 1; 0.6% Stage 2). Hypertension and pre-hypertension increased with increasing body mass index. Sex, race, and classification as either at-risk for overweight or overweight were independently associated with pre-hypertension. Only classification as overweight was associated with hypertension. CONCLUSIONS: Application of new classification guidelines for adolescents with elevated BP reveals approximately 20% are at risk for hypertension. Further research determining the significance of each BP category and refining definitions to account for BP variability is warranted.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

Effect of short-term rosuvastatin treatment on estimated glomerular filtration rate.

To define the effect of short-term rosuvastatin treatment on the estimated glomerular filtration rate (eGFR), the database of controlled clinical trials in the Rosuvastatin Clinical Development Program was reviewed. Thirteen studies comprising 3,956 rosuvastatin-treated patients were selected based on a serum creatinine measurement at 6 or 8 weeks after initiation of rosuvastatin treatment, randomization to approved and marketed rosuvastatin doses (5 to 40 mg), and unchanged rosuvastatin dose from treatment initiation (baseline) through 6 to 8 weeks of treatment. eGFR was determined with the Modification of Diet in Renal Disease formula. eGFR significantly increased for each dose of rosuvastatin individually and for all doses combined compared with baseline (range +0.9 to +3.2 ml/min/1.73 m2). Further analysis of 5 blinded, placebo-controlled trials comprising 525 patients showed an increase in eGFR of +0.8 ml/min/1.73 m2 (95% confidence interval +0.1 to +1.5) for all rosuvastatin-treated patients, which was significantly different from baseline (p <0.04) and from a change of -1.5 ml/min/1.73 m2 in the placebo-treated patients (95% confidence interval -2.5 to -0.5, p <0.001). The increase in eGFR for rosuvastatin-treated patients was consistent across all major demographic and clinical subgroups of interest, including patients with baseline proteinuria, baseline eGFR <60 ml/min/1.73 m2, and in patients with hypertension and/or diabetes. In conclusion, these results are consistent with previous rosuvastatin studies that showed an upward trend in eGFR with long-term treatment (> or =96 weeks) and with the hypothesis that statins may have pleiotropic mechanisms of action that include beneficial renal effects.

Effect of stimulants on 24-h ambulatory blood pressure in children with ADHD: a double-blind, randomized, cross-over trial.

Millions of children with attention deficit hyperactivity disorder (ADHD) are treated with stimulant medications. To evaluate cardiovascular risk, 24-h ambulatory blood pressure monitoring (ABPM) was performed on and off medication. Thirteen subjects underwent APBM both on stimulant therapy and placebo using a placebo-controlled, double-blind, randomized, cross-over design. After a 3-day run-in followed by a 24-h monitoring period, subjects crossed over to the alternate therapy for repeated ABPM. Subjects demonstrated elevations in most hemodynamic parameters derived from ABPM during the active treatment period. Total diastolic blood pressure (69.7 mmHg vs 65.8 mmHg, p =0.02) and waking diastolic blood pressure (75.5 mmHg vs 72.3 mmHg, p =0.03) were significantly higher during active treatment. Total heart rate was also significantly higher during active treatment (85.5 beats/min vs 79.9 beats/min, p =0.004). The rate-pressure product (the product of systolic blood pressure x heart rate), an index of myocardial oxygen demand, was higher during active treatment (9,958 vs 9,076, p =0.008). This study provides evidence for a possible negative cardiovascular effect of stimulant medications in children with ADHD. This potential cardiovascular risk should be balanced against the beneficial behavioral effects of this class of medication.

Effect of rosuvastatin or atorvastatin on urinary albumin excretion and renal function in type 2 diabetic patients.

