Cardiac Dysfunction and Mortality in

HIV-Infected Children
The Prospective P2C2 HIV Multicenter Study
Steven E. Lipshultz, MD; Kirk A. Easley, MS; E. John Orav, PhD; Samuel Kaplan, MD;
Thomas J. Starc, MD, MPH; J. Timothy Bricker, MD; Wyman W. Lai, MD, MPH;
Douglas S. Moodie, MD; George Sopko, MD, MPH; Steven D. Colan, MD; for the Pediatric
Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P2C2 HIV) Study Group

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
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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
(P0.02 for each). Decreased LV FS (P0.001) and increased wall thickness (P0.004) were also predictive of
increased mortality after adjustment for CD4 count (P0.001), clinical center (P0.001), and encephalopathy
(P0.001). 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. (Circulation. 2000;102:1542-1548.)
Key Words: viruses mortality pediatrics AIDS

C hildren infected with the human immunodeficiency

virus (HIV) may develop a wide range of cardiovas-
cular abnormalities, some of which are known to be
associated with poor survival.13 In addition, we recently
reported that among HIV-infected children, baseline echo-
cardiographic abnormalities are common, persistent, and
often progressive.1
To determine the clinical value of baseline echocardio-
graphic findings as predictors of mortality, we studied chil-
dren with vertically transmitted HIV infection participating in
a National Heart, Lung, and Blood Institute study, Pediatric
Pulmonary and Cardiac Complications of Vertically Trans-
mitted HIV Infection (P2C2 HIV). We examined 9 echocar-
diographic measures of left ventricular (LV) structure and
function at enrollment to determine whether any abnormali-
ties predicted mortality after adjustment for demographic
variables and other risk factors. We also constructed longi-
tudinal profiles of the echocardiographic measurements to
determine how early the predictors could distinguish between
survivors and nonsurvivors.

Received August 5, 1999; revision received May 8, 2000; accepted May 8, 2000.
From the Division of Pediatric Cardiology (S.E.L.), University of Rochester Medical Center and Childrens Hospital at Strong and Department of
Pediatrics (S.E.L.), University of Rochester School of Medicine and Dentistry, Rochester, NY; Department of Cardiology (S.E.L., S.D.C.), Childrens
Hospital, Department of Pediatrics, Harvard Medical School (S.E.L., S.D.C.), Department of Pediatrics, Boston Medical Center and Boston University
School of Medicine (S.E.L.), and Department of Medicine, Brigham and Womans Hospital (E.J.O.), Boston, Mass; Department of Biostatistics and
Epidemiology (K.A.E.) and Department of Pediatrics, Division of Pediatric Cardiology (D.S.M.), Cleveland Clinic Foundation, Cleveland, Ohio;
Department of Pediatrics, Division of Pediatric Cardiology, University of California, Los Angeles Medical Center and School of Medicine, Los Angeles
(S.K.); Department of Pediatrics, Division of Pediatric Cardiology, Mt Sinai School of Medicine (W.W.L.), and Department of Pediatrics, Division of
Pediatric Cardiology, Presbyterian Hospital/Columbia University College of Physicians and Surgeons (T.J.S.), New York, NY; Department of Pediatrics,
Division of Pediatric Cardiology, Baylor College of Medicine, Houston, Tex (J.T.B.); and the National Heart, Lung, and Blood Institute, Bethesda, Md
(G.S.).
Guest Editor for this article was David A. Sahn, MD, Oregon Health Sciences University, Portland.
Correspondence to Dr Steven E. Lipshultz, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Ave, Box 631,
Rochester, NY 14642. E-mail steve_lipshultz@urmc.rochester.edu
2000 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

1542
 Lipshultz et al
Methods
We have previously described the P2C2 HIV study, a natural history
study of cardiac and pulmonary complications of vertically transmit-
ted HIV infection at 5 clinical centers (10 hospitals) in different parts
of the United States.4 Although 2 prospective cohorts of HIV-
infected children were included in the study design, this report is
limited to the older HIV-infected cohort (group 1). Briefly, 205
group 1 children 28 days old with documented maternally trans-
mitted HIV infection were enrolled between May 1990 and April
1993. Recruitment of patients occurred in pediatric clinics (hospital-
based and non hospital-based) and inpatient wards, resulting in a
sequential enrollment of all consenting patients. The protocol was
approved by the institutional review board at each center. Informed
consent was obtained from the patient, the parent, or the legal
guardian. Patient interval histories were obtained during visits to the
clinic or retrospectively from medical records. The other prospective
cohort consisted of 600 infants born to HIV-infected mothers
enrolled during pregnancy or before 28 days postpartum. They are
not included in the present article because the covariates measured at
birth are very different from those measured in a cohort of patients
who enroll at later ages and are mostly symptomatic.
All children underwent protocol-directed echocardiographic test-
ing every 4 months regardless of clinical status using Hewlett
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Packard 500, 1000, 1500, and Acuson 128 XP equipment. All
echocardiograms were centrally remeasured by 1 of 3 technicians
unaware of the clinical status of the patient. For each echocardio-
graphic study, children 4 years old were sedated if necessary. 2D
echocardiography and Doppler studies with stress-velocity analysis
were performed for each child.1 Afterload was measured as merid-
ional end-systolic LV wall stress. LV mass was calculated from the
M-mode measurements by the method of Devereux et al.5
Normative values for the echocardiographic measures according
to age or body surface area were developed from 285 healthy
children (these external control subjects were not part of the P2C2
HIV study) measured at the same central interpretation unit in the
same manner as the patients.1 To adjust for growth, z scores were
created for the HIV-infected children by taking each echocardio-
graphic measure, subtracting the age-appropriate or body surface
areaappropriate mean, and dividing by 1 SD. Therefore, a z score of
0 represents a measurement equal to the normal mean value for the
childs age or body surface area, whereas a z score of 2 represents
a measurement 2 SD below average. Age correction was used for
fractional shortening (FS), wall stresses, blood pressure, and heart
rate; body surface area correction was used for LV dimension,
end-diastolic posterior wall thickness, and mass.1
The prognostic variables were measured at the time of the initial
echocardiogram. Covariates were chosen because of prior work
suggesting that they were important for cardiovascular morbidity and
mortality.13 Baseline covariates were sex, race, clinical center, CD4
cell count z score, height and weight z scores,6 CDC HIV-disease
stage, encephalopathy, a diagnosis of Pneumocystis carinii pneumo-
nia, chest radiographic findings, any zidovudine exposure, and age at
initial echocardiogram. Baseline measures of cardiac function were
FS, end-diastolic dimension, end-systolic dimension, heart rate, LV
mass, end-systolic wall stress (afterload), wall thickness, contractil-
ity, and diastolic blood pressure. Each of the echocardiographic
parameters was dichotomized at 2 SD except FS (2 SD),
contractility (2 SD), and wall thickness (1 SD because too few
children exceeded 2 SD). An abnormal chest radiograph was defined
by the presence of nodular densities, reticular densities, parenchymal
consolidation, or increased bronchovascular markings. These radio-
graphs were read with a standardized tool7 at each center by a
pediatric radiologist unaware of the childs clinical status. CD4
lymphocyte counts were determined from the first available reading
within 6 months of the initial echocardiogram at laboratories using
AIDS Clinical Trials Group quality assurance protocols. z scores
were determined for CD4 counts8 and for height and weight6 and
were categorized as either 2 or 2. Serum was analyzed for
HIV-1 RNA concentration by quantitative HIV-1 RNA polymerase
chain reaction.9 The 1994 revised CDC classification system10 was
Cardiac Function and Pediatric HIV Mortality 1543
used to classify each child according to the most severe clinical HIV
stage up to the time of first echocardiogram.
Statistical Analyses
Cumulative survival was estimated with the Kaplan-Meier method.
Log-rank tests were used to compare survival according to baseline
clinical characteristics and baseline measures of cardiac function,
with groups defined by dichotomized z scores. Relative risks were
calculated to measure the degree of association between the baseline
cardiac function z scores and survival by fitting the Cox
proportional-hazards regression model separately for each baseline
echocardiographic measurement. The Spearman rank-order correla-
tion coefficient was used to determine the association between
echocardiographic parameters. All tests were 2-sided and unadjusted
for multiple comparisons. A value of P0.05 indicated statistical
significance.
Forward and backward stepwise selection were used to choose
prognostic variables for a Cox proportional-hazards regression
model, and both methods led to the same results. Only factors that
were significant at P0.05 in the univariable analyses were included
in the multivariable analyses. The relative risk and its 95% CI were
calculated for each factor in the presence of others in the final model.
Repeated-measures analyses were performed for each cardiac
function measurement and z score to examine the amount of time
before death that a predictor could discriminate children who died
from those who were still alive at the end of follow-up. For each
cardiac outcome, these analyses performed by SAS Proc Mixed
provided separate estimates of the mean and 95% CIs according to
vital status and time before the last echocardiogram or death.
Results
Patient Population
Of the 205 enrolled children, a central analysis of echocar-
diographic data was performed for 193 children, who consti-
tute the study cohort. The remaining 12 children were not
included because of inability to centrally remeasure the initial
echocardiogram (5 children, of whom 4 died and 1 was lost to
follow-up), 1 large atrial septal defect, pulmonary hyperten-
sion and wall motion abnormalities (2 children, 1 of whom
died), and absence of an echocardiogram (4 children, of
whom 2 died and 2 were lost to follow-up).
Most of the children were black (86 children) or Hispanic
(73 children), and only 22 children were asymptomatic before
the initial echocardiogram. The median age at the first
echocardiogram was 2.1 years and the median CD4 cell count
was 690/mm3 (median z score, 1.92 SD; the normal CD4
cell count for a 2-year-old was 2298/mm3).8 Table 1 shows
the cumulative survival, with 64 of the 193 study children
dying. The overall 5-year survival was 64% (95% CI, 56.6%
to 71.3%). The median length of follow-up for the 129
children alive at last contact was 60 months. Of the 27 lost to
follow-up, additional data on vital status were obtained for 21
children.
Univariable Predictors of Mortality
Survival was not affected by race or ethnicity, sex, age
category (0 to 1, 1 to 2, 2 to 4, 4 years), or chest radiograph
findings (Table 1). However, when a Cox model was used
with the actual noncategorized age, the association between
age and mortality was significant (P0.02). Survival was
lower for children who were short for age (P0.001) or
underweight for age (P0.001) at baseline. The presence of
encephalopathy and increasing severity of CDC symptoms at
 1544 Circulation September 26, 2000

