The authors have declared that no competing interests exist.
Conceived and designed the experiments: NSI MC DEG DB NK CU. Performed the experiments: NSI MC CU. Analyzed the data: NSI MC CU. Contributed reagents/materials/analysis tools: NSI MC. Wrote the paper: NSI MC CU DB DEG.
‡ These authors also contributed equally to this work.
Cardiac involvement in HIV infected children has been frequently reported, but whether this is due to HIV infection itself or to antiretroviral treatment (ART) is unknown.
This cross sectional study involved 114 vertically-acquired HIV-infected (56 ART-naive, 58 ART-exposed) and 51 healthy children in Jakarta, Indonesia. Echocardiography was performed to measure dimensions of the left ventricle (LV) and systolic functions. We applied general linear modeling to evaluate the associations between HIV infection/treatment status and cardiac parameters with further adjustment for potential confounders or explanatory variables. Findings are presented as (adjusted) mean differences between each of the two HIV groups and healthy children, with 95% confidence intervals and p values.
Compared to healthy children, ART-naïve HIV-infected children did not show significant differences in age-and-height adjusted cardiac dimensions apart from larger LV internal diameter (difference 2.0 mm, 95%CI 0.2 to 3.7), whereas ART exposed HIV infection showed thicker LV posterior walls (difference = 1.1 mm, 95%CI 0.5 to 1.6), larger LV internal diameter (difference = 1.7 mm, 95%CI 0.2 to 3.2) and higher LV mass (difference = 14.0 g, 7.4 to 20.5). With respect to systolic function, reduced LV ejection fraction was seen in both ART-naïve HIV infected (adjusted difference = -6.7%, -11.4 to -2.0) and, to a lesser extent, in ART-exposed HIV infected children (difference = -4.5%, -8.5 to -0.4). Inflammation level seemed to be involved in most associations in ART-exposed HIV-infected, but few, if any, for decreased function in the ART-naive ones, whereas lower hemoglobin appeared to partially mediate chamber dilation in both groups and reduced function, mainly in ART-exposed children.
ART-naive HIV infected children have a substantial decrease in cardiac systolic function, whereas the ART-exposed have thicker ventricular walls with larger internal diameter and higher mass, but less functional impairment.
HIV infection in children remains an important global health challenge, not only because the incidence is still rising in some parts of the world, [
Reports about cardiac abnormalities in HIV-infected children have come from both the pre- and post- highly-active antiretroviral treatment (ART) era, when studies mainly differed in the type of study population, whether focusing on untreated or treated subjects.[
We performed a cross-sectional analysis on 114 HIV infected and 51 healthy children enrolled in an ongoing cohort established in June 2013 in Jakarta, Indonesia. HIV infected children (56 ART-naïve and 58 ART-exposed) were recruited from the pediatric HIV clinics of Cipto Mangunkusumo National General Hospital, Koja District Hospital, and the
Healthy children with the same age range were invited specifically for this research, from the area around the Cipto Mangunkusumo hospital by directly approaching parents and community leaders and providing leaflets explaining the purpose and procedures of the study. Of the total of 55 children invited, 3 declined to participate because parents/guardians were not able to accompany the child to the hospital or refusal to blood sampling and 1 was excluded due to dysmorphic features suggestive of a syndrome.
Given this study was a part of a larger study aiming at investigating cardiovascular effects of HIV infection in children, in which carotid intima media thickness (cIMT) was the primary outcome, sample size was estimated as such to achieve an 80% power to detect a difference of 25 micrometers in cIMT between the HIV and healthy children with a level of significance of 0.05 using a two-sided two-sample t-test and an estimated standard deviation of 40. This resulted in a minimum of 42 children to be recruited to each group.
For every child participant, written informed consent was obtained from parents or guardians on behalf of children. Children also gave assent and we did not perform echocardiography and blood test for those who refused. This study has been approved by the Ethics Committee of Faculty of Medicine University of Indonesia, Jakarta, Indonesia.
