Infants of HIV-positive mothers exposed to ART show improved LV contractility and fractional shortening during the first 2 years of life compared to a non-ART exposed cohort of HIV-negative infants born to HIV-positive mothers. However, ART exposure was also associated with reduced LV mass, septal thickness, and dimension, that were also below normal. In other settings, these 3 changes can lead to progressive LV dysfunction.20–22
The long-term cardiac effects of fetal exposure to ART are unclear. Our findings are consistent with the hypothesis that control of myocardial growth differs from control of myocardial function and that ART exposure is associated with less myocardial growth but better myocardial function.
Higher LV contractility leads to a smaller LV end-systolic volume, a higher wall thickness and hence lowers LV wall stress at end-systole. A fall in LV wall stress reduces the stimulus to LV hypertrophy, and hence, lower LV mass is the anticipated response to higher LV contractility.
Our ART-exposed cohort had better maternal health than did the P2
-HIV cohort and better infant LV contractility and fractional shortening. Left ventricular fractional shortening normalized in both groups by age 2 years, except for CHAART-1 females, and LV contractility was better in the CHAART-1 group and remained normal or slightly above normal across all visits. Adding the significant maternal variables to the final multivariate models did not change the ART exposure effects on echocardiographic parameters, suggesting that ART itself, and not improved maternal health, affects LV function either directly or indirectly. We incorrectly speculated that improved maternal health resulted in improved LV contractility and fractional shortening.6
As in rodents,23,24
ART exposure inhibited myocardial growth, being associated with decreased septal thickness, LV dimension and mass. These changes suggest either an overall loss of cardiac tissue with ART exposure, an inability of the septum to grow in response to increasing body-surface area, or both. Weight-for-height was not significantly different by ART exposure with follow-up, suggesting that BSA-normalized Z-scores for these variables are appropriate.
Although our results suggest that ART is associated with early, improved LV function, longitudinal changes in other factors may lead to increasing mechanical stress, such as lower LV mass, that may result in increased LV afterload, that could compromise long-term LV function, a finding found in anthracycline-treated childhood cancer survivors.20–22
Mechanistically, these changes could be induced by apoptosis and by decreased hypertrophic-signaling mechanisms related to ART-growth inhibiting effects, ART-associated DNA mitochondrial mutations or gene polymorphism shifts,23–25
mechanisms similar to that for pediatric cancer survivors with doxorubicin-associated cardiomyopathy, a well-characterized example of late cardiotoxicity following an early childhood drug exposure.26
Perinatal myocardiocyte injury and death are significantly related to inflammation.27
The Fetal Inflammatory Response Syndrome is associated with increased neonatal morbidity.28
Immune Reconstitution Inflammatory Syndrome in ART-exposed HIV-infected mothers may heighten inflammation that contributes to myocardiocyte injury and reduced neonatal LV mass.29
Exposure to ART was also associated with higher heart rates, which have been associated with rapid progression of childhood HIV-associated disease.30
Sustained tachycardia, as observed with ART exposure, may be cause or effect, but with secondary LV hypoplasia, may explain our LV growth findings. Mild LV restrictive disease, with a reduced capacity for LV dilation and with a secondary tachycardia, is also possible. Reduced end-diastolic volume, as the initial limiting factor to cardiac output with secondary compensatory tachycardia is certainly the anticipated response to detraining and to a restrictive cardiomyopathy, so this sequence is also plausible. Alternatively, the decreased LV growth may be secondary to a direct ART effect, such as mitochondrial DNA damage from ART-associated oxidative stress resulting in LV hypoplasia that contributes to the observed increased LV contractility and heart rate, especially in girls.23–25
The effects of ART exposure on LV mass, dimension, fractional shortening, and septal thickness were more pronounced in girls. These differences might predict early and advanced cardiovascular disease in girls as they age. Our findings are similar to zidovudine's effects in mice, where females were more sensitive to ART than were males.31
Similarly, newborn girls have greater myocardial injury marker elevations than do newborn boys.27
Doxorubicin cardiotoxicity suggests an increased vulnerability of the developing female myocardium.20–22
The magnitude of the Z-score differences in this study may appear to be small relative to those that guide the daily clinical decisions by cardiologists. However, their magnitude is consistent with findings in doxorubicin-treated pediatric cancer survivors,20–22
who 20 to 30 years later have a 15-fold increase in the rate of heart failure compared with siblings and an 8.2-fold increase in cardiac mortality compared with U.S. population mortality data.32,33
Zidovudine and its metabolites cross the placenta and are found in the fetal heart.34
The hypothesis that zidovudine may be associated with cardiac mitochondrial dysfunction is supported by animal studies and by limited clinical data.35–39
Yet, zidovudine monotherapy showed no effect on the same LV structure and function measurements in the current study in either HIV-negative or positive children.11,12
Follow-up studies of HIV-negative infants born to HIV-positive women have found neither detrimental effects of perinatal zidovudine exposure nor clinically important cardiovascular disease.8–10,12,40–42
Combination ART (96% of CHAART-1 infants had combination therapy) has early and marked effects on LV structure and function. In rodents, combination ART produces more mitochondrial DNA mutