Douglas S. Moodie

Absence of Cardiac Toxicity of Zidovudine in Infants

Background Some evidence suggests that 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 58 HIV-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, contract...

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.

Marfan's syndrome: natural history and long-term follow-up of cardiovascular involvement

A retrospective analysis was undertaken to define the natural history and long-term follow-up of a group of patients with Marfans syndrome. Eighty-four patients were diagnosed between January 1959 and June 1987 as having Marfans syndrome; 68% were male; their ages ranged from 2 to 67 years (mean 26.6). Sixteen patients constituted the early surgical group (those who underwent surgery before 1979; mean age 36.1 years). Nineteen patients constituted the late surgical group (surgery in 1979 or later; mean age 33.3 years). The nonsurgical group comprised 49 patients (mean age 19.3 years). Fifty-seven percent of the patients had a diastolic murmur and 38% had cardiomegaly at presentation. Fifty-seven percent underwent cardiac catheterization, which revealed aortic root dilation (85%), aortic regurgitation (73%), aortic dissection (33%) and mitral regurgitation (36%). Thirteen of the 19 patients in the late surgical group received a composite graft repair of the ascending aorta as compared with only 2 of the 16 in the early surgical group. Follow-up information was obtained on 81 (96%) of 84 patients; the follow-up time was 2 to 332 months (mean 99). Thirty-one of the 81 patients died at age 3 to 63 years (mean age 35 years); 87% of the known causes of death were related to the cardiovascular system. Sixty-one percent of deaths were the result of aortic dissection or rupture or sudden cardiac death. Of the 50 survivors, 98%, including all patients in the late surgical group, were in functional class I or II. Overall survival at 5, 10 and 15 years after operation was 78.4%, 57.1% and 49.5%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Dysfunction and Mortality in HIV-Infected Children The Prospective P2C2 HIV Multicenter Study

BackgroundLeft ventricular (LV) dysfunction is common in children infected with the human immunodeficiency virus (HIV), but its clinical importance is unclear. Our objective was to determine whether abnormalities of LV structure and function independently predict all-cause mortality in HIV-infected children. Methods and ResultsBaseline echocardiograms were obtained on 193 children with vertically transmitted HIV infection (median age, 2.1 years). Children were followed up for a median of 5 years. Cox regression was used to identify measures of LV structure and function predictive of mortality after adjustment for other important demographic and baseline clinical risk factors. The time course of cardiac variables before mortality was also examined. The 5-year cumulative survival was 64%. Mortality was higher in children who, at baseline, had depressed LV fractional shortening (FS) or contractility; increased LV dimension, thickness, mass, or wall stress; or increased heart rate or blood pressure (P ≤0.02 for each). Decreased LV FS (P <0.001) and increased wall thickness (P =0.004) were also predictive of increased mortality after adjustment for CD4 count (P <0.001), clinical center (P <0.001), and encephalopathy (P <0.001). FS showed abnormalities for up to 3 years before death, whereas wall thickness identified a population at risk only 18 to 24 months before death. ConclusionsDepressed LV FS and increased wall thickness are risk factors for mortality in HIV-infected children independent of depressed CD4 cell count and neurological disease. FS may be useful as a long-term predictor and wall thickness as a short-term predictor of mortality.

Long-term function of the morphologic right ventricle in adult patients with corrected transposition of the great arteries

Because of the concern about the ability of the morphologic right ventricle (MRV) to function over a long term as a systemic ventricle, adult patients with congenitally corrected transposition of the great arteries (CCTGA) were evaluated to determine the long-term function of the MRV. Morphologic right ventricular function was assessed by functional clinical classification and angiographic ejection fraction in 18 adult patients with congenitally corrected transposition of the great arteries. These patients had a mean age of 30.2 +/- 14.5 years (range 10 to 67 years). All but one had hemodynamically significant lesions, the most common being left atrioventricular valve regurgitation (11 patients), ventricular septal defect (seven patients), atrial septal defect (four patients), and pulmonic stenosis (three patients). The mean MRV ejection fraction at presentation was 55% +/- 11.5% (range 24% to 74%). Twelve of the 18 patients (67%) were followed clinically, with a mean follow-up time of 9.9 +/- 7.1 years (range 1 to 22 years). Eight were reassessed angiographically, with a mean MRV ejection fraction of 51.3% +/- 10.7% (range 30% to 67%). The other four were followed up clinically and evaluated by two-dimensional echocardiography, with normal MRV function in two patients. Eight of 12 patients (67%) were in functional class I at follow-up, one was in functional class II, one was in functional class III, and two had died. Our data suggest that the morphologic right ventricle can function appropriately over a long term in adult patients with congenitally corrected transposition of the great arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Chest Pain in Pediatric Patients Presenting to a Cardiac Clinic

Records of 67 pediatric patients with a primary complaint of chest pain were reviewed to determine the frequency of associated cardiac disease. Only four of 67 (6%) had chest pain associated with cardiac diseases that usually cause chest pain. Fifty-seven (85%) patients had chest pain in which no clear cause could be determined. Of these 57, 20 patients also had isolated congenital cardiac anomalies, i.e., atrial septal defect. A causal relationship of these lesions to the chest pain could not be established. Thirty-four of the 37 patients with chest pain and no cardiac abnormalities were evaluated by telephone at a mean of 13 months after their clinic assessment. Twenty-nine of the 34 were either asymptomatic or had reduced symptoms. There was no correlation between duration of symptoms prior to their clinical study and the persistence of chest pain at follow-up. From this study, we conclude that chest pain in pediatric patients is infrequently due to cardiac disease even when associated with previously unsuspected, isolated congenital cardiac lesions. Idiopathic chest pain tends to be self-limited.

Cystic medial necrosis of the aorta in patients without Marfan's syndrome: Surgical outcome and long-term follow-up

A retrospective analysis was performed to determine the surgical outcome and long-term follow-up of patients with documented cystic medial necrosis of the aorta. Ninety-three patients were diagnosed as having cystic medial necrosis at the Cleveland Clinic between July 1963 and December 1987 (72% men aged 26 to 77 years, mean 55). Patients who met the standard diagnostic criteria for Marfans syndrome were deliberately excluded. Sixty-eight percent of the patients had a diastolic murmur and chest roentgenogram revealed a dilated aortic arch in 58% and cardiomegaly in 63%. Cardiac catheterization in 76 patients demonstrated aortic root dilation in 78%, aortic regurgitation in 72%, aortic dissection in 32% and coronary artery disease in 32%. Ninety patients underwent surgery including composite graft repair with reimplantation of the coronary arteries in 34%. Follow-up, obtained on 90 (97%) of the 93 patients, ranged in duration from 0 to 137 months (mean 29). Thirty-four of the 90 patients died (age range 30 to 75 years, mean 60). Ninety-four percent of the known causes of death were related to the cardiovascular system; 65% were the result of aortic dissection or rupture or sudden death. Ninety-six percent of survivors were in New York Heart Association functional class I or II. Overall estimated survival at 1, 3 and 5 years was 72.2%, 63.5% and 57.4%, respectively. Actuarial survival in patients who underwent composite graft reconstruction was 84% at 5 years. The presence of a diastolic murmur at initial presentation was associated with a poor prognosis (p = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

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.