HIV infection diagnosis was established based on the WHO 2007 criteria. Under 18 months of age, diagnosis was established based on a positive HIV DNA or RNA PCR examination, whereas for those aged 18 months or older, it was defined by positive HIV antibodies. Disease severity was classified based on the WHO clinical and immunological staging criteria [
To measure cardiac structural and systolic function parameters, we performed standard (B-mode, M mode) echocardiography, following the recommendation of the American Society of Echocardiography.[
Echocardiograms were available for 155 children (50 ART-naïve and, 54 ART-exposed HIV infected, 51 healthy). The remaining children did not have echocardiography data because they refused the examination (2 subjects), were transferred to another hospital (1), died (1), or did not show up for the appointment (6). Examinations were performed by one of the investigators (NSI) for the first 134 children, while the remaining children were examined by two trained cardiology fellows. The agreement between examiners were priorly assessed in 10 children, revealing an intraclass correlation coefficient (two-way mixed modeling) of 86.7 (95%CI 79.0 to 91.7). Results were also randomly validated offline on stored digital loops by a pediatric cardiologist consultant (MMD). All procedures were done in the Echocardiography Laboratory of Department of Child Health University of Indonesia—Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia.
Age and height were a priori set as potential confounders in the association between HIV infection and cardiac parameters as there variables are likely to be associated with HIV infection and heart dimension and function. [
We obtained data on age and smoking exposure using a standard questionnaire filled by parents or caregivers, whereas body weight and height were measured using a standard method. [
Baseline characteristics are described as mean, median, or proportion as appropriate and differences across HIV status groups were tested using Chi-square, oneway ANOVA, or Kruskal-Wallis tests, respectively.
To investigate the effects of HIV infection on cardiac structures/functions, we performed univariable and multivariable general linear modeling with HIV status as a fixed factor and cardiac parameters (LVPWd, LVIDd, LV mass, RWT, EF, FS, TAPSE) as separate dependent variables. The same models were used for adjustment for age and height as potential confounders. We considered height a better indicator of growth and body size than weight as it is less affected by acute changes, such as volume status or other pathological conditions (ascites, organ enlargement) that may accompany HIV infection in children. To describe the potential explanatory roles of hsCRP level, systolic and diastolic blood pressures, and hemoglobin level, we graphically presented effects of adding each of these to the confounder adjusted model. We also did sensitivity analyses by only including children who had never received ART at all and by excluding 2 ART-exposed children previously managed in another hospital.
Findings are presented as crude and adjusted mean differences with 95% confidence intervals and corresponding p-values. A 95% confidence interval not including zero, corresponding to a p-value of <0.05 was considered statistically significant. All analyses were performed using SPSS version 19 and RStudio 0.98.507 for Mac.
Characteristics | ART-naïve HIV n = 50 | ART-exposed HIV n = 54 | Non-HIV N = 51 | P-value |
---|---|---|---|---|
Age (years) |
3.7 (0.6–11.5) | 5.3 (0.6–12.2) | 6.4 (2.4–14.0) | 0.02 |
Male gender, n (%) | 23 (46.0) | 25 (46.3) | 24 (47.1) | 0.99 |
Low SES, n (%) | 20 (40.8) | 31 (57.4) | 10 (19.6) | 0.001 |
Parental smoking exposure after birth, n (%) | ||||
Mother | 4 (8.5) | 6 (11.3) | 0 (0) | 0.06 |
Father/other household member | 37 (74.0) | 47 (87.0) | 34 (66.7) | 0.04 |
Parental smoking exposure during pregnancy, n (%) | ||||
Mother | 7 (15.2) | 8 (15.4) | 1 (2.0) | 0.04 |
Father/other household member | 37 (74.0) | 45 (83.3) | 35 (68.6) | 0.21 |
Parent(s) as primary caregiver, n (%) | 27 (54.0) | 17 (31.5) | 42 (84.0) | <0.001 |
Spontaneous delivery, n (%) | 37 (78.7) | 45 (83.3) | 39 (79.6) | 0.82 |
Ever breastfed, n (%) | 34 (73.9) | 40 (75.5) | 50 (98.0) | 0.002 |
Family history of CVD | 16 (34.0) | 14 (26.4) | 3 (6.1) | 0.003 |
Body weight (kg), n = 147 | 13.0 (6.8) | 17.4 (6.1) | 22.5 (9.5) | <0.001 |
Body height (cm), n = 147 | 93.4 (19.1) | 104.8 (16.9) | 116.5 (17.7) | <0.001 |
Body mass index (kg/m2), n = 147 | 14.3 (2.3) | 15.4 (2.4) | 15.9 (2.8) | 0.001 |
Waist circumference (cm), n = 126 | 48.8 (9.8) | 51.1 (6.5) | 55.1 (8.5) | 0.002 |
Waist-to-hip ratio | 1.02 (0.87–1.20) | 1.03 (0.83–1.16) | 0.98 (0.88–1.09) | 0.001 |
Systolic BP (mmHg), n = 136 | 101.0 (10.9) | 99.9 (10.5) | 102.3 (9.6) | 0.50 |
Diastolic BP (mmHg), n = 136 | 62.3 (9.6) | 60.4 (7.7) | 61.1 (7.4) | 0.55 |
Hb (mg/dL) level, n = 142 | 11.2 (6.9–19.8) | 11.5 (4.2–14.6) | 12.7 (10.2–14.6) | <0.001 |
hs-CRP, median (range), nmol/L | 37 (0–2759) | 48 (371–5507) | 5 (0–155) | <0.001 |
Chronic infection (ever) |
43 (91.5) | 31 (64.6) | 0 (0) | <0.001 |
Severe infection |
20 (51.3) | 5 (12.2) | 0 (0) | <0.001 |
HIV clinical stage 3 or 4 | 48 (90.6) | 32 (61.6) | <0.001 | |
CD4 absolute level (n = 74) | 441 (2–2716) | 1255 (4–2301) | - | <0.001 |
CD4% (n = 71) | 12 (0–49) | 30 (4–47) | - | <0.001 |
Viral load (n = 23) | 320 (59–47914) | 544 (0–1.2*106) | ||
LVPWd (mm) | 5.8 (1.4) | 6.7 (1.6) | 6.0 (1.4) | |
LVIDd (mm) | 31.0 (6.3) | 32.7 (4.9) | 33.4 (4.1) | |
IVSd (mm) | 6.5 (1.4) | 7.1 (1.4) | 6.8 (1.4) | |
LV mass (gram) | 43.2 (18.6) | 58.5 (20.3) | 50.1 (17.2) | |
LV mass index (gram/m2) | 74.2 (26.7) | 84.1 (25.5) | 62.3 (12.9) | <0.001 |
RWT | 0.38 (0.12) | 0.42 (0.12) | 0.36 (0.09) | |
LVEF (%) | 61.3 (13.2) | 63.1 (9.7) | 67.7 (5.4) | |
LVFS (%) | 33.4 (13.2) | 33.5 (9.7) | 36.0 (5.4) | |
TAPSE (mm) | 16.5 (3.5) | 18.9 (4.2) | 20.2 (3.3) |
Note: LVPWd = left ventricular posterior wall thickness at end-diastole; LVIDd = left ventricular internal diameter at end-diastole; IVSd = inter ventricular septal thickness; RWT = relative wall thickness; LV mass = left ventricular mass; LVEF = left ventricular ejection fraction; LVFS = left ventricular fractional shortening; TAPSE = tricuspid annular plane systolic excursion.
#Kruskal Wallis test; Values are means (SD) unless otherwise indicated.
*Chronic infection included tuberculosis, persistent diarrhea, and chronic otitis media; severe infection included sepsis, pyelonephritis, pneumonia, and CNS infection.
**See Tables
Note: LVPWd = left ventricular posterior wall thickness at end-diastole; LVIDd = left ventricular internal diameter at end-diastole; LV mass = left ventricular mass; RWT = relative wall thickness; Hb = hemoglobin level; BP = systolic and diastolic blood pressure.
