A randomized clinical trial to evaluate the single-dose pharmacokinetics, pharmacodynamics, and safety of sitagliptin in pediatric patients with type 2 diabetes.

OBJECTIVE: To evaluate the single-dose pharmacokinetics (PK), pharmacodynamics (PD), and safety of sitagliptin in pediatric patients with type 2 diabetes mellitus (T2DM). STUDY DESIGN: This was a randomized, placebo-controlled, double-blind evaluation of sitagliptin in 35 patients 10 to 17 years old with T2DM at 7 clinical research sites. The safety, tolerability, PK, and PD (dipeptidyl peptidase-4 [DPP-4] inhibition and aspects of glucose metabolism) of single doses of 50, 100, and 200 mg were assessed. Appropriate transformations on the PK parameters were used and back-transformed summary statistics are reported. RESULTS: Adverse experiences were reported by eight study participants; all were of mild intensity except one (intravenous site pain of moderate intensity). PK characteristics in the young patients were comparable to reference adult data, with geometric mean ratios (youths/adults) for AUC0-∞ , Cmax , and C24hr of 0.82, 1.04, and 0.74, respectively. Single doses of 50, 100, and 200 mg sitagliptin inhibited 67.2%, 73.8%, and 81.2% of plasma DPP-4 activity over 24 hours, respectively. Least squares (LS) mean glucose concentrations 2 hours after an oral glucose tolerance test or a meal tolerance test decreased in study participants treated with sitagliptin, compared to placebo, while active LS mean glucagon-like peptide 1 concentrations increased significantly at all sitagliptin doses in both tests. CONCLUSIONS: Single doses of sitagliptin as high as 200 mg were generally well tolerated in 10- to 17-year-old male and female study participants with T2DM, and a daily sitagliptin dose of 100 mg is appropriate for evaluation in Phase III safety and efficacy studies in pediatric patients with T2DM. (ClinicalTrials.gov: NCT00730275).

Cardiovascular disease in adult survivors of childhood cancer.

Treatment advances have increased survival in children with cancer, but subclinical, progressive, irreversible, and sometimes fatal treatment-related cardiovascular effects may appear years later. Cardio-oncologists have identified promising preventive and treatment strategies. Dexrazoxane provides long-term cardioprotection from doxorubicin-associated cardiotoxicity without compromising the efficacy of anticancer treatment. Continuous infusion of doxorubicin is as effective as bolus administration in leukemia treatment, but no evidence has indicated that it provides long-term cardioprotection; continuous infusions should be eliminated from pediatric cancer treatment. Angiotensin-converting enzyme inhibitors can delay the progression of subclinical and clinical cardiotoxicity. All survivors, regardless of whether they were treated with anthracyclines or radiation, should be monitored for systemic inflammation and the risk of premature cardiovascular disease. Echocardiographic screening must be supplemented with screening for biomarkers of cardiotoxicity and perhaps by identification of genetic susceptibilities to cardiovascular diseases; optimal strategies need to be identified. The health burden related to cancer treatment will increase as this population expands and ages.

Associations Between Dietary Intake Before 6 Months of Age and Rapid Weight Gain Among HIV-exposed Uninfected Infants.

INTRODUCTION: HIV-exposed, uninfected (HEU) infants are potentially at risk for cardiovascular disease due to in utero exposures. Feeding practices of the infant could compound this risk. Few studies have, however, evaluated dietary intake of HEU infants. We determined dietary factors associated with rapid weight gain (RWG) among HEU infants from birth to 6 months followed at the University of Miami HIV Screening Program. METHODS: In this cross-sectional analysis, logistic regression was used to determine dietary factors associated with RWG defined as a >0.67 SD change in weight-for-age z score from birth to assessment (0.3-6 months). Other covariates included demographics, birth, maternal and gestational characteristics, and antiretroviral exposures. RESULTS: A total of 86 full-term HEU infants with a mean age of 3.4 months (SD 1.8 months) were included in this analysis. Fifty-five percent of mothers were obese. Overall, 39.5% of infants exhibited RWG. A significant association between consumption of infant cereal and RWG (odds ratio, 3.52; 95% confidence interval, 1.02-12.10) was found after adjusting for birth weight, current age, and energy intake. Those infants who consumed the highest tertile of protein were less likely to gain weight rapidly after adjusting for the same covariates (odds ratio, 0.15; 95% confidence interval, 0.02-0.94). CONCLUSIONS: Overall differences in weight gain during early infancy are at least partly explained by means of infant feeding in young HEU infants in the United States. Dietary counseling for families of HEU should reinforce current feeding practice recommendations of the American Academy of Pediatrics.

