Philip R. Khoury

Increased incidence of non-insulin-dependent diabetes mellitus among adolescents

OBJECTIVE To determine whether a rise in the diagnosis of non-insulin- dependent diabetes mellitus (NIDDM) has accompanied the rise in obesity in the pediatric population, as it has among adults. STUDY DESIGN Medical records of 1027 consecutive patients from birth to age 19 years with a diagnosis of diabetes from 1982 to 1995 at a regional, university-affiliated pediatric diabetes referral center were reviewed and classified according to criteria of the National Diabetes Data Group. RESULTS The number of patients with a diagnosis of NIDDM rose from approximately 4% of new diagnoses of diabetes in patients from birth to age 19 years before 1992, to 16% in 1994. Among patients 10 to 19 years of age, NIDDM accounted for 33% of diagnoses of diabetes in 1994. The incidence of adolescent NIDDM in Greater Cincinnati increased tenfold, from 0.7/100,000 per year in 1982 to 7.2/100,000 per year in 1994. The mean (+/- SD) age and body mass index at presentation were 13.8 +/- 1.9 years and 37.7 +/- 9.6 kg/m2, respectively. The overall female/male ratio was 1.7:1, and female patients were seen 1 year earlier than male patients (p < 0.01). Male subjects had a higher body mass index than female subjects (p < 0.05). A first-degree relative with NIDDM was identified for 65% of patients. At presentation, 21% of the patients had had a diagnosis of at least one other condition associated with obesity. CONCLUSION There is an increasing incidence of NIDDM among adolescents in Greater Cincinnati, accompanying the national rise in adolescent obesity. Obesity and strong family histories of NIDDM are important risk factors. Because NIDDM leads to long-term morbidity, the prevention of obesity as well as early identification of overt disease, is critical.

Left Ventricular Geometry and Severe Left Ventricular Hypertrophy in Children and Adolescents With Essential Hypertension

BACKGROUND Left ventricular (LV) hypertrophy has been established as an independent risk factor for cardiovascular disease in adults. Recent research has refined this relationship by determining a cutpoint of 51 g/m(2.7) for LV mass index indicative of increased risk and defining LV geometric patterns that are associated with increased risk. The purpose of this study was to evaluate severe LV hypertrophy and LV geometry in children and adolescents with essential hypertension. METHODS AND RESULTS A cross-sectional study of young patients (n=130) with persistent blood pressure elevation above the 90th percentile was conducted. Nineteen patients (14%) had LV mass greater than the 99th percentile; 11 of these were also above the adult cutpoint of 51 g/m(2.7). Males, subjects with greater body mass index, and those who had lower heart rate at maximum exercise were at significantly (P<.05) higher risk of severe LV hypertrophy. In addition, 22 patients (17%) had concentric LV hypertrophy, a geometric pattern that is associated with increased risk of cardiovascular disease in adults. Seven patients had LV mass index above the cutpoint and concentric hypertrophy. No consistent significant determinants of LV geometry were identified in these children and adolescents with hypertension. CONCLUSIONS Severe LV hypertrophy and abnormal LV geometry are relatively prevalent in young patients with essential hypertension. These findings suggest that these patients may be at risk for future cardiovascular disease and underscore the importance of recognition and treatment of blood pressure elevation in children and adolescents. Weight loss is an important component of therapy in young patients with essential hypertension who are overweight.

Age-Specific Reference Intervals for Indexed Left Ventricular Mass in Children

BACKGROUND In older children, one of the standards for indexing left ventricular mass (LVM) is height raised to an exponential power of 2.7. The purpose of this study was to establish a normal value for the pediatric age group and to determine how, if at all, LVM/height(2.7) varies in children. METHODS M-mode echocardiography was performed in 2,273 nonobese, healthy children (1,267 boys, 1,006 girls; age range 0-18 years). Curves were constructed for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th quantiles of LVM/height(2.7). RESULTS In children aged > 9 years, median LVM/height(2.7) ranged from 27 to 32 g/m(2.7) and had little variation with age. However, in those aged < 9 years, LVM/height(2.7) varied significantly, and percentiles for newborns and infants were approximately double the levels for older children and adolescents: the 95th percentile ranged from 80 g/m(2.7) for newborns to 40 g/m(2.7) for 11-year-olds. CONCLUSION For patients aged > 9 years, quantiles of LVM/height(2.7) vary little, and values > 40 g/m(2.7) in girls and > 45 g/m(2.7) in boys can be considered abnormal (ie, > 95th percentile). However, for patients aged < 9 years, the index varies with age, and therefore, measured LVM/height(2.7) must be compared with percentile curves, which are provided. This variation in LVM/height(2.7) in younger children indicates that a better indexing method is needed for this age group. Nevertheless, these data are valuable in that they provide normal values with which patient data can be compared.