The effect of rosuvastatin or atorvastatin on urinary albumin excretion (UAE) was determined in type 2 diabetic patients. A randomized, double-blind, parallel-group, response-based design compared rosuvastatin 10mg (titrated to 40 mg) with atorvastatin 10mg (titrated to 80 mg) in type 2 diabetic patients with dyslipidemia, with dose titration to an LDL-C target of <3.0 mmol/L. Overnight timed urine collections were obtained at baseline, 8 and 16 weeks to UAE. Glomerular filtration rate (GFR) was determined using the Modification of Diet in Renal Disease formula. Patients with paired, UAE collections of at least 8h duration were analyzed (n=344). No significant change from baseline in UAE was observed for either treatment group or between-treatment groups at 16 weeks, and median UAE for both treatment groups remained within normal limits (rosuvastatin 4.5 microg/min, atorvastatin 5.0 microg/min). A similar absence of change from baseline was observed for 51 patients with UAE above the normal range at study entry (>20 microg/min). No significant change in GFR from baseline after 16 weeks was observed for either treatment group. These data provide reassurance that type 2 diabetic patients can be treated with higher efficacy statins without clinically meaningful effects on urinary albumin excretion.

Characteristics of hypertensive children identified by primary care referral compared with school-based screening.

OBJECTIVES: To determine whether there are clinical differences between children referred for hypertension evaluation from a primary care practice and children with hypertension detected through school-based screening. Study design Referral patients (n=58) were compared with 44 screening patients with hypertension from school-based screening of 5102 students. All subjects underwent 24-hour ambulatory blood pressure (BP) monitoring. White coat hypertension was defined as 24-hour mean BP <95th percentile and BP load <25%. RESULTS: Referral subjects were more likely to be male and had higher body mass index than screening subjects but did not differ by age or ethnic distribution. Average clinic BP values tended to be higher among referral patients (140/79 vs 135/76 mm Hg, P=.07); however, the hypertension severity was closely matched when clinic BP was indexed to the subject-specific 95th percentile. Ambulatory mean BP, BP indices, and BP loads showed no differences by subject source for 24-hour, wake, or sleep periods. White coat hypertension prevalence did not differ between referral and screening subjects (28% vs 30%, P=.83). CONCLUSION: These findings suggest that hypertensive children identified by subspecialty referral are representative of the overall population of hypertensive children in the community, thereby supporting the generalizability of clinic-based research in pediatric hypertension.

Overweight, ethnicity, and the prevalence of hypertension in school-aged children.

OBJECTIVES: To describe the current prevalence of pediatric hypertension and the relationships between gender, ethnicity, overweight, and blood pressure. METHODS: School-based screening was performed in 5102 children (13.5 +/- 1.7 years) from May through November 2002. Age, gender, ethnicity, weight, and height were ascertained, and body mass index (BMI) was calculated as weight (kg)/height (m2). Overweight was defined as BMI > or =95th percentile. Students with blood pressure >95th percentile on the first screening underwent a second screening 1 to 2 weeks later, and then a third screening if blood pressure was >95th percentile at the second screening. RESULTS: Ethnicity distribution was 44% white, 25% Hispanic, 22% African American, and 7% Asian. Overall, overweight prevalence was 20%, which varied significantly by ethnicity (31% Hispanic, 20% African American, 15% white, and 11% Asian). The prevalence of elevated blood pressure after first, second, and third screenings was 19.4%, 9.5%, and 4.5%, respectively. Elevated blood pressure on first screening was highest among Hispanics (25%) and lowest among Asians (14%). Ethnic differences in the prevalence of hypertension (elevated blood pressure on 3 screenings) were not significant after controlling for overweight. The prevalence of hypertension increased progressively as the BMI percentile increased from < or =5th percentile (2%) to > or =95th percentile (11%). After adjustment for gender, ethnicity, overweight, and age, the relative risk of hypertension was significant for gender (relative risk: 1.50; confidence interval: 1.15, 1.95) and overweight (relative risk: 3.26; confidence interval: 2.50, 4.24). CONCLUSIONS: These results confirm an evolving epidemic of cardiovascular risk in youth, as evidenced by an increase in the prevalence of overweight and hypertension, notably among ethnic minority children.

Overweight as a risk factor in children: a focus on ethnicity.

The prevalence of overweight in youth is increasing dramatically in the United States. The intimate relationship of obesity and overweight with cardiovascular risk factors and diabetes in adults raises concern for the likelihood of subsequent disease development in children. Ethnic minorities are so disproportionately affected by overweight that a call to action is necessary. The International Society on Hypertension in Blacks convened this work group as part of a larger effort to focus on cardiovascular risk protection beginning in childhood and adolescence, entitled the "Children are Our Messengers: Changing the Health Message" initiative. This summary article reviews the data on cardiovascular risk factors and overweight in ethnic children and adolescents, and culminates in a practical algorithm for evaluating overweight children for cardiovascular risk.