A multicenter study of diet quality on birth weight and gestational age in infants of HIV-infected women.

We determined factors associated with diet quality and assessed the relationship between diet quality, birth weight, and gestational age in a prospective national multicenter cohort study. We evaluated diet quality with the Healthy Eating Index (HEI, scale 0-100) in the third trimester of pregnancy with three 24-hr multiple-pass dietary recalls in 266 HIV+ women enrolled in the Pediatric HIV/AIDS Cohort Study. Covariates included demographics, food security, pre-pregnancy body mass index, HIV disease severity, substance use, and antiretroviral exposures. A two-stage multivariate process using classification and regression trees (CART) followed by multiple regression described HEI tendencies, controlled possible confounding effects, and examined the association of HEI with birth weight and gestational age. To assess the stability of the CART solution, both the HEI 2005 and 2010 were evaluated. The mean HEI scores were 56.1 and 47.5 for the 2005 and 2010 HEI, respectively. The first-stage CART analysis examined the relationship between HEI and covariates. Non-US born versus US-born mothers had higher HEI scores (15-point difference, R2  = 0.28). There was a secondary partition due to alcohol/cigarette/illicit drug usage (3.5-point difference, R2  = 0.03) among US-born women. For the second-stage CART adjusted multiple regression, birth weight z-score was positively related to HEI 2005 and 2010 (partial r's > 0.13, P's ≤ 0.0398), but not gestational age (r = 0.00). We conclude that diet quality among HIV+ women is associated with higher birth weight. Despite the influence of a large cultural effect and poor prenatal behaviors, interventions to improve diet in HIV+ women may help to increase birth weight.

HIV Infection and Carotid Artery Intima-media Thickness: Pooled Analyses Across 5 Cohorts of the NHLBI HIV-CVD Collaborative.

BACKGROUND: Age and human immunodeficiency virus (HIV) treatment may affect the association of HIV infection with atherosclerosis. METHODS: We used identical carotid artery B-mode ultrasonographic methods in 5 cohorts participating in the National Heart, Lung, and Blood Institute HIV-CVD Collaborative to measure intima-media thickness of the right far wall of the common carotid artery (CCA-IMT) and carotid artery bifurcation (BIF-IMT) between 2010 and 2013. Participants aged 6-75 years were either HIV infected or uninfected. Linear regression assessed associations of CCA-IMT and BIF-IMT with HIV infection and cardiovascular disease risk factors, within age and HIV treatment groups. Adjustment variables included sex, race/ethnicity, smoking, height, weight, and use of antihypertensive and lipid-lowering drugs. RESULTS: We studied 867 HIV-infected and 338 HIV-uninfected male and 696 HIV-infected and 246 HIV-uninfected female participants. Among both middle-aged (30-49 years) and older adults (50-75 years), HIV-infected participants had CCA-IMT and BIF-IMT values that were similar to or lower than those in HIV-uninfected participants. In contrast, among those aged 6-29 years, HIV infection was associated with higher CCA-IMT and BIF-IMT values. Among HIV-infected participants, associations of higher systolic blood pressure and lower high-density lipoprotein cholesterol with Carotid artery intima-media thickness strengthened with age. CONCLUSIONS: The effects of HIV on carotid artery structure may differ across the lifespan, with traditional determinants of cardiovascular disease burden playing a larger role and HIV playing a lesser role in older adults than in young adults and children.

Impaired mitochondrial function is abrogated by dexrazoxane in doxorubicin-treated childhood acute lymphoblastic leukemia survivors.