Indexing left ventricular mass to account for differences in body size in children and adolescents without cardiovascular disease

Left ventricular (LV) mass has been established as an independent risk factor for cardiovascular disease morbidity and mortality. To account for differences in body size, a variety of factors have been proposed for indexing LV mass. Dual energy x-ray absorptiometry provides a measure of lean body mass which can be used as a comparison with other more clinically applicable methods of standardization. The study included 192 subjects (100 male, 103 white) aged 6 to 17 years. Lean body mass was determined by dual energy x-ray absorptiometry and LV mass was calculated from M-mode echocardiographic measurements. There were significant differences by gender (males 98.7 g, females 80.3g, p < 0.001), but not race, for unindexed LV mass. Indexing LV mass by lean body mass eliminated the difference by gender. Log-log regression analysis revealed that the optimal height exponent for indexing LV mass was height3 (95% confidence interval, 2.8 to 3.1). LV mass/height3 provided the most consistently high intraclass correlation with LV mass/lean body mass versus indexing with body surface area, height, height2, and height2.7 across the 4 race/gender groups. LV mass indexed by height3 eliminated differences in LV mass by gender (males 26.1 +/- 4.72 g/m3, females 25.5 +/- 4.8 g/m3, p = NS). The proposed method for indexing LV mass by height3 should be useful in the clinical setting. The 90th and 95th percentiles of LV mass/height3 provide cutpoints for determining the presence of LV hypertrophy in children and adolescents.

Effect of Lean Body Mass, Fat Mass, Blood Pressure, and Sexual Maturation on Left Ventricular Mass in Children and Adolescents: Statistical, Biological, and Clinical Significance

BACKGROUND Left ventricular hypertrophy has been established as an independent risk factor for the development of cardiovascular morbidity and mortality. It is clear that left ventricular mass increases during childhood and adolescence with body growth. The extent to which other factors, such as obesity, stage of sexual maturation, and level of blood pressure, determine left ventricular mass has been controversial. METHODS AND RESULTS The study was a cross-sectional evaluation of the relationship of left ventricular mass determined by echocardiography with lean body mass and fat mass determined by dual-energy x-ray absorptiometry, which is the most valid and reliable method for determination of body composition in children and adolescents. The relationship of left ventricular mass with the stage of sexual maturation and with systolic and diastolic blood pressure was also evaluated. Two hundred one subjects (105 boys, 96 girls; 103 white and 98 black) 6 to 17 years old were studied. Age (r = .72), height (r = .81), weight (r = .84), body surface area (r = .87), sexual maturation (r = .75), lean body mass (r = .86), fat mass (r = .54), systolic BP (r = .58), and diastolic BP (r = .48) were all univariate correlates of left ventricular mass. In a multiple regression analysis, only lean body mass, fat mass, and systolic blood pressure were statistically significant independent correlates of left ventricular mass. Lean body mass alone explained 75% of the variance of left ventricular mass, whereas fat mass and systolic blood pressure explained only 1.5% and 0.5% of the variance, respectively. Lean body mass was the strongest determinant of left ventricular mass in all four race-sex groups. CONCLUSIONS This study provides an opportunity to separate the effects on left ventricular mass of lean body mass resulting from linear growth from those of fat mass resulting from obesity. Lean body mass, fat mass, and systolic blood pressure all have a statistically significant independent association with left ventricular mass, suggesting that all three play an important biological role in determining left ventricular mass. However, fat mass and systolic blood pressure have only a small impact on left ventricular mass. This indicates that fat mass and blood pressure would be expected to be of only minor clinical importance in determining left ventricular mass in normal children and adolescents.

Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion

OBJECTIVES Neurologic deficits are common after the Norwood procedure for hypoplastic left heart syndrome. Because of the association of deep hypothermic circulatory arrest with adverse neurologic outcome, regional low-flow cerebral perfusion has been used to limit the period of intraoperative brain ischemia. To evaluate the impact of this technique on brain ischemia, we performed serial brain magnetic resonance imaging in a cohort of infants before and after the Norwood operation using regional cerebral perfusion. METHODS Twenty-two term neonates with hypoplastic left heart syndrome were studied with brain magnetic resonance imaging before and at a median of 9.5 days after the Norwood operation. Results were compared with preoperative, intraoperative, and postoperative risk factors to identify predictors of neurologic injury. RESULTS Preoperative magnetic resonance imaging (n = 22) demonstrated ischemic lesions in 23% of patients. Postoperative magnetic resonance imaging (n = 15) demonstrated new or worsened ischemic lesions in 73% of patients, with periventricular leukomalacia and focal ischemic lesions occurring most commonly. Prolonged low postoperative cerebral oximetry (<45% for >180 minutes) was associated with the development of new or worsened ischemia on postoperative magnetic resonance imaging (P = .029). CONCLUSIONS Ischemic lesions occur commonly in neonates with hypoplastic left heart syndrome before surgery. Despite the adoption of regional cerebral perfusion, postoperative cerebral ischemic lesions are frequent, occurring in the majority of infants after the Norwood operation. Long-term follow-up is necessary to assess the functional impact of these lesions.

Severe left ventricular hypertrophy in pediatric dialysis: prevalence and predictors.

Abstract Left ventricular hypertrophy (LVH) has been recognized as an independent risk factor for cardiovascular morbidity and mortality in adults with end-stage renal disease. However, the prevalence and severity of LVH in children on chronic dialysis therapy is not well established. Retrospectively, 64 chronic dialysis patients, aged 20 months to 22 years, on chronic dialysis had echocardiographic evaluation of LV mass (LVM) and geometry. Forty-eight (75%) children had LVH, including 22 of 26 (85%) on hemodialysis (HD) and 26 of 38 (68%) on peritoneal dialysis (PD). The prevalence of LVH in patients on HD was significantly higher than those on PD (P=0.02). Abnormal LV geometry was found in 51 of 64 (80%) patients: 25 patients (39%) had eccentric hypertrophy, 3 (5%) had concentric remodelling, and 23 (36%) had concentric LVH. Twenty-six children (41%) had severe LVH, defined as LVM index greater than 51 g/m2.7, which is associated with a fourfold greater risk for development of cardiovascular disease in adults. Patients with severe LVH had a significantly lower hemoglobin level (P=0.027) and longer duration of renal disease prior to the start of dialysis therapy (P=0.003) than patients without LVH. Multiple logistic regression analysis revealed HD as opposed to PD as a significant independent predictor for severe LVH (P=0.036). Higher systolic blood pressure remained in the final model as an independent predictor with a borderline level of significance (P=0.065). The results indicate that severe LVH and abnormal left ventricular geometry are common in young dialysis patients. Better control of blood pressure, anemia, and hypervolemia may be important in prevention or improving LVH.

Increased Arterial Stiffness is Found in Adolescents with Obesity or Obesity-Related Type 2 Diabetes Mellitus

Objective Adults with obesity or obesity-related type 2 diabetes (T2DM) are at higher risk for cardiovascular disease possibly due to increased arterial stiffness. We sought to determine if arterial stiffness is increased in youth with obesity or T2DM as compared with lean controls. Methods Youth age 10–24 years (N = 670, 62% non-Caucasian, 35% male) were examined. They were stratified by the 85th% of BMI as lean (L=241), obese (O=234) or obese with T2DM (T2DM=195). Questionnaire, anthropometric, BP, laboratory (fasting glucose, insulin, HbA1c, lipids, CRP), physical activity, and DXA were collected. Brachial artery distensibility (BrachD), pulse wave velocity (PWV) and augmentation index (AIx) were measured. Group differences were evaluated by ANOVA. General linear multivariate models were constructed to elucidate independent determinates of arterial stiffness. Results CV risk profile deteriorated from L to O to T2DM group. There was a progressive increase in AIx and PWV-trunk with progressive decline in BrachD from L to O to T2DM individuals (all P < 0.05). Group (status as L, O or T2DM) was an independent predictor of arterial stiffness even after adjusting for CV risk factors. Conclusion Arterial stiffness is increased in young individuals with obesity and obesity-related T2DM even after correction for risk factors.