Crude | Model 1 | Model 2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mean difference | 95%CI | P | Mean difference | 95%CI | P | Mean difference | 95%CI | P | |||
LVPWd (mm) | Non-HIV | Ref | Ref | ||||||||
ART-naïve HIV | All 50 | -0.25 | -0.83 to 0.33 | 0.40 | 0.14 | -0.44 to 0.74 | 0.63 | 0.43 | -0.21 to 1.08 | 0.18 | |
41 Never ART | -0.34 | -0.93 to 0.25 | 0.26 | 0.13 | -0.50 to 0.75 | 0.69 | 0.44 | -0.23 to 1.12 | 0.20 | ||
ART-exposed HIV | 0.67 | 0.10 to 1.24 | 0.02 | 0.86 | 0.30 to 1.41 | <0.001 | 1.07 | 0.50 to 1.65 | <0.001 | ||
IVSd (mm) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -0.23 | -0.82 to 0.34 | 0.42 | 0.11 | -0.48 to 0.70 | 0.73 | 0.27 | -0.37 to 0.91 | 0.42 | |
41 Never ART | -0.31 | -0.89 to 0.27 | 0.30 | 0.10 | -0.53 to 0.70 | 0.78 | 0.28 | -0.39 to 0.95 | 0.41 | ||
ART-exposed HIV | 0.28 | -0.29 to 0.86 | 0.33 | 0.46 | -0.01 to 1.02 | 0.11 | 0.45 | -0.13 to 0.10 | 0.13 | ||
LVIDd (mm) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -2.45 | -4.53 to -0.37 | 0.02 | 0.21 | -1.53 to 1.94 | 0.82 | 1.98 | 0.24 to 3.72 | 0.03 | |
41 never ART | -3.11 | -5.26 to -0.96 | 0.005 | 0.11 | -1.77 to 2.0 | 0.91 | 2.08 | 0.17 to 0.40 | 0.03 | ||
ART-exposed HIV | -0.70 | -2.71 to 1.31 | 0.50 | 0.35 | -1.25 to 1.95 | 0.67 | 1.69 | 0.15 to 3.23 | 0.03 | ||
RWT | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | 0.03 | -0.02 to 0.07 | 0.24 | 0.02 | -0.03 to 0.06 | 0.52 | 0.01 | -0.04 to 0.06 | 0.64 | |
41 never ART | 0.02 | -0.03 to 0.07 | 0.44 | 0.01 | -0.04 to 0.06 | 0.74 | 0.004 | -0.06 to 0.06 | 0.90 | ||
ART-exposed HIV | 0.06 | 0.02 to 0.10 | 0.007 | 0.06 | 0.01 to 0.10 | 0.01 | 0.05 | 0.06 to 0.10 | 0.03 | ||
LV mass (gram) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -6.96 | -14.98 to 1.05 | 0.09 | 0.41 | -6.62 to 7.43 | 0.91 | 3.83 | -3.28 to 10.93 | 0.29 | |
41 never ART | -8.19 | -16.32 to -0.05 | 0.049 | 2.46 | -4.46 to 9.37 | 0.48 | 6.86 | 0.09 to 13.64 | 0.047 | ||
ART-exposed HIV | 8.39 | 0.42 to 16.36 | 0.04 | 11.88 | 5.12 to 18.65 | <0.001 | 13.99 | 7.44 to 20.54 | <0.001 |
Note: Model 1: adjusted for age; Model 2: adjusted for age, and height
ART exposed HIV infected children had thicker LV posterior walls (LVPWd), both in crude (0.7mm, p = 0.02) and after adjustment for age and height (1.1mm, p <0.001), and higher LV mass (crude 8.4g, p = 0.04; adjusted 14.0g, p<0.001) although the difference in inter ventricular septal thickness (IVSd) was not statistically significant. The RWT also tended to be higher in ART-exposed HIV infected children both on crude (difference 0.06, p = 0.007) and age-and-height adjusted analysis (difference = 0.05, p = 0.03). On adjusted analysis, ART exposed HIV infected children also had larger LVIDd (1.7mm, p = 0.03). Inflammation level seemed to partially explain the effects of ART-exposed HIV infection in children on the observed structural changes, while hemoglobin level appeared to account for larger internal diameter only (
In terms of left ventricular systolic function (
Note: EF = ejection fraction; FS = fractional shortening; TAPSE = tricuspid annular plane systolic excursion; Hb = hemoglobin level; BP = systolic and diastolic blood pressure.