BACKGROUND: Impaired cardiac function in doxorubicin-treated childhood cancer survivors is partly mediated by the disruption of mitochondrial energy production. Doxorubicin intercalates into mitochondrial DNA (mtDNA) and disrupts genes encoding for polypeptides that make adenosine triphosphate. METHODS: This cross-sectional study examined mtDNA copy numbers per cell and oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) in 64 childhood survivors of high-risk acute lymphoblastic leukemia (ALL) who had been treated on Dana-Farber Cancer Institute childhood ALL protocols and had received doxorubicin alone (42%) or doxorubicin with the cardioprotectant dexrazoxane (58%). The number of mtDNA copies per cell and the OXPHOS enzyme activity of nicotinamide adenine dinucleotide dehydrogenase (complex I [CI]) and cytochrome c oxidase (complex IV [CIV]) were measured with quantitative real-time polymerase chain reaction immunoassays and thin-layer chromatography, respectively. RESULTS: At a median follow-up of 7.8 years after treatment, the median number of mtDNA copies per cell for patients treated with doxorubicin alone (1106.3) was significantly higher than the median number for those who had also received dexrazoxane (310.5; P = .001). No significant differences were detected between the groups for CI or CIV activity. CONCLUSIONS: Doxorubicin-treated survivors had an increased number of PBMC mtDNA copies per cell, and concomitant use of dexrazoxane was associated with a lower number of mtDNA copies per cell. Because of a possible compensatory increase in mtDNA copies per cell to maintain mitochondrial function in the setting of mitochondrial dysfunction, overall OXPHOS activity was not different between the groups. The long-term sustainability of this compensatory response in these survivors at risk for cardiac dysfunction over their lifespan is concerning.

Health-Related Quality of Life and Functional Status Are Associated with Cardiac Status and Clinical Outcome in Children with Cardiomyopathy.

OBJECTIVES: To measure the health-related quality of life (HRQOL) and functional status of children with cardiomyopathy and to determine whether they are correlated with sociodemographics, cardiac status, and clinical outcomes. STUDY DESIGN: Parents of children in the Pediatric Cardiomyopathy Registry completed the Child Health Questionnaire (CHQ; age ≥ 5 years) and Functional Status II (Revised) (age ≤ 18 years) instruments. Linear and Cox regressions were used to examine hypothesized associations with HRQOL. RESULTS: The 355 children evaluated at ≥ 5 years (median 8.6 years) had lower functioning (CHQ Physical and Psychosocial Summary Scores 41.7 ± 14.4 and 47.8 ± 10.7) than that of healthy historical controls. The most extreme CHQ domain score, Parental Impact-Emotional, was one SD below normal. Younger age at diagnosis and smaller left ventricular end-diastolic dimension z score were associated independently with better physical functioning in children with dilated cardiomyopathy. Greater income/education correlated with better psychosocial functioning in children with hypertrophic and mixed/other types of cardiomyopathy. In the age ≥ 5 year cohort, lower scores on both instruments predicted earlier death/transplant and listing for transplant in children with dilated and mixed/other types of cardiomyopathy (P < .001). Across all ages (n = 565), the Functional Status II (Revised) total score was 87.1 ± 16.4, and a lower score was associated with earlier death/transplant for all cardiomyopathies. CONCLUSIONS: HRQOL and functional status in children with cardiomyopathy is on average impaired relative to healthy children. These impairments are associated with older age at diagnosis, lower socioeconomic status, left ventricular size, and increased risk for death and transplant. Identification of families at risk for functional impairment allows for provision of specialized services early in the course of disease. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005391.

Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

BACKGROUND: Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries and abdominal aorta risk scores, as a result of prolonged exposure to HIV and antiretroviral therapy. METHODS AND RESULTS: Coronary arteries and abdominal aorta PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified, and trends in scores over time were assessed. Forty-eight percent and 24% of the perinatally HIV-infected adolescents had coronary arteries and abdominal aorta scores ≥1, representing increased cardiovascular disease risk factor burden. Significant predictors of coronary arteries scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of abdominal aorta scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in coronary arteries and abdominal aorta risk scores were observed over the 4-year study period. CONCLUSIONS: A substantial proportion of perinatally HIV-infected youth have high PDAY scores, reflecting increased aggregate atherosclerotic cardiovascular disease risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.

Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy.

BACKGROUND: Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. METHODS: We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir-unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. RESULTS: Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs -0.18) or weight (-0.71 vs -0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, -9.5, -1.2; P = .013) in the tenofovir-exposed infants. CONCLUSIONS: Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01310023.

Prenatal Cocaine Exposure and Cardiometabolic Disease Risk Factors in 18- to 20-Year-Old African Americans.

