Polymorphisms of ABCC5 and NOS3 genes influence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia.

Anthracyclines are efficient chemotherapy agents. However, their use is limited by anthracycline-induced cardiotoxicity (CT). We investigated the influence of polymorphisms in doxorubicin metabolic and functional pathways on late-onset CT as estimated by echocardiography in 251 childhood acute lymphoblastic leukemia (cALL) patients. Association analyses revealed a modulating effect of two variants: A-1629 T in ABCC5, an ATP-binding cassette transporter, and G894T in the NOS3 endothelial nitric oxide synthase gene. Individuals with the ABCC5 TT-1629 genotype had an average of 8-12% reduction of ejection (EF) and shortening fractions (SF; EF: P<0.0001, and SF: P=0.001, respectively). A protective effect of the NOS3 TT894 genotype on EF was seen in high-risk patients (P=0.02), especially in those who did not receive dexrazoxane (P=0.002). Analysis of an additional cohort of 44 cALL patients replicated the ABCC5 association but was underpowered for NOS3. In summary, we identified two biomarkers that may contribute to cALL anthracycline CT risk stratification.

The imperative to prevent and treat childhood obesity: why the world cannot afford to wait.

In the past 20 years, the prevalence of obesity in the United States increased almost 50% among adults and by 300% in children. Today, 9.7% of all U.S. infants up to 2 years old have abnormally high weight-for-recumbent length; 25% of children under age 5 are either overweight or obese; and 17% of adolescents are obese. Ethnic disparities in the rates of obesity are also large and apparent in childhood. Further, 44% of obese adolescents have metabolic syndrome. Obese children tend to become obese adults; thus, in a decade, young adults will likely have much higher risks of chronic disease, which has tremendous implications for the healthcare system. However, early childhood may be the best time to prevent obesity. Teachers' healthy eating choices are positively associated with changes in body mass index percentiles for children, for example. In addition, 8 million children attend afterschool programs, which can successfully promote health and wellness and successfully treat obesity. This childhood epidemic of obesity and its health-related consequences in adolescents should be a clinical and public health priority. However, this major public health problem cannot be managed solely in clinical settings. Rather, public health strategies must be integrated into home and family, school and community-based settings.

Cardiac, aortic, and pulmonary arteriopathy in HIV-infected children: the Prospective P2C2 HIV Multicenter Study.

Arteriopathy in human immunodeficiency virus (HIV)-infected patients is being increasingly recognized, especially in children. However, few studies have histologically evaluated the coronary arteries in HIV-infected children, and none have systematically assessed the aorta and pulmonary arteries. The coronary arteries, thoracic aorta, and the main and branch pulmonary arteries from the postmortem hearts of 14 HIV-infected children were systematically reviewed for vasculopathic lesions and compared with 14 age-matched controls. Findings from the HIV-infected children were compared with clinical, laboratory, and other postmortem findings. Coronary arteriopathy, seen in seven (50%) of the HIV-infected children, was primarily calcific, and it was associated with decreased CD3 and CD4 peripheral blood counts. Large vessel arteriopathy, seen in 9 (64%) of the 14 HIV-infected children, was primarily centered on the vasa vasorum and consisted mainly of medial hypertrophy and chronic inflammation. Large vessel lesions were associated with increased left ventricular mass z-scores (P = 0.02), and 78% of patients with large vessel arteriopathy had postmortem cardiomegaly. Coronary and large vessel arteriopathies are common in pediatric HIV-infection and have different clinicopathologic features suggesting different pathogenesis.

Maternal and infant factors associated with failure to thrive in children with vertically transmitted human immunodeficiency virus-1 infection: the prospective, P2C2 human immunodeficiency virus multicenter study.