TABLE 1. Cumulative Survival Among 193 HIV-Infected Children According to Baseline Clinical Characteristics
Deaths Cumulative Survival (%)SEM

Characteristic n n % 1y 5y P
All children 193 64 33.2 89.62.2 64.03.8
Sex
Male 89 31 34.8 92.12.9 62.95.5 0.70
Female 104 33 31.7 87.43.3 64.95.1
Race or ethnicity
White 28 6 21.4 96.43.5 76.48.7 0.20
Black 86 27 31.4 88.23.5 65.95.6
Hispanic 73 30 41.1 89.03.7 56.06.2
Other 6 1 16.7
Clinical center
1 28 14 50.0 78.67.8 52.29.7 0.02
2 38 8 21.1 92.14.4 78.16.9
3 40 19 47.5 87.25.4 45.29.1
4 34 11 32.4 91.24.9 66.78.2
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5 53 12 22.6 94.33.2 72.37.2

Age at initial echocardiogram, y
01 40 15 37.5 92.24.3 58.28.4 0.70
12 48 12 25.0 85.45.1 74.56.4
24 47 17 36.2 89.44.5 59.87.8
4 58 20 34.5 91.43.7 62.97.1
CD4 count z score within 6 mo of first echocardiogram
2 87 50 57.5 80.54.3 36.86.0 0.001
2 97 11 11.3 97.91.5 87.73.7
CDC symptom status before or at time of echocardiogram
Asymptomatic 22 5 22.7 100.0 77.310.2 0.001
A 32 3 9.4 100.0 89.26.0
B 36 8 22.2 94.43.9 75.27.7
C 103 48 46.6 82.43.8 49.35.4
Baseline encephalopathy before or at time of
echocardiogram
No 149 41 27.5 94.61.9 69.74.1 0.001
Yes 44 23 52.3 72.16.8 44.28.1
Height z score
2 53 26 49.1 75.06.0 46.97.5 0.001
2 140 38 27.1 95.01.9 70.34.2
Weight z score
2 39 25 64.1 74.47.0 33.28.1 0.001
2 154 39 25.3 93.42.0 72.14.0
Zidovudine before echocardiogram
No 57 13 22.8 100.0 74.56.2 0.03
Yes 136 51 37.5 85.13.1 59.54.6
P carinii pneumonia before echocardiogram
No 164 49 29.9 90.22.3 67.73.9 0.02
Yes 29 15 51.7 86.26.4 42.610.6
Chest radiograph findings within 6 mo of first
echocardiogram
Abnormal 61 24 39.3 93.33.2 53.67.4 0.28
Normal 121 36 29.8 88.42.9 70.04.4
 Lipshultz et al Cardiac Function and Pediatric HIV Mortality 1545