OBJECTIVE: The long-term effects of prenatal cocaine exposure (PCE) on physical health are largely unknown. No human studies support or refute a relationship between PCE and the long-term risk for cardiovascular and/or metabolic disease. We investigated the association of PCE on primary cardiometabolic disease risk factors in African Americans (AA) aged 18 to 20 years. DESIGN: Cohort, longitudinal, prospective. SETTING: Miami-Dade County, Florida, and the University of Miami Miller School of Medicine/Jackson Memorial Medical Center. PARTICIPANTS: Healthy full-term inner-city AA adolescents (aged 18 to 20 years, n=350) previously enrolled at birth from 1990-1993. MAIN OUTCOME MEASURES: Fasting serum insulin, glucose, lipids, and high-sensitivity C-reactive protein; systolic and diastolic blood pressures; and the components and prevalence of the metabolic syndrome. RESULTS: There were no PCE-associated differences in cardiometabolic disease risk factors including the metabolic syndrome and its individual components in AAs aged 18 to 20 years. CONCLUSIONS: The results of our study do not support an association between PCE and increased cardiometabolic disease risk in AAs aged 18 to 20 years. Whether PCE is associated with cardiovascular or metabolic disease in adulthood would require further investigation.

Anthracycline-related cardiotoxicity in childhood cancer survivors.

PURPOSE OF REVIEW: Anthracyclines have markedly improved the survival rates of children with cancer. However, anthracycline-related cardiotoxicity is also well recognized and can compromise the long-term outcome in some patients. The challenge remains of how to balance the chemotherapeutic effects of anthracycline treatment with its potentially serious cardiovascular complications. Here, we review the pathophysiology, risk factors, clinical manifestations, prevention, and treatment of anthracycline-related cardiotoxicity. RECENT FINDINGS: Some risk factors and biomarkers associated with an increased probability of anthracycline-related cardiotoxicity have been identified. Modifying the structural forms and dosages of anthracyclines and coadministering cardioprotective agents may prevent some of these cardiotoxic effects. Cardiovascular complications have also been treated with angiotensin-converting enzyme inhibitors, ß-blockers, and growth hormone replacement therapy. Cardiac transplantation remains the treatment of last resort. SUMMARY: Despite major advances in cancer treatment, anthracycline-related cardiotoxicity remains a major cause of morbidity and mortality in survivors of childhood cancer. Promising areas of research include: use of biomarkers for early recognition of cardiac injury in children receiving chemotherapy, development and application of cardioprotective agents for prevention of cardiotoxicity, and advancements in therapies for cardiac dysfunction in children after anthracycline treatment.

Cardiotoxicity and cardioprotection in childhood cancer.

Children diagnosed with cancer are now living longer as a result of advances in treatment. However, some commonly used anticancer drugs, although effective in curing cancer, can also cause adverse late effects. The cardiotoxic effects of anthracycline chemotherapy, such as doxorubicin, and radiation can cause persistent and progressive cardiovascular damage, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Examples of risk factors for cardiotoxicity in children include higher anthracycline cumulative dose, higher dose of radiation, younger age at diagnosis, female sex, trisomy 21 and black race. However, not all who are exposed to toxic treatments experience cardiotoxicity, suggesting the possibility of a genetic predisposition. Cardioprotective strategies under investigation include the use of dexrazoxane, which provides short- and long-term cardioprotection in children treated with doxorubicin without interfering with oncological efficacy, the use of less toxic anthracycline derivatives and nutritional supplements. Evidence-based monitoring and screening are needed to identify early signs of cardiotoxicity that have been validated as surrogates of subsequent clinically significant cardiovascular disease before the occurrence of cardiac damage, in patients who may be at higher risk.

Body mass index and waist circumference of HIV-infected youth in a Miami cohort: comparison to local and national cohorts.