OBJECTIVE: Many children with human immunodeficiency virus-1 (HIV-1) have chronic problems with growth and nutrition, yet limited information is available to identify infected children at high risk for growth abnormalities. Using data from the prospective, multicenter P2C2 HIV study, we evaluated the relationships between maternal and infant clinical and laboratory factors and impaired growth in this cohort. METHODS: Children of HIV-1-infected women were enrolled prenatally or within the first 28 days of life. Failure to thrive (FTT) was defined as an age- and sex-adjusted weight z score < or =-2.0 SD. Maternal baseline covariates included age, race, illicit drug use, zidovudine use, CD4+ T-cell count, and smoking. Infant baseline predictors included sex, race, CD4+ T-cell count, Centers for Disease Control stage, HIV-1 RNA, antiretroviral therapy, pneumonia, heart rate, cytomegalovirus, and Epstein-Barr virus infection status. RESULTS: The study cohort included 92 HIV-1-infected and 439 uninfected children. Infected children had a lower mean gestational age, but birth weights, lengths, and head circumferences in the 2 groups were similar. Mothers of growth-delayed infants were more likely to have smoked tobacco and used illicit drugs during pregnancy. In repeated-measures analyses of weight and length or height z scores, the means of the HIV-1-infected group were significantly lower at 6 months of age (P <.001) and remained lower throughout the first 5 years of life. In a multivariable Cox regression analysis, FTT was associated with a history of pneumonia (relative risk [RR] = 8.78; 95% confidence interval [CI]: 3.59-21.44), maternal use of cocaine, crack, or heroin during pregnancy (RR = 3.17; 95% CI: 1.51-6.66), infant CD4+ T-cell count z score (RR = 2.13 per 1 SD decrease; 95% CI: 1.25-3.57), and any antiretroviral therapy by 3 months of age (RR = 2.77; 95% CI: 1.16-6.65). After adjustment for pneumonia and antiretroviral therapy, HIV-1 RNA load remained associated with FTT in the subset of children whose serum was available for viral load analysis. CONCLUSIONS: Clinical and laboratory factors associated with FTT among HIV-1-infected children include history of pneumonia, maternal illicit drug use during pregnancy, lower infant CD4+ T-cell count, exposure to antiretroviral therapy by 3 months of age (non-protease inhibitor), and HIV-1 RNA viral load.

HIV-associated cardiovascular complications: a new challenge for emergency physicians.

Cardiac complications associated with the AIDS may present to emergency physicians and are often secondary to opportunistic infections or malignancy, but may also be associated with other aspects of the human immunodeficiency virus (HIV) or its treatment. In this review article, we will discuss HIV-associated cardiac disease which may be encountered in the ED, emphasizing the prevalence, pathogenesis, and treatment of related disorders.

The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity.

PURPOSE: To compare the protective effect of dexrazoxane (DRZ) against cardiotoxicity induced by doxorubicin (DXR) and mitoxantrone (MTX). METHODS: Adult male spontaneously hypertensive rats (SHR) were treated with 1 mg/kg DXR (i.v.) or 0.5 mg/kg MTX (i.v.), either alone or 30 min after 25 mg/kg DRZ (i.p.) weekly for up to 12 weeks. Animals treated with DXR alone either died (n = 2) or were killed (n = 3) at a cumulative dose of 10 mg/kg. The severity of cardiac lesions (cytoplasmic vacuolization and myofibrillar loss) were graded semiquantitatively by light microscopy on a scale of 0 to 3. RESULTS: Cardiac lesions were observed in all SHR given DXR or MTX alone, and were attenuated in those given DRZ prior to either DXR (mean lesion scores 2.7 vs 1.5; P < 0.05) or MTX (mean lesion scores 2.0 vs 1.25; P < 0.05). Cardioprotection was also demonstrated by monitoring serum levels of cardiac troponin T (cTnT), which were elevated in all animals receiving DXR or MTX alone. These elevations were attenuated in SHR given the combination of DXR and DRZ (mean values 0.79 ng/ml vs 0.24 ng/ml; P < 0.05) and MTX and DRZ (mean values 0.19 ng/ml vs 0.04 ng/ ml; P < 0.05). Biochemical studies have shown that both DXR and MTX form potentially cardiotoxic complexes with iron. ADR-925 (the hydrolysis product of DRZ) and other chelators (EDTA, diethylenetriaminepentaacetic acid and desferrioxamine) removed Fe(III) from its complex with MTX or DXR. CONCLUSIONS: The present study showed that DRZ significantly attenuates the cardiotoxicity induced by DXR and MTX, and that this protective activity can be assessed by morphological evaluation of cardiac tissues and by monitoring the concentrations of cTnT in serum.

Reliability of multicenter pediatric echocardiographic measurements of left ventricular structure and function: the prospective P(2)C(2) HIV study.