Youth With Obesity and Obesity-Related Type 2 Diabetes Mellitus Demonstrate Abnormalities in Carotid Structure and Function

Background— Adults with obesity or type 2 diabetes mellitus (T2DM) are at higher risk for stroke and myocardial infarction. Increased carotid intima-media thickness (cIMT) and stiffness are associated with these adverse outcomes. We compared carotid arteries in youth who were lean, were obese, or had T2DM. Methods and Results— Carotid ultrasound for cIMT measurement was performed, the Young elastic modulus and beta stiffness index were calculated, and anthropometric and laboratory values and blood pressure were measured in 182 lean, 136 obese, and 128 T2DM youth (aged 10 to 24 years). Mean differences were evaluated by ANOVA. Independent determinants of cIMT, Young elastic modulus, and beta stiffness index were determined with general linear models. Cardiovascular risk factors worsened from lean to obese to T2DM groups. T2DM subjects had greater cIMT than that in lean and obese subjects for the common carotid artery and bulb. For the internal carotid artery, cIMT measurements in both obese and T2DM groups were thicker than in the lean group. The carotid arteries were stiffer in obese and T2DM groups than in the lean group. Determinants of cIMT were group, group×age interaction, sex, and systolic blood pressure for the common carotid artery (r2=0.17); age, race, and systolic blood pressure for the bulb (r2=0.16); and age, race, sex, systolic blood pressure, and total cholesterol for the internal carotid artery (r2=0.21). Age, systolic blood pressure, and diastolic blood pressure were determinants of all measures of carotid stiffness, with sex adding to the Young elastic modulus (r2=0.23), and body mass index Z score, group, and group×age interaction contributing to the beta stiffness index (r2=0.31; all P<0.0001). Conclusions— Youth with obesity and T2DM have abnormalities in carotid thickness and stiffness that are only partially explained by traditional cardiovascular risk factors. These vascular changes should alert healthcare practitioners to address cardiovascular risk factors early to prevent an increase in the incidence of stroke and myocardial infarction.

Cardiac and Vascular Adaptation in Pediatric Patients with Chronic Kidney Disease: Role of Calcium-Phosphorus Metabolism

In children, cardiac abnormalities such as increased left ventricular mass (LVM) and diastolic dysfunction develop at the time of mild to moderate chronic renal insufficiency (CRI) and progress as renal function deteriorates. It was hypothesized that in this age group, vascular abnormalities develop early in the course of chronic kidney disease (CKD) in parallel with cardiac abnormalities and become more severe as end-stage disease is reached. Echocardiography and ultrasound of the carotid artery were performed on 44 patients with CKD stages 2 to 4 (CRI group), 16 patients who were on maintenance dialysis, and 35 healthy individuals. Carotid artery intima-media thickness (cIMT) was measured and distensibility and stiffness were calculated to assess carotid artery structure and function. Both the CRI and dialysis groups had greater cIMT, higher LVM index, and poorer diastolic function than the control subjects (P < 0.0001). Children who were on dialysis had greater cIMT and higher LVM index than those with CRI (P < 0.001) and greater arterial stiffness than both CRI patients and control subjects (P < 0.001). Arterial compliance was similar in CRI and control subjects. In all patients with CKD (CRI and dialysis), increased calcium-phosphorus product predicted increased cIMT. Increased serum phosphorus and intact parathyroid hormone predicted increased arterial stiffness. Elevated intact parathyroid hormone was a predictor of increased LVM index and poor diastolic function. In dialysis patients, the cumulative dose of phosphate binders and calcitriol predicted abnormal vascular structure and function. It is concluded that vascular abnormalities are already present in children and adolescents during early stages of CKD; they are more severe in children who are on maintenance dialysis and are related to abnormal calcium-phosphorus metabolism.