The effects of obesity, gender, and ethnic group on left ventricular hypertrophy and geometry in hypertensive children: a collaborative study of the International Pediatric Hypertension Association.

OBJECTIVE: To determine the prevalence of left ventricular hypertrophy (LVH) in a multiethnic group of children and adolescents with hypertension. DESIGN/METHODS: Pooled data from 1998 to 2001 from 3 sites belonging to the International Pediatric Hypertension Association were reviewed. Patients undergoing echocardiography to detect LVH as part of the evaluation for hypertension were included for analysis. Left ventricular mass was calculated from 2-dimensional guided M-mode echocardiographic measurements of the left ventricle. Left ventricular mass index (LVMI) was calculated as left ventricular mass/height(2.7). LVH by adult criteria was defined as LVMI > 51 g/m(2.7) and by pediatric criteria as LVMI > 38.6 g/m(2.7). Left ventricle geometry was classified as concentric, concentric remodeling, eccentric, or normal. RESULTS: Data on 129 patients with a mean age of 13.6 +/- 3.6 years were analyzed. The population was 67% male, 46.5% white, 38.0% African American, and 15.5% Hispanic. The prevalence of LVH was 15.5% using adult criteria and 41.1% using pediatric criteria. Increasing body mass index (BMI) was associated with a higher LVMI. Using either pediatric or adult criteria LVH was associated with BMI > or =95th percentile for age and gender. LVH and concentric hypertrophy were identified most frequently in Hispanic children. CONCLUSIONS: LVH occurs commonly in children with hypertension and is associated with an increased BMI. LVH may be more prevalent in Hispanic children than in other ethnic groups. Prevention and treatment of obesity is important in reducing the cardiovascular risk for children with hypertension. Further evaluation of the frequency of LVH in multiethnic populations is needed.

Cardiovascular risk factors and sequelae in hypertensive children identified by referral versus school-based screening.

To determine whether systematic differences exist between hypertensive children referred for evaluation by primary care providers and children identified through community-based screening, cardiovascular risk factors and surrogate markers of hypertensive injury were compared based on subject source (referral versus screening). Children referred to a hypertension clinic for persistently elevated blood pressure were compared with children identified as hypertensive during school screening of 5102 students in Houston public schools. M-mode echocardiography of the left ventricle was performed and subsequently reviewed by 2 independent sonographers blinded to identifying subject information. Subsets of subjects also underwent carotid artery ultrasound for measurement of intimal-medial thickness, overnight urine collections for microalbuminuria, and fasting serum cholesterol, triglycerides, and glucose. Ninety-seven total subjects (54 screening and 43 referral) met inclusion criteria and had technically adequate echocardiography performed. The prevalence of left ventricular hypertrophy (LVH) was 37%. Referral subjects demonstrated significantly greater left ventricular mass index (38.8 versus 34.2 g/m(2.7); P<0.01) and a higher prevalence of LVH (49% versus 28%; P<0.05). Among subjects who underwent carotid ultrasound (n=75), carotid intimal-medial thickness was significantly higher in referral subjects (0.61 versus 0.57, P<0.05). When controlling for BMI z score, which was significantly higher in referral subjects, systematic differences by subject source did not persist. These findings suggest that hypertensive children who are predominantly overweight, independent of the manner in which patients come to medical attention, will manifest evidence of more severe cardiovascular disease assessed by surrogate markers such as left ventricular mass index or carotid artery intimal medial thickness.

Carotid ultrasonography for detection of vascular abnormalities in hypertensive children.