BACKGROUND: To assess the reliability of pediatric echocardiographic measurements, we compared local measurements with those made at a central facility. METHODS AND RESULTS: The comparison was based on the first echocardiographic recording obtained on 735 children of HIV-infected mothers at 10 clinical sites focusing on measurements of left ventricular (LV) dimension, wall thicknesses, and fractional shortening. The recordings were measured locally and then remeasured at a central facility. The highest agreement expressed as an intraclass correlation coefficient (ICC=0.97) was noted for LV dimension, with much lower agreement for posterior wall thickness (ICC=0.65), fractional shortening (ICC=0.64), and septal wall thickness (ICC=0.50). The mean dimension was 0.03 cm smaller in central measurements (95% prediction interval [PI], -0.32 to 0.25 cm) for which 95% PI reflects the magnitude of differences between local and central measurements. Mean posterior wall thickness was 0.02 cm larger in central measurements (95% PI, -0.18 to 0.22 cm). Mean fractional shortening was 1% smaller in central measurements. However, the 95% PI was -10% to 8%, indicating that a fractional shortening of 32% measured centrally could be anywhere between 22% and 40% when measured locally. Central measurements of mean septal thickness were approximately 0.1 cm thicker than local ones (95% PI, -0.18 to 0.34 cm). Centrally measured wall thickness was more closely related to mortality and possibly was more valid than local measurements. CONCLUSIONS: Although LV dimension was reliably measured, local measurements of LV wall thickness and fractional shortening differed from central measurements.

Dilation of the aortic root in children infected with human immunodeficiency virus type 1: The Prospective P2C2 HIV Multicenter Study.

BACKGROUND: Vascular lesions have become more evident in human immunodeficiency virus type 1 (HIV)-infected patients as the result of earlier diagnosis, improved treatment, and longer survival. Aortic root dilation in HIV-infected children has not previously been described. This study was undertaken to determine the prevalence of aortic root dilation in HIV-infected children and to evaluate some of the potential pathogenic mechanisms. METHODS: Aortic root measurements were incorporated into the routine echocardiographic surveillance of 280 children of HIV-infected women: an older cohort of 86 HIV-infected children and a neonatal cohort of 50 HIV-infected and 144 HIV-uninfected children. RESULTS: By repeated-measures analyses, mean aortic root measurements were significantly increased in HIV-infected children versus HIV-uninfected children (P values of < or =.04 and < or =.005 at 2 and 5 years of age, respectively, for aortic annulus diameter, sinuses of Valsalva, and sinotubular junction). Heart rate, systolic blood pressure, stroke volume, hemoglobin, and hematocrit were not significantly associated with aortic root size. Left ventricular dilation, increased serum HIV RNA levels, and lower CD4 cell count measurements were associated with aortic root dilation at baseline. CONCLUSIONS: Mild and nonprogressive aortic root dilation was seen in children with vertically transmitted HIV infection from 2 to 9 years of age. Aortic root size was not significantly associated with markers for stress-modulated growth; however, aortic root dilation was associated with left ventricular dilation, increased viral load, and lower CD4 cell count in HIV-infected children. As prolonged survival of HIV-infected patients becomes more prevalent, some patients may require long-term follow-up of aortic root size.

Pathogenesis of HIV-associated cardiovascular complications.

Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults. The introduction of HAART regimens has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV-infected people expected. However, early data raised concerns about HAART being associated with an increase in both peripheral and coronary arterial diseases. In this review we discuss HIV-associated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era.

Epidemiology of cardiovascular involvement in HIV disease and AIDS.

The epidemiology of cardiac complications related to HIV including cardiomyopathy, increased left ventricular mass, myocarditis, pericardial effusion, endocarditis, and malignancy are discussed. A large number of HIV-infected individuals will present with cardiac complications in the next decade as chronic viral infection, co-infections, drug therapy, and immunosuppression affect the heart. Understanding the nature and course of cardiac illness related to HIV infection will allow appropriate monitoring, early intervention and therapy, and will provide a baseline to evaluate the effects of new therapeutic regimens such as highly active antiretroviral therapy on the cardiovascular system.

Cardiac manifestations of HIV infection in infants and children.

Cardiac manifestations of HIV infection in children are common, but etiologies, contributing factors, and the natural history are largely unexplored. The Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted Human Immunodeficiency Virus Infection Study (P2C2 HIV Study) was initiated in 1989 by the National Heart, Lung and Blood Institute, USA. A primary objective of this study is to examine the epidemiology of cardiovascular problems associated with HIV infection in a cohort of children vertically infected. Findings of the study thus far show that cardiovascular problems associated with HIV infection including left ventricular dysfunction and increased left ventricular mass are common and clinically important indicators of survival for children infected with HIV.

Cardiovascular monitoring and therapy for HIV-infected patients.

Cardiovascular complications are important contributors to morbidity and mortality in HIV-infected patients. These complications can usually be detected at subclinical levels with monitoring, which can help guide targeted interventions. This article reviews available data on types and frequency of cardiovascular manifestations in HIV+ patients and proposes monitoring strategies aimed at early subclinical detection. In particular, we recommend routine echocardiography for HIV+ patients, even those with no evidence of cardiovascular disease. We also review preventive and therapeutic cardiovascular interventions. For procedures that have not been studied in HIV+ patients, we extrapolate from evidence-based guidelines for the general population.