TABLE 2. Cumulative Survival Among 193 HIV-Infected Children According to Baseline

Echocardiographic Measurements
Deaths Cumulative Survival (%)SEM

Measurement z score n n % 1y 5y P
LV mass 2 165 43 26.1 92.72.0 70.63.9 0.001
2 24 20 83.3 66.79.6 20.08.4
End-diastolic dimension 2 176 50 28.4 92.02.1 69.03.8 0.001
2 17 14 82.4 64.711.6 14.19.0
End-systolic dimension 2 159 42 26.4 93.02.0 71.03.9 0.001
2 34 22 64.7 73.57.6 31.68.8
FS 2 56 32 57.1 73.06.0 38.17.3 0.001
2 137 32 23.4 96.31.6 74.44.1
Heart rate 2 152 44 29.0 92.72.1 68.34.1 0.006
2 41 20 48.8 78.06.5 47.98.5
Contractility 2 33 16 48.5 75.87.5 50.09.1 0.01
2 144 45 31.3 93.02.1 65.54.4
End-diastolic posterior wall thickness 1 159 47 29.6 91.12.3 68.43.9 0.02
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1 34 17 50.0 82.46.5 44.59.5

Afterload 2 141 42 29.8 92.92.2 67.44.3 0.002
2 36 19 52.8 77.86.9 42.99.3
Diastolic blood pressure 2 173 53 30.6 91.32.2 67.33.8 0.003
2 17 11 64.7 70.611.1 33.111.8

baseline were both associated with higher mortality
(P0.001). Survival also differed among clinical centers
(P0.02). Other factors associated with lower cumulative
survival included suppressed CD4 cell counts (P0.001), a
history of zidovudine therapy (P0.03), and Pneumocystis
carinii pneumonia diagnosed before the initial echocardio-
gram (P0.02).
The relationship between mortality and baseline impaired
cardiac function is shown in Table 2 and Figure 1. Mortality
was higher in children with a depressed baseline FS
(P0.001). A similar pattern was noted for contractility
(P0.01). Mortality was also significantly higher for children
with increased end-diastolic dimension (P0.001), end-sys-
tolic dimension (P0.001), wall stress (P0.002), heart rate
(P0.006), LV mass (P0.001), end-diastolic posterior wall
thickness (P0.02 for 1 SD), or diastolic blood pressure
(P0.003).
Figure 1 illustrates the impact on cumulative survival of
each of the clinical and echocardiographic measures that are
also significant in the multivariable models described below.
Alternative analyses using Cox proportional-hazards models
separately for each echocardiographic measure as a continu-
ous z score produced similar results. An increased risk of
death per 1 SD change in z score occurred with increased LV
mass (relative risk, 1.84; P0.001), increased end-diastolic
dimension (relative risk, 1.69; P0.001), increased end-sys-
tolic dimension (relative risk, 1.68; P0.001), decreased FS
(relative risk, 1.39; P0.001), increased heart rate (relative
risk, 1.34; P0.001), increased wall thickness (relative risk,
1.29; P0.009), depressed contractility (relative risk, 1.30;
P0.001), and increased afterload (relative risk, 1.25;
P0.001). Survival was not affected by baseline diastolic
blood-pressure z scores when analyzed as a continuous
variable (P0.31).
Statistically significant associations were found between
FS and contractility (0.56), end-diastolic dimension
(0.31), end-systolic dimension (0.61), afterload
(0.63), and LV mass (0.31) at baseline. Wall
thickness and LV mass were also closely correlated at
baseline (0.45).
Multivariable Predictors of Mortality
Data were available for all covariates in 184 children (9
children who did not have a CD4 cell count within 6 months
of the baseline echocardiogram could not be included in the
analyses). A multivariable Cox model using stepwise selec-
tion was used to identify a subset of covariates as independent
risk factors for survival. CD4 count z score, clinical center,
encephalopathy, and age at initial echocardiography remained
significantly associated with survival. Factors that did not
remain significant included zidovudine exposure, P carinii
pneumonia, and continuous-weight z score.
After these significant nonechocardiographic covariates
had been included, the Cox model was refitted separately for
each echocardiographic z score. FS (P0.001), contractility
(P0.001), end-systolic dimension (P0.001), LV wall
thickness (P0.008), and LV mass (P0.007) remained
significant. Heart rate, afterload, and end-diastolic dimension
lost significance after adjustment for nonechocardiographic
covariates.
In the final model in Table 3, both decreased FS z score
(P0.001) and increased wall thickness z score (P0.004)
were independent prognostic risk factors of mortality after
adjustment for CD4 count z score (P0.001), encephalopathy
 1546 Circulation September 26, 2000
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Figure 1. Cumulative survival for 193 HIV-infected children according to baseline clinical characteristics and baseline echocardiograph-
ic measurements. A, CD4 cell count z score; B, encephalopathy; C, FS z score; D, LV mass z score; E, wall thickness z score; F, end-
diastolic dimension z score; G, end-systolic dimension z score; and H, contractility (stress-velocity index) z score.