OBJECTIVES: Human immunodeficiency virus (HIV)-infected youth are healthier because of effective antiretroviral therapies. We compared anthropometric measurements and prevalence of overweight and obesity between perinatally HIV-infected youth, a local HIV-uninfected comparison group, and 2007 to 2010 National Health and Nutrition Examination Survey (NHANES) data. In addition, we compared only African American HIV-infected youth with NHANES African Americans. METHODS: Height, weight, body mass index (BMI), and waist circumference (WC) of HIV-infected youth, aged 10 to 19 years, were compared among groups. BMI percentiles were categorized as underweight (<5%), normal (5% to <85%), overweight (85% to <95%), and obese (≥ 95%). Clinical correlates were modeled as predictors of BMI and WC. RESULTS: A total of 134 HIV-infected (including 103 African Americans) (mean age 16.5 years), 75 HIV-uninfected (mean age 14.2 years), and 3216 NHANES (including 771 NHANES African Americans) (mean age 15.0 years) youth were included in the analysis. Height and weight z scores of HIV-infected youth were lower than those of HIV-uninfected and NHANES (P ≤ 0.056) youth. BMI, WC, and BMI category were not statistically different between groups. In the HIV-infected African American group, BMI z score was lower (0.49 vs 0.76, P = 0.04) compared with NHANES African Americans. There were no significant predictors of BMI or WC for the HIV-infected group. CONCLUSIONS: HIV-infected children have similar BMIs and WCs as uninfected children both locally and nationally and show similar high rates of obesity and overweight. When compared with a more racially similar African American national sample, HIV-infected children have a lower BMI, suggesting that there may be persistent anthropometric differences in HIV.

Impact of hemochromatosis gene mutations on cardiac status in doxorubicin-treated survivors of childhood high-risk leukemia.

BACKGROUND: Doxorubicin is associated with progressive cardiac dysfunction, possibly through the formation of doxorubicin-iron complexes leading to free-radical injury. The authors determined the frequency of hemochromatosis (HFE) gene mutations associated with hereditary hemochromatosis and their relationship with doxorubicin-associated cardiotoxicity in survivors of childhood high-risk acute lymphoblastic leukemia. METHODS: Peripheral blood was tested for 2 common HFE allelic variants: C282Y and H63D. Serum cardiac troponin-T (cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP), which are biomarkers of cardiac injury and cardiomyopathy, respectively, were assayed during therapy. Left ventricular (LV) structure and function were assessed with echocardiography. RESULTS: A total of 184 patients had DNA results for at least 1 variant, and 167 had DNA results for both: 24% carried H63D and 10% carried C282Y. Heterozygous C282Y genotype was associated with multiple elevations in cTnT concentrations (P = .039), but not NT-proBNP. At a median of 2.2 years (range, 1.0 years-3.6 years) after diagnosis, the mean Z-scores for LV fractional shortening (-0.71 [standard error (SE), 0.25]; P = .008), mass (-0.84 [SE, 0.17]; P < .001), and end-systolic (-4.36 [SE, 0.26], P < .001) and end-diastolic (-0.68 [SE, 0.25]; P = .01) posterior wall thickness were found to be abnormal in children with either allele (n = 32). Noncarriers (n = 63) also were found to have below-normal LV mass (-0.45 [SE, 0.15]; P = .006) and end-systolic posterior wall thickness (-4.06 [SE, 0.17]; P < .001). Later follow-up demonstrated similar results. CONCLUSIONS: Doxorubicin-associated myocardial injury was associated with C282Y HFE carriers. Although LV mass and wall thickness were found to be abnormally low overall, they were even lower in HFE carriers, who also had reduced LV function. Screening newly diagnosed cancer patients for HFE mutations may identify those at risk for doxorubicin-induced cardiotoxicity.

Growth and body composition of uninfected children exposed to human immunodeficiency virus: comparison with a contemporary cohort and United States National Standards.

OBJECTIVE: To compare growth and body composition of uninfected children exposed to HIV with a contemporary HIV-unexposed group and to US references. STUDY DESIGN: Uninfected children exposed to HIV under 2 years were enrolled into a longitudinal observational study and unexposed children under 2 years of age in a cross-sectional evaluation. Weights, lengths, head circumferences, skinfold thicknesses, and arm and thigh circumferences were measured and adjusted for age using Centers for Disease Control and National Health and Nutrition Examination Survey standards. Uninfected children exposed to HIV were compared with an unexposed nearest-neighbor matched comparison group. Uninfected children exposed to HIV were compared by age to Centers for Disease Control standards for growth measures and National Health and Nutrition Examination Survey standards for body composition. RESULTS: One hundred eleven uninfected children exposed to HIV and 82 children not exposed to HIV were evaluated. For the matched comparison for both groups, the mean age was 10 months, 59% were male, and 73% were African American. No statistical differences were found in anthropometric measurements between uninfected children who were or were not exposed to HIV. Uninfected children exposed to HIV were smaller than US standards at birth with mean (SD) weight-for-age and weight-for-length z-scores of -0.39 (1.06); P = .002 and -0.35 (1.04); P = .005, respectively. Over the first 2 years of life, there was a trend toward increasing weight-for-age z-score, length-for-age z-score, and weight-for-length z-score in uninfected children exposed to HIV. Subscapular and triceps skinfolds among uninfected children exposed to HIV were lower than national standards and there was a trend that mid-upper arm circumference decreased over time. CONCLUSIONS: Growth and body composition of uninfected children who were or were not exposed to HIV were similar. Uninfected children exposed to HIV weigh less at birth and show a pattern of slightly accelerated growth in the first 2 years of life. Uninfected children exposed to HIV had less subcutaneous fat and decreasing mid-upper arm circumference over time when compared with US standards.