Pathogenesis of HIV-associated cardiomyopathy.

Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) regimens have tracked the incidence and course of human immunodeficiency virus (HIV) infection in relation to cardiac illness in both children and adults. HAART regimens have significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV+ subjects expected. However, early data raised concerns about HAART's being associated with an increase in both peripheral and coronary arterial diseases. A variety of potential etiologies have been postulated in HIV-related heart disease, including myocardial infection with HIV itself, opportunistic infections, viral infections, autoimmune response to viral infection, drug-related cardiotoxicity, nutritional deficiencies, and prolonged immunosuppression. In this review article we discuss HIV-associated cardiovascular complications, focusing on pathogenetic mechanisms that may play a role in diagnosis, management, and therapy of these complications.

Non-invasive assessment of rejection in pediatric transplant patients: serologic and echocardiographic prediction of biopsy-proven myocardial rejection.

BACKGROUND: Cardiac allograft rejection is a multifocal immune process that is currently assessed using biopsy-guided histologic classification systems (International Society for Heart and Lung Transplantation). Cardiac troponin T and I are established serologic markers of global myocyte damage. The use of load-independent measures of contractility have also been shown to accurately assess the presence of ventricular dysfunction. Little is known about their utility in accurately predicting rejection in the pediatric age group. We undertook the present study to compare rejection grade with echocardiographic and serologic estimates of transplant rejection-related myocardial damage. METHODS: We compared histologic rejection grades (0 to 4) with patient characteristics, echocardiographic measurements, catheterization measurements, and biochemical markers for 86 evaluations in 37 transplant recipients at Children's Hospital. RESULTS: In univariate analyses, biopsy scores correlated (p < 0.05) inversely with left ventricular systolic function (shortening fraction) and contractility (stress velocity index, SVI), and directly with mitral E-wave amplitude. In multivariate analyses, lower contractility and higher mitral E-wave amplitude remained significantly (p < or = 0.01) associated with rejection (SVI, p = 0.002, odds ratio = 0.393; E wave, p = 0.0002, odds ratio = 228). Most rejection episodes were associated with elevation of biochemical markers of myocardial injury. Although troponin I was weakly associated with differences between rejection grades (p = 0.034), troponin T, creatine kinase-MB fraction, and C-reactive protein did not differ with biopsy-rejection scores. Serum markers had a poor predictive capacity for biopsy-detected rejection. Troponin T and I did correlate with increased left ventricular wall thickness and mass. CONCLUSION: Progressively depressed left ventricular contractility and diastolic function are found with worsening pediatric heart transplant rejection-biopsy score; however, sensitive and specific serum markers do not correspond to the degree of active myocardial injury. The use of echocardiographic measures of contractility is associated with a specificity of 91.8% but low sensitivity of 66.7%. Overall we found poor concordance between serum markers and grade of rejection. It is unclear whether myocardial injury as assessed by serum markers, echocardiography, or histologic scoring is more important for assessment of acute rejection or long-term outcome, but it does not appear that serum and tissue markers of rejection can be used interchangeably.

Cardiac structure and function in fetuses of mothers infected with HIV: the prospective PCHIV multicenter study.

BACKGROUND: This study was designed to determine if vertically transmitted HIV infection and maternal infection with HIV are associated with altered cardiovascular structure and function in utero. METHODS: Fetal echocardiography was performed in 173 fetuses of 169 HIV-infected mothers (mean gestational age, 33.0 weeks; SD = 3.7 weeks) at 5 centers. Biparietal diameter, femur length, cardiovascular dimensions, and Doppler velocities through atrioventricular and semilunar valves and the umbilical artery were measured. Measurements were converted to z scores based on published normal data. RESULTS: Fetuses determined after birth to be HIV-infected had similar echocardiographic findings as fetuses later determined to be HIV-uninfected except for slightly smaller left ventricular diastolic dimensions (P =.01). The femur length (P =.03) was also smaller in the fetuses postnatally identified as HIV-infected. Differences in cardiovascular dimensions and Doppler velocities were identified between fetuses of HIV-infected women and previously published normal fetal data. The reason for the differences may be a result of maternal HIV infection, maternal risk factors, or selection bias in the external control data. CONCLUSIONS: Vertically transmitted HIV infection may be associated with reduced left ventricular size but not with altered cardiac function in utero. Fetuses of HIV-infected mothers may have abnormal cardiovascular structure and function and increased placental vascular resistance, regardless of whether the fetuses are subsequently found to be infected with HIV.

Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group.

BACKGROUND: Perinatal exposure to zidovudine may cause cardiac abnormalities in infants. We prospectively studied left ventricular structure and function in infants born to mothers infected with the human immunodeficiency virus (HIV) in order to determine whether there was evidence of zidovudine cardiac toxicity after perinatal exposure. METHODS: We followed a group of infants born to HIV-infected women from birth to five years of age with echocardiographic studies every four to six months. Serial echocardiograms were obtained for 382 infants without HIV infection (36 with zidovudine exposure) and HIV-58 infected infants (12 with zidovudine exposure). Repeated-measures analysis was used to examine four measures of left ventricular structure and function during the first 14 months of life in relation to zidovudine exposure. RESULTS: Zidovudine exposure was not associated with significant abnormalities in mean left ventricular fractional shortening, end-diastolic dimension, contractility, or mass in either non-HIV-infected or HIV-infected infants. Among infants without HIV infection, the mean fractional shortening at 10 to 14 months was 38.1 percent for those never exposed to zidovudine and 39.0 percent for those exposed to zidovudine (mean difference, -0.9 percent; 95 percent confidence interval, -3.1 percent to 1.3 percent; P=0.43). Among HIV-infected infants, the mean fractional shortening at 10 to 14 months was similar in those never exposed to zidovudine (35.4 percent) and those exposed to the drug (35.3 percent) (mean difference, 0.1 percent; 95 percent confidence interval, -3.7 percent to 3.9 percent; P=0.95). Zidovudine exposure was not significantly related to depressed fractional shortening (shortening of 25 percent or loss) during the first 14 months of life. No child over the age of 10 months had depressed fractional shortening. CONCLUSIONS: Zidovudine was not associated with acute or chronic abnormalities in left ventricular structure or function in infants exposed to the drug in the perinatal period.

Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: a prospective assessment.

OBJECTIVE: To examine the cardiac toxicity as measured by elevations in serum cardiac troponin T (cTnT) and to compare creatine kinase (CK) and creatine kinase MB (CK-MB) and findings on electrocardiography (ECG) as markers of cardiac toxicity with cTnT during the infusion of intravenous terbutaline for the treatment of severe asthma in children. STUDY DESIGN: Prospective cohort study of patients receiving intravenous terbutaline for severe asthma. RESULTS: Only 3 (10%) of the 29 patients had elevations in cTnT. Each underwent mechanical ventilation for >72 hours, which was the earliest point at which cTnT elevations were identified. Eighteen (62%) patients had an elevation in CK, and 3 had an elevation in CK-MB fraction without an elevated cTnT. Twenty (69%) patients had ECG findings consistent with ischemia, and 19 of these patients had the ischemic findings on their preterbutaline ECG. Elevations in CK and CK-MB and ischemic changes on ECG did not correlate with elevations in cTnT. Both mechanical ventilation (P =.02) and prolonged administration (>72 hours) of intravenous terbutaline (P =. 02) were significantly associated with elevations in cTnT. CONCLUSIONS: We found no clinically significant cardiac toxicity from the use of intravenous terbutaline for severe asthma as measured by serum cTnT elevations.

Electrocardiography and 24-hour electrocardiographic ambulatory recording (Holter monitor) studies in children infected with human immunodeficiency virus type 1. The Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV-1 Infection Study Group.

Limited data are available on the electrocardiogram and ambulatory electrocardiogram recording (Holter) in children infected with the human immunodeficiency virus type 1 (HIV-1). The purpose of this study was to estimate the prevalence and cumulative incidence of rhythm and conduction abnormalities in HIV-1-infected children. Electrocardiograms and Holter monitoring studies were performed annually on 205 HIV-1-infected children enrolled after 28 days of life (group I), 93 HIV-1-infected infants enrolled during pregnancy or during the first 28 days of life (group IIa), and 463 HIV-1-uninfected infants enrolled during pregnancy or during the first 28 days of life (group IIb). The 5-year cumulative incidence in the group I children of second-degree atrioventricular block or supraventricular or ventricular tachycardia was 13.4%, and the 5-year incidence was higher for the older infected group I children (16.8% for children > or =4 years old at first study and 11.4% for children <4 years, p = 0.04). The mean corrected QT interval was also longer for the older infected group I children (p = 0.002) and prolonged in the HIV-1-infected compared to the HIV-1-uninfected group II children (p = 0.02). None of the children had atrial fibrillation or flutter. Arrhythmias are uncommon in children infected with HIV-1 and in children of HIV-1-infected mothers and the arrhythmias identified tend to be benign. Therefore, routine Holter monitoring does not appear to be indicated in asymptomatic children.