(P0.001), and clinical center (center 1 versus center 5,
P0.001; center 3 versus center 5, P0.03). The adjusted
relative risk for FS was 1.31 per 1 SD drop, and for wall
thickness was 1.35 per 1 SD increase. Age, LV mass,
contractility, and dimension lost significance and were not
retained in the model. Because LV mass and wall thickness
were highly correlated, the model was also fitted with LV
mass instead of wall thickness; both FS (P0.001) and LV
mass (P0.04) were independently associated with survival
after adjustment for CD4 count, encephalopathy, and clinical
center. Likewise, the model was also fitted with LV contrac-
tility instead of FS; both wall thickness (P0.02) and
contractility (P0.006) were independently associated with
survival after adjustment for CD4 count, encephalopathy, and
clinical center.
High FS or contractility and low LV mass were found not
to be risk factors for death. However, we did find an additive
relationship between LV wall thickness and dimension.
Cumulative 5-year survival for the 18 children with elevated
(1 SD) ventricular dimension and elevated (0.5 SD) wall
thickness was 22.5%. In contrast, survival among the 100
children with normal dimension and thickness was 76.2%
(P0.001). Five-year survival was 64.2% among 40 children
with only increased thickness and 51.7% among 35 children
with only increased dimension.
In a subset of 157 patients for whom HIV RNA copy
number was available, decreased FS and increased wall
thickness z scores still remained significant predictors of
mortality after adjustment for HIV RNA copy number (ana-
lyzed on a logarithmic base 10 scale) (P0.04), CD4 cell

TABLE 3. Multivariable Analysis of Factors Associated With Survival for Children Infected With HIV
Effect Estimated Standard Error Relative Riskexp () 95% CI P
FS z score (per 1 SD decrease) 0.2704 0.0639 1.31 1.161.49 0.001
Wall thickness z score (per 1 SD increase) 0.2987 0.1029 1.35 1.101.65 0.004
CD4 count z score (per 1 SD decrease) 1.5029 0.2405 4.49 2.817.20 0.001
Encephalopathy (yes/no) 1.2312 0.3059 3.43 1.886.24 0.001
Clinical center 1 (1/5) 1.7995 0.3870 6.05 2.8312.91 0.001
Clinical center 3 (3/5) 0.7126 0.3354 2.04 1.063.94 0.03
 Lipshultz et al Cardiac Function and Pediatric HIV Mortality 1547
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Figure 2. Longitudinal change in echocardiographic measurements for survivors and nonsurvivors (64 dead and 129 alive). Time trend
lines represent mean and 95% CIs according to time before last echocardiogram or death (months). A, FS z score; B, wall thickness z
score; C, LV mass z score; D, contractility (stress-velocity index) z score; E, FS (%); F, wall thickness (cm, adjusted for body surface
area); G, LV mass (g, adjusted for body surface area); and H, end-systolic dimension z score.

count z score (P0.001), encephalopathy (P0.001), and
clinical center (center 1 versus center 5, P0.001; center 3
versus center 5, P0.02). The relative risk was 1.39 per 1 SD
increase (P0.004) for wall thickness and 1.41 per 1 SD
decrease (P0.001) for FS. Replacing wall thickness z score
with LV mass z score provided similar findings.
Timing of Mortality
Figure 2 shows the model-based means and 95% CIs for
measurements and z scores according to time before the last
echocardiogram or death for the 64 children who died and the
129 children who remained alive at last contact. Figure 2, A
and E, indicates that within 18 months of death, the mean FS
z score was 2.0, with a mean FS 31%. On the basis of
the separation in curves that starts at 36 months, depressed FS
may be a useful marker for increased mortality for up to 3
years before death. In contrast, LV contractility (Figure 2D)
did not differ between survivors and nonsurvivors until 2
years before death. LV mass (Figure2, C and G) and
end-systolic dimension (Figure 2H) show a difference be-
tween survivors and nonsurvivors 2 years before death,
suggesting that these may be long-term prognostic indicators.
LV wall thickness (Figure 2, B and F) shows a difference
only 18 to 24 months before the final echocardiogram. At the
time of death, echocardiographic measurements differed be-
tween survivors and nonsurvivors for FS (mean z score,
1.11 and 2.32; mean FS, 32.3% and 29.8%), LV mass
(mean z score, 0.29 and 1.75; mean LV mass, 60.7 and
73.8 g), wall thickness (mean z score, 0.14 and 0.46; mean
wall thickness, 0.63 and 0.67 cm), end-diastolic dimension
(mean z score, 0.20 and 1.31; mean end-diastolic dimension,
3.62 and 3.81 cm), end-systolic dimension (mean z score,
0.70 and 2.25; mean end systolic dimension, 2.44 and 2.74
cm), and contractility (mean z score, 0.94 and 1.88).
Discussion
Baseline echocardiographic abnormalities in HIV-infected
children were associated with cumulative all-cause mortality.
In multivariable analyses, baseline depressed LV systolic
performance and increased LV wall thickness made statisti-
cally significant contributions to the prediction of mortality
after adjustment for immunodeficiency, HIV viral load,
encephalopathy, and clinical center. We show that echocar-
diographic measurements (z scores) of LV structure and
performance provide noninvasive, independent markers of
disease and death in HIV-infected children that may be
clinically useful.
Both contractility and FS were predictive of survival in
univariable analyses. In multivariable analyses, however, FS
was a more important predictor. This is not surprising,
considering that FS represents the end products of multiple
 1548 Circulation September 26, 2000
processes, including preload, afterload, heart rate, and con-
tractility, all of which may be disturbed in these patients.
Differences in survival between clinical centers did not
appear to be attributable to disease differences at baseline,
because the center differences remained significant in multi-
variable models after disease variables were included. Ther-
apeutic differences during follow-up or unidentified patient
features we have not accounted for may be responsible.
However, these survival differences among clinical centers
may suggest differences in patient populations and not
differences in the use of antiretroviral therapies, because
90% of the cohort received antiretroviral medications, and
only a small subset took protease inhibitors.9
The study has some limitations. All-cause mortality was
analyzed instead of cardiac death because of the low autopsy
rate (19 of the 71 children). However, a report by the P2C2
HIV multidisciplinary mortality review committee found that
among 93 group 1 and group 2 children who had an
HIV-related death, 11 (11.8%) had chronic cardiac disease as
the underlying cause of death, and 48 (51.6%) had evidence
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of chronic cardiac disease.11 The children in the sample were
those who came in for clinical visits and whose parents or
guardians consented to cardiopulmonary function testing, and
so the children may not be representative of the more general
population of HIV-infected children (eg, increased disease
severity). Echocardiographic measurements from children
with impaired growth rates similar to those of the HIV-
infected children would have provided more appropriate
control data than the healthy control children used in this
study.
In summary, echocardiographic measures of LV structure
and function are independent and potentially useful long-term
and short-term predictors of overall mortality in HIV-infected
children. The regular use of serial echocardiograms in this
population may identify children at risk who may benefit
from more careful examination and potentially effective
interventions12 to alter the course of the disease. Future
studies may determine whether treatment of baseline echo-
cardiographic abnormalities associated with increased mor-
tality is beneficial.
Acknowledgments
This study was supported by the National Heart, Lung, and Blood
Institute (NO1-HR-96037, NO1-HR-96038, NO1-HR-96039, NO1-
HR-96040, NO1-HR-96041, NO1-HR-96042, and NO1-HR-96043)
and in part by the National Institutes of Health (RR-00865, RR-
00188, RR-02172, RR-00533, RR-00071, RR-00645, RR-00685,
and RR-00043).
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 Cardiac Dysfunction and Mortality in HIV-Infected Children: The Prospective P2C2 HIV
Multicenter Study
Steven E. Lipshultz, Kirk A. Easley, E. John Orav, Samuel Kaplan, Thomas J. Starc, J. Timothy
Bricker, Wyman W. Lai, Douglas S. Moodie, George Sopko, Steven D. Colan and for the
Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection (P 2 C
2 HIV) Study Group
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Circulation. 2000;102:1542-1548
doi: 10.1161/01.CIR.102.13.1542
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