To determine whether hypertension and overweight status are associated with increased carotid intimal-medial thickness (cIMT) in children, vascular ultrasonography was performed in newly diagnosed hypertensive patients ( n=53) and normotensive controls ( n=33). Hypertensive subjects were identified either by referral or by systematic school-based hypertension screening. Hypertension was defined as blood pressure above the 95th percentile based on current Task Force criteria, and overweight was defined as body mass index (BMI) >25 kg/m(2). cIMT was assessed by high-resolution vascular ultrasonography of the distal common carotid artery. Hypertensive subjects had a higher cIMT than normotensive subjects (0.62 vs. 0.53 mm, P<0.00001). This difference remained significant after controlling for the effects of gender, race, age, height, weight, and BMI. Similarly, overweight subjects had a higher cIMT than normal-weight subjects (0.63 vs. 0.54 mm, P<0.0001). Subjects with both systolic and diastolic hypertension had higher cIMT than those with isolated systolic hypertension (0.67 vs. 0.60, P<0.05). cIMT showed significant positive pairwise correlation with age, height, weight, BMI, and systolic blood pressure. Among all clinical variables analyzed, cIMT was most strongly correlated with BMI ( r=0.53, P<0.001). These results provide further evidence that vasculopathy occurs in association with known cardiovascular risk factors such as hypertension and obesity during childhood.

Carotid artery intimal-medial thickness and left ventricular hypertrophy in children with elevated blood pressure.

OBJECTIVES: To determine the association between carotid artery intimal-medial thickness (cIMT) and left ventricular mass index (LVMI) in children with elevated blood pressure. METHODS: Study subjects (n = 32; mean age: 13.9 +/- 2.7 years) were untreated new referrals to a pediatric hypertension clinic with confirmed elevated blood pressure. LVM was calculated from 2-dimensionally guided m-mode echocardiographic measurements of the left ventricle. LVMI was calculated as LVM (g)/height (m)2.7, and left ventricular hypertrophy (LVH) was defined as LVMI >95th percentile. Carotid artery duplex ultrasound was performed by protocol by experienced vascular sonographers who were unaware of the echocardiography results. The thickest IMT complex of the far wall of the distal common carotid artery was measured in longitudinal B-mode section using a high-resolution linear array of 8 MHz. RESULTS: The prevalence of LVH and increased cIMT was 41% and 28%, respectively. Subjects with increased cIMT had higher LVMI (46.8 g/m2.7 vs 31.4 g/m2.7) than those with normal cIMT. The LVH prevalence was 89% (8 of 9) among subjects with increased cIMT as compared with 22% (5 of 23) in subjects with normal cIMT. cIMT was positively correlated with body mass index (r = 0.43), interventricular septal thickness (r = 0.58), posterior wall thickness (r = 0.54), and LVMI (r = 0.54). cIMT and LVMI were positively associated after accounting for age, gender, and body mass index. CONCLUSIONS: These findings raise the possibility that carotid duplex ultrasound, by indicating the presence of early arterial wall changes, may be useful for predicting other cardiovascular sequelae in hypertensive children.

Obesity hypertension in children: a problem of epidemic proportions.

Obesity has become an increasingly important medical problem in children and adolescents. In national surveys from the 1960s to the 1990s, the prevalence of overweight in children grew from 5% to 11%. Outcomes related to childhood obesity include hypertension, type 2 diabetes mellitus, dyslipidemia, left ventricular hypertrophy, nonalcoholic steatohepatitis, obstructive sleep apnea, orthopedic problems, and psychosocial problems. Once considered rare, primary hypertension in children has become increasingly common in association with obesity and other risk factors, including a family history of hypertension and an ethnic predisposition to hypertensive disease. Obese children are at approximately a 3-fold higher risk for hypertension than nonobese children. In addition, the risk of hypertension in children increases across the entire range of body mass index (BMI) values and is not defined by a simple threshold effect. As in adults, a combination of factors including overactivity of the sympathetic nervous system (SNS), insulin resistance, and abnormalities in vascular structure and function may contribute to obesity-related hypertension in children. The benefits of weight loss for blood pressure reduction in children have been demonstrated in both observational and interventional studies. Obesity in childhood should be considered a chronic medical condition that is likely to require long-term management. Ultimately, prevention of obesity and its complications, including hypertension, is the goal.

Beta-blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial.