Crude | Model 1 | Model 2 | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Mean difference | 95%CI | P | Mean difference | 95%CI | P | Mean difference | 95%CI | P | |||
LVEF (%) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -6.42 | -10.35 to -2.49 | 0.002 | -7.07 | -11.33 to -2.81 | 0.001 | -6.68 | -11.41 to -1.95 | 0.006 | |
41 Never ART | -6.10 | -10.00 to -2.12 | 0.002 | -6.86 | -11.16 to -2.55 | 0.002 | -6.18 | -10.97 to -1.40 | 0.01 | ||
ART-exposed HIV | -4.66 | -8.41 to -0.90 | 0.02 | -4.92 | -8.74 to -1.10 | 0.01 | -4.46 | -8.49 to -0.42 | 0.03 | ||
LVFS (%) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -2.54 | -5.21 to 0.13 | 0.06 | -2.14 | -4.95 to 0.67 | 0.13 | -1.30 | -4.32 to 1.72 | 0.40 | |
41 Never ART | -3.14 | -5.88 to -0.40 | 0.03 | -2.98 | -5.95 to -0.01 | 0.05 | -2.33 | -5.55 to 0.88 | 0.15 | ||
ART-exposed HIV | -2.47 | -5.09 to 0.16 | 0.07 | -2.27 | -4.93 to 0.39 | 0.10 | -1.78 | -4.51 to 0.95 | 0.20 | ||
TAPSE (mm) | Non-HIV | Ref | Ref | Ref | |||||||
ART-naïve HIV | All 50 | -3.64 | -5.15 to -2.12 | <0.001 | -2.20 | -3.63 to -0.77 | 0.003 | -0.61 | -2.17 to 0.79 | 0.42 | |
41 Never ART | -3.64 | -5.22 to -2.05 | <0.001 | -1.77 | -3.29 to -0.25 | 0.02 | 0.20 | -1.36 to 1.75 | 0.80 | ||
ART-exposed HIV | -1.26 | -2.73 to 0.22 | 0.10 | -0.71 | -2.04 to 0.63 | 0.30 | 0.20 | -1.11 to 1.53 | 0.77 |
Note: Model 1: adjusted for age; Model 2: adjusted for age and height
Analyses excluding ART-naïve HIV infected children who had a brief period of treatment in the past (Tables
This study shows that ART-naive HIV infected children had markedly lower LV ejection fraction with chamber dilation than healthy children. ART-exposed HIV infection showed structural changes with thicker LV posterior wall, chamber dilation, and higher LV mass, and a lesser degree of decreased systolic function. Degree of inflammation seemed to be involved in the effects of ART-exposed HIV infection on both structural and functional changes, except for the higher LV mass, while for the ART-naïve, it partially explained the larger LV internal diameter, but provided little explanation for the decreased systolic function. Lower hemoglobin level appeared to account for larger internal diameter in both ART-naïve and ART-exposed and decreased systolic function particularly in ART-exposed HIV infected children.
Previous studies evaluating cardiac involvement in HIV infection in children involved larger sample size [
We only addressed basic parameters of cardiac structures and functions in HIV-infected children and had not yet looked at the occurrence of cardiac disease entities, which are probably more relevant for pediatric clinical practice.[
We found that ART-naïve HIV infected children had compromised ventricular systolic function with chamber dilatation, while the ART-exposed children had less functional impairment despite thicker LV posterior wall, larger internal diameter, and higher mass. This was never explicitly reported before as in most studies, ART-naïve and ART-exposed HIV-infected children were pooled into one group, showing various cardiac structural changes, such as hypertrophic or abnormal ventricular mass, [
Mechanisms underlying cardiac involvement in HIV-infected children remain poorly understood. Multiple factors may be involved, including HIV-induced cytokine or proteolytic enzyme release, co-infection, nutritional deficiency, autoimmune response to infecting pathogens, ART cardio toxicity, or direct viral cell invasion.[
From the perspective of clinical practice, our findings underline the detrimental cardiac effects of ART-naïve HIV infection, which should raise awareness to provide early treatment and more elaborate care for this kind of patients. As ART does not completely solve the cardiac problems and even may have long term disadvantageous effects, a regular follow up of cardiac status may be required for HIV-infected children. This is of particular importance as increased wall thickness and depressed systolic function have been reported as a significant predictor for mortality in HIV-infected children independent of CD4 cell count.[
In conclusion, ART-naive HIV infected children have a substantial decrease in cardiac systolic functions accompanied by chamber dilatation. In ART-exposed HIV infected children, thicker ventricular walls with higher mass and chamber dilatation dominate, with less functional impairment.
(SAV)