Mark D. Schluchter

Left Ventricular Structure and Function in Children Infected With Human Immunodeficiency Virus The Prospective P2C2 HIV Multicenter Study

BACKGROUND The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood. METHODS AND RESULTS A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area-adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up. CONCLUSIONS Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.

Inotropic effects of angiotensin II on human cardiac muscle in vitro.

The direct effects of angiotensin II (Ang II) on human cardiac muscle were investigated using isolated trabecular muscles from failing and functionally normal hearts. Atrial and ventricular trabeculae were studied. Results demonstrated a positive inotropic effect of Ang II on human cardiac muscle. Comparison of the effects of Ang II among groups indicated that the responsiveness tended to be greater in atrial and normal muscle compared with failing muscle. Results of this study also demonstrated heterogeneity in the responsiveness to Ang II among human muscles, which was not correlated with patient age, sex, diagnosis, prior treatment with angiotensin converting enzyme inhibitor, or heart function. A significant correlation between response to Ang II and response to isoproterenol was demonstrated in failing ventricular trabeculae, which may suggest that defects in beta-adrenergic responsiveness in the failing human ventricle are accompanied by a loss of responsiveness to Ang II. Studies were extended to the Syrian cardiomyopathic hamster and its control. A dose-dependent inotropic response occurred in normal hamster ventricular muscle but was significantly diminished in cardiomyopathic muscle. Ang II did not shorten the timing of contraction, and pretreatment with adrenergic-blocking agents did not shift the dose-response curve, indicating that the response was not cyclic AMP mediated. This study demonstrates for the first time that Ang II can exert an inotropic effect directly on human cardiac muscle and confirms that there is a direct effect of Ang II on hamster cardiac muscle. The study further suggests, however, that the inotropic response to Ang II in cardiac muscle is heterogeneous and may be diminished by heart failure.

Small-sample adjustments to tests with unbalanced repeated measures assuming several covariance structures

Recent advances in methods for analysis of longitudinal data arid incomplete repeated measures have been in the area of maximum likelihood (ML) and restricted maximum likelihood (REML) methods (e.g., Laird and Ware, 1982 Biometrics, Jennrich and Schluchter, 1986 Biometrics). This paper outlines the ML and REML approaches to the analysis of incomplete repeated measures data and growth curves, and then examines methods for small-sample adjustment of asymptotic Wald-type chi-square tests constructed from ML and REML estimates under four different assumed covariance structures. These adjustments involve transformation of the Wald Ghi-square statistic to an approximate F-statistic. In certain cases when data are complete and balanced, the transformed test statistics have exact F-distribution under the null hypothesis. The first three covariance structures: (1) Compound Symmetry, (2) First-Order Autoregressive, and (3) Multivariate (unstructured), are examined in the context of the analysis of a repeated measur...

Cardiovascular status of infants and children of women infected with HIV-1 (P2C2 HIV): a cohort study

BACKGROUND Data from cross-sectional and short-term longitudinal studies have suggested that children infected with HIV-1 might have cardiovascular abnormalities. We aimed to investigate this hypothesis in a long-term cohort study. METHODS We measured cardiovascular function every 4-6 months for up to 5 years in a birth cohort of 600 infants born to women infected with HIV-1. We included 93 infants infected with HIV-1 and 463 uninfected infants (internal controls) from the same cohort. We also included a cross-sectionally measured comparison group of 195 healthy children born to mothers who were not infected with HIV-1 (external controls). FINDINGS Children infected with HIV-1 had a significantly higher heart rate at all ages (mean difference 10 bpm, 95% CI 8-13) than internal controls. At birth, both cohort groups of children had similar low left ventricular (LV) fractional shortening. At 8 months, fractional shortening was similar in internal and external controls, whereas in children infected with HIV-1, fractional shortening remained significantly lower than in controls for the first 20 months of life (mean difference from internal controls at 8 months 3.7%, 2.3-5.1). LV mass was similar at birth in both cohort groups, but became significantly higher in children with HIV-1 from 4-30 months (mean difference 2.4 g at 8 months, 0.9-3.9). CONCLUSIONS Vertically-transmitted HIV-1 infection is associated with persistent cardiovascular abnormalities identifiable shortly after birth. Irrespective of their HIV-1 status, infants born to women infected with HIV-1 have significantly worse cardiac function than other infants, suggesting that the uterine environment has an important role in postnatal cardiovascular abnormalities.

Reliability of Multicenter Pediatric Echocardiographic Measurements of Left Ventricular Structure and Function The Prospective P2C2 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 ≈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.