Antihypertensive medications are used extensively in children despite a paucity of randomized, placebo-controlled trials. This study was among the first randomized, controlled pediatric antihypertensive medication trials, in which the combination drug bisoprolol fumarate/hydrochlorothiazide (B/HT) was compared with placebo. The study comprised a 2-week single-blind placebo screening period, a 6-week double-blind dose titration period, a 4-week double-blind dose maintenance period, and a 2-week double-blind dose-tapering period. One hundred and forty subjects were enrolled to achieve 94 randomized subjects treated either with B/HT ( n=62) or placebo ( n=32). B/HT induced significant reductions compared with placebo for average sitting systolic blood pressure (SiSBP) (9.3 vs. 4.9 mmHg, P<0.05) and sitting diastolic blood pressure (SiDBP) (7.2 vs. 2.7 mmHg, P<0.05). The placebo-subtracted BP reductions were greater in younger children and those with more-severe baseline hypertension. The percentage of subjects with BP less than the 90th percentile at study completion was 45% for B/HT and 34% for placebo ( P=NS). Although the study demonstrated that B/HT reduced BP safely compared with placebo, the large placebo effect and failure of most subjects to achieve target BP control make it uncertain whether B/HT is appropriate first-line therapy for pediatric hypertension, particularly in adolescents with mild-to-moderate BP elevation.

Isolated systolic hypertension, obesity, and hyperkinetic hemodynamic states in children.

OBJECTIVE: To determine the factors that contribute to the pathogenesis of isolated systolic hypertension in children. METHODS: School-based measurement was performed of blood pressure (BP), heart rate, weight, and height in 2460 students (49% Hispanic, 31% black, 13% white) 12 to 16 years of age in 8 urban public schools. An independent group of 71 untreated children underwent 24-hour ambulatory BP monitoring (ABPM) to confirm clinic hypertension and assess circadian BP patterns. RESULTS: Hypertension and obesity were found in 17% and 23% of students, respectively. Among hypertensive students, 88% (363/413) had isolated systolic hypertension. Hypertension was more prevalent in obese than nonobese students (33% vs 11%, P <.0001). Obese hypertensive students had higher resting heart rate than nonobese normotensive patients (85.9 vs 79.6 beats/min, P <.001). Among patients who underwent ABPM, isolated systolic hypertension was found in 51% (36/71) by clinic BP and in 62% (18/29) with confirmed hypertension by ABPM. Blood pressure variability during daytime and sleep periods was higher in obese than nonobese patients for systolic BP (P <.01) and diastolic BP (P <.05). CONCLUSIONS: The findings of increased heart rate and BP variability in obese children with isolated systolic hypertension suggest that sympathetic nervous system hyperactivity may contribute to its pathogenesis.

Ambulatory blood pressure and left ventricular mass index in hypertensive children.

To determine whether ambulatory blood pressure is more predictive of left ventricular hypertrophy than is casual blood pressure in hypertensive children, echocardiography and ambulatory blood pressure data from 37 untreated hypertensive children were analyzed. Left ventricular mass was calculated using the Devereux equation, left ventricular mass index was calculated as left ventricular mass (in grams)/height(2.7) (in meters), and left ventricular hypertrophy was defined as left ventricular mass index >51 g/m(2.7). Average blood pressure, blood pressure load, and blood pressure index (average blood pressure divided by pediatric ambulatory blood pressure 95th percentile) were calculated. Left ventricular mass index was strongly correlated with 24-hour systolic blood pressure index (r=0.43, P=0.008) and was also correlated with 24-hour systolic blood pressure (r=0.34, P=0.037), 24-hour systolic blood pressure load (r=0.38, P=0.020), wake systolic blood pressure load (r=0.37, P=0.025), sleep systolic blood pressure (r=0.33, P=0.048), and sleep systolic blood pressure load (r=0.38, P=0.021). Left ventricular mass index did not correlate with age, weight, clinic blood pressure, or ambulatory diastolic blood pressure. The overall prevalence of left ventricular hypertrophy was 27%. The prevalence of left ventricular hypertrophy was 47% (8 of 17) in patients with both systolic blood pressure load >50% and 24-hour systolic blood pressure index >1.0, compared with 10% (2 of 20) in patients without both criteria (P=0.015). These data suggest ambulatory blood pressure monitoring may be useful for the clinical assessment of hypertensive children by identifying those at high risk for the presence of end organ injury.