Dietary quality, caloric intake, and adiposity of childhood cancer survivors and their siblings: an analysis from the cardiac risk factors in childhood cancer survivors study.

Childhood cancer survivors are at increased risk of cardiovascular disease, in part because of adiposity. Whether survivors have healthy diets and whether dietary quality is associated with adiposity among survivors are not known. Survivors and siblings from the Cardiac Risk Factors in Childhood Cancer Survivors Study completed 3-day food records that were used to estimate daily caloric intake relative to recommended and dietary quality using the Healthy Eating Index-2005 (HEI). Medical records were reviewed for cancer therapies. Body composition was measured by dual-energy x-ray absorptiometry. Of 91 childhood cancer survivors and 30 sibling controls, there were no marked differences in mean daily caloric intakes (98% vs. 100% of recommended) or HEI total scores (55.5 vs. 53.3), respectively, with both groups scoring worst for the consumption of dark green vegetables and whole grains. Survivors exposed to cranial irradiation had lower total HEI scores (-6.4, P = 0.01). Among survivors, better dietary quality, as reflected by the total HEI score, was associated with decreasing percent body fat (ß = -0.19, P = 0.04). Survivors consume diets similar to their siblings although these diets are only moderately adherent to current guidelines. Decreased dietary quality is associated with higher body fat and receipt of cranial irradiation in survivors.

Exercise capacity in long-term survivors of pediatric cancer: an analysis from the Cardiac Risk Factors in Childhood Cancer Survivors Study.

BACKGROUND: Childhood cancer survivors may have premature symptomatic cardiovascular and non-cardiovascular diseases that contribute to reduced capacity for physical activity. Studies of exercise capacity and identification of risk factors for reduced capacity in survivors are limited. PROCEDURE: We assessed maximal myocardial oxygen consumption (V(O(2)max), a measure of exercise capacity) in survivors at least 4 years after cancer diagnosis and sibling controls. We evaluated associations between V(O(2)max) and age, sex, treatments, cardiac structure and function, biomarkers, endocrine function, and physical activity. RESULTS: Of 72 survivors (mean age, 22 years; range, 8.0-40 years) and 32 siblings (mean age, 20.2 years; range, 8-46 years), about half were male. Mean time since diagnosis was 13.4 years (range, 4.5-31.6 years). In age- and sibling-pair adjusted analyses, V(O(2)max) was lower in survivors than siblings (males, 28.53 vs. 30.90 ml/kg/minute, P = 0.08; females, 19.81 vs. 23.40 ml/kg/minute, P = 0.03). In males, older age (P = 0.01), higher percent body fat (P < 0.001) and high or low left ventricular (LV) mass Z-scores (P = 0.03) predicted lower V(O(2)max). In females, older age (P < 0.001), methotrexate exposure (P = 0.01), and higher, but normal, LV load-dependent contractility (P = 0.02) predicted lower V(O(2)max). CONCLUSIONS: Fitness for most survivors and controls was poor and generally lower in survivors, particularly females. Older age, higher body fat, methotrexate exposure, and extremes of LV mass/function were associated with lower V(O(2)max) in survivors. Because physical activity can improve nutritional and cardiac conditions, survivors should be encouraged to exercise regularly with close monitoring.

Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure.