Sensitivity and Specificity of the Tilt Table Test in Young Patients with Unexplained Syncope

The usefulness of the head‐up tilt testing (HUT) has heen previously addressed in diagnosing vasovagal neuroregulatory syncope in the teenage population. However, data concerning sensitivity and specificity is deficient due to the lack of control groups. We compared the response to HUT in young patients referred because of syncope or near syncope (n = 44, mean age 16 ± 3 years SD) to healthy young volunteers with a normal physical examination and no previous history of syncope (n = 18, mean age 16 ± 2 years) and io determine the sensitivity and specificity of HUT. The graded tilt protocol was performed at 15°, 30°, and 45° (each for 2 min), and then 60° for 20 minutes. Cuff blood pressure was measured every minute and lead IIECG was continuously monitored. Results; 25 of the 44 patients (57%) developed a vasovagaJ response or became symptomatic after 13.8 ± 5.7 minutes of HUT. Three of the 18 volunteers (17%) had a vasovagal response and became symptomatic after 9 ± 3 minutes of HUT. There was no statistical difference among the four groups (with and without tilt induced vasovagal response) in terms of age and baseline hemodynamic data. The sensitivity of 20 minutes HUT was 57% and its specificity was 83%. The presyncopal hemodynamic response in patients with history of syncope that was characterized by a significant decrease in systolic blood pressure and lack of increase of diastolic blood pressure as compared with baseline and with other groups. Gonclusions: 20 minutes at 60° HUT has a high specificity for the diagnosis of vasovagal syncope. Its limited sensitivity is counterbalanced by the advantage of limiting the incidence of false‐positive results in patients without the vasovagal syndrome.

Cardiac complications in children with human immunodeficiency virus infection. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group, National Heart, Lung, and Blood Institute.

Objective. Although numerous cardiac abnormalities have been reported in HIV-infected children, precise estimates of the incidence of cardiac disease in these children are not well-known. The objective of this report is to describe the 2-year cumulative incidence of cardiac abnormalities in HIV-infected children. Methodology: Design. Prospective cohort (Group I) and inception cohort (Group II) study design. Setting. A volunteer sample from 10 university and public hospitals. Participants. Group I consisted of 205 HIV vertically infected children enrolled at a median age of 22 months. This group was comprised of infants and children already known to be HIV-infected at the time of enrollment in the study. Most of the children were African-American or Hispanic and 89% had symptomatic HIV infection at enrollment. The second group included 611 neonates born to HIV-infected mothers, enrolled during fetal life or before 28 days of age (Group II). In contrast to the older Group I children, all the Group II children were enrolled before their HIV status was ascertained. Interventions. According to the study protocol, children underwent a series of cardiac evaluations including two-dimensional echocardiogram and Doppler studies of cardiac function every 4 to 6 months. They also had a 12- or 15-lead surface electrocardiogram (ECG), 24-hour ambulatory ECG monitoring, and a chest radiograph every 12 months. Outcome Measures. Main outcome measures were the cumulative incidence of an initial episode of left ventricular (LV) dysfunction, cardiac enlargement, and congestive heart failure (CHF). Because cardiac abnormalities tended to cluster in the same patients, we also determined the number of children who had cardiac impairment which we defined as having either left ventricular fractional shortening (LV FS) ≤25% after 6 months of age, CHF, or treatment with cardiac medications. Results: Cardiac Abnormalities. In Group I children (older cohort), the prevalence of decreased LV function (FS ≤25%) was 5.7% and the 2-year cumulative incidence (excluding prevalent cases) was 15.3%. The prevalence of echocardiographic LV enlargement (LV end-diastolic dimension z score >2) at the time of the first echocardiogram was 8.3%. The cumulative incidence of LV end-diastolic enlargement was 11.7% after 2 years. The cumulative incidence of CHF and/or the use of cardiac medications was 10.0% in Group I children. There were 14 prevalent cases of cardiac impairment (LV FS ≤25% after 6 months of age, CHF, or treatment with cardiac medications) in Group I. After excluding these prevalent cases, the 2-year cumulative incidence of cardiac impairment was 19.1% among Group I children and 80.9% remained free of cardiac impairment after 2 years of follow-up. Within Group II (neonatal cohort), the 2-year cumulative incidence of decreased LV FS was 10.7% in the HIV-infected children compared with 3.1% in the HIV-uninfected children. LV dilatation was also more common in Group II infected versus uninfected children (8.7% vs 2.1%). The cumulative incidence of CHF and/or the use of cardiac medications was 8.8% in Group II infected versus 0.5% in uninfected subjects. The 1- and 2-year cumulative incidence rates of cardiac impairment for Group II infected children were 10.1% and 12.8%, respectively, with 87.2% free of cardiac impairment after the first 2 years of life. Mortality. In the Group I cohort, the 2-year cumulative death rate from all causes was 16.9% [95% CI: 11.7%–22.1%]. The 1- and 2-year mortality rates after the diagnosis of CHF (Kaplan-Meier estimates) were 69% and 100%, respectively. In the Group II cohort, the 2-year cumulative death rate from all causes was 16.3% [95% CI: 8.8%–23.9%] in the HIV-infected children compared with no deaths among the 463 uninfected Group II children. Two of the 4 Group II children with CHF died during the 2-year observation period and 1 more died within 2 years of the diagnosis of CHF. The 2-year mortality rate after the diagnosis of CHF was 75%. Conclusions. This study reports that in addition to subclinical cardiac abnormalities previously reported by the P2C2 Study Group, an important number of HIV-infected children develop clinical heart disease. Over a 2-year period, approximately 10% of HIV-infected children had CHF or were treated with cardiac medications. In addition, approximately 20% of HIV-infected children developed depressed LV function or LV dilatation and it is likely that these abnormalities are hallmarks of future clinically important cardiac dysfunction. Cardiac abnormalities were found in both the older (Group I) as well as the neonatal cohort (Group II) (whose HIV infection status was unknown before enrollment) thereby minimizing potential selection bias based on previously known heart disease. Based on these findings, we recommend that clinicians need to maintain a high degree of suspicion for heart disease in HIV-infected children. All HIV-infected infants and children should have a thorough baseline cardiac evaluation. Patients who develop symptoms of heart or lung disease should undergo more detailed cardiac examinations including ECG and cardiac ultrasound.

Log-linear analysis of censored survival data with partially observed covariates

Abstract Log-linear models provide a flexible means of extending life table techniques for the analysis of censored survival data with categorical covariates, as discussed by Holford (1980) and Laird and Olivier (1981). We extend this methodology to incorporate cases in which one or more of the categorical covariates are sometimes missing. Maximum likelihood estimates of the parameters are calculated using data from all cases. This can result in large gains in efficiency over standard methods that require the exclusion of cases with incomplete data. With this approach, we assume that the hazard function, conditional on the covariates, is a stepwise function over disjoint intervals of time. The model has two parts: a log-linear model describing the hazard parameters, and a multinomial model describing the probabilities in the contingency table defined by the covariates. The main interest is in the model for the hazard parameters. We show how to calculate maximum likelihood estimates of parameters of the mo...

Chest radiographic data acquisition and quality assurance in multicenter studies

Background. Multicenter studies rely on data derived from different institutions. Forms can be designed to standardize the reporting process allowing reliable comparison of data. Objective. The purpose of the report is to provide a standardized method, developed as a part of a multicenter study of vertically transmitted HIV, for assessing chest radiographic results. Materials and methods. Eight hundred and five infants and children were studied at five centers; 3057 chest radiographs were scored. Data were entered using a forced-choice, graded response for 12 findings. Quality assurance measures and inter-rater agreement statistics are reported. Results. The form used for reporting chest radiographic results is presented. Inter-rater agreement was moderate to high for most findings, with the best correlation reported for the presence of bronchovascular markings and/or reticular densities addressed as a composite question (kappa = 0.71). The presence of nodular densities (kappa = 0.56) and parenchymal consolidation (kappa = 0.57) had moderate agreement. Agreement for lung volume was low. Conclusion. The current tool, developed for use in the pediatric population, is applicable to any study involving the assessment of pediatric chest radiographs for a large population, whether at one or many centers.

HIV Vertical Transmission Rate Determinations Are Subject to Differing Definitions and Therefore Different Rates

The HIV infection status of a cohort of 600 prospectively followed children born to HIV infected mothers was determined using HIV peripheral blood culture tests at 0, 3, and 6 months of age, HIV serology at > or = 15 months, and CDC AIDS criteria. We estimated transmission rates using five methods which differed in how HIV indeterminates are handled. These methods were applied at two points in time to illustrate effects of length of follow-up of the cohort on results. In January 1997, 30 months after the last birth, transmission rate estimates ranged from 15.5% (known positives/known positives x known negatives) to 18.1% (known positives x those with one positive culture x deaths/entire cohort minus those lacking negative cultures at age > or = 5 months). Estimates ranged from 14.8% to 20.7% using the subcohort of 284 children followed > or = 12 months as of May 1993. These results indicate that methods for assigning HIV infection status and for handling HIV indeterminates should be carefully defined when estimating transmission rates.