BACKGROUND: In adults with heart failure, elevated levels of fibroblast growth factor 23 (FGF23) are associated with mortality. Data on FGF23 levels in pediatric heart failure are lacking. PATIENTS AND METHODS: We conducted a cross-sectional study of 17 healthy children (mean age 13 years) and 20 pediatric patients with heart failure (mean age 12 years) who underwent echocardiography and for whom the following measurements were taken: plasma FGF23 and parathyroid hormone (PTH) and serum phosphate, creatinine and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Symptom severity was assessed with the New York Heart Association and the Ross classification systems. RESULTS: Of the 20 patients, 11 had dilated cardiomyopathy, four had congenital heart disease, three had hypertrophic cardiomyopathy, one had a failing heart transplant and one had pulmonary hypertension. Mean phosphate levels in these patients were within the reported reference range for healthy children. Median PTH levels were in the normal range in patients and controls. The median FGF23 level was higher in patients versus controls (110.9 vs. 66.4 RU/ml; P = 0.03) and higher in patients on diuretics versus other patients (222.4 vs. 82.1 RU/ml; P = 0.01). Levels of FGF23 and NT-proBNP were directly correlated (r = 0.47, P = 0.04), and patients with greater physical functional impairment had higher FGF23 levels (142.5 in those with moderate-severe limitation vs. 92.8 RU/ml in those with no limitation; P = 0.05). Among patients with dilated cardiomyopathy, higher FGF23 levels were associated with a greater left ventricular end-diastolic diameter (r = 0.63, P = 0.04). CONCLUSION: FGF23 levels are elevated in children with heart failure and are associated with diuretic use, severity of heart failure and left ventricular dilation.

Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study.

Anthracycline-treated childhood cancer survivors experience cardiac damage that results in decreased left ventricular (LV) mass, leading to increased LV wall stress, which underlies their greater risk of cardiomyopathy. Many of these survivors also are at risk of growth hormone (GH) abnormalities from cranial irradiation exposure, although it is unknown whether such exposure is associated with cardiotoxicity. Echocardiograms and insulin-like growth factor-1 (IGF-1), a marker of GH, were measured in 130 anthracycline-treated childhood cancer survivors, 59 of whom had been exposed to cranial irradiation, a mean 10 years after their cancer diagnosis. Echocardiographic parameters and IGF-1 were standardized relative to age or body surface area using data from sibling control subjects and expressed as the percentage difference from normal values. The results showed that after adjustment for other risk factors, survivors exposed to cranial irradiation had an additional 12 % decrease in LV mass compared with unexposed survivors (P < 0.01) and an additional 3.6 % decrease in LV dimension (P = 0.03). Survivors exposed to cranial irradiation also had a 30.8 % decrease in IGF-1 relative to normal values, which was greater than the 10.5 % decrease in unexposed survivors (P < 0.01). The above findings led us to conclude that in anthracycline-treated childhood cancer survivors a mean 10 years after their diagnosis, those with cranial irradiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation also was associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect, suggesting that GH replacement therapy may help to prevent the development of cardiotoxicity.

A high school-based voluntary cardiovascular risk screening program: issues of feasibility and correlates of electrocardiographic outcomes.

Risk factors for adult cardiovascular events can be identified from the prenatal period through childhood. We performed a cardiovascular risk-screening program in students from grades 9-12 in 7 high schools in Hillsborough County, FL. We obtained blood pressure (BP) measurements and calculated body mass index (BMI) as risk factors for future cardiovascular events as well as obtained an electrocardiogram (ECG) for the purposes of detecting possible life-threatening arrhythmias. Of ~14,000 students contacted, 600 (4 %) participated in the screening. Of these, 517 (86 %) were diagnosed with normal, 71 (12 %) with borderline, and 12 (1 %) with abnormal ECGs. Although no participant had any cardiac history, two of the abnormal ECGs indicated a cardiac diagnosis associated with the potential for sudden cardiac death. Both systolic and diastolic BP increased as the ECG diagnosis moved from normal (115.6/73.8) through borderline (121.0/75.9) to an abnormal (125.0/80.7) diagnosis (all P ≤ .0016). An increase in BMI was only observed when an ECG diagnosis was abnormal (P = .0180). Boys had a greater prevalence (18.97 %) of borderline or abnormal ECGs compared with girls (6.75 %), whereas no discernible differences were seen in ECG diagnosis between white and nonwhite individuals (15.09 and 12.26 %, respectively). Although participation rates were low, a high school-based cardiovascular risk-screening program including ECG is feasible. Although ECG diagnosis tended to be related to other known cardiovascular risk factors (BP, BMI), the utility of an abnormal ECG in adolescence as a predictor of future cardiovascular risk will require further evaluation in more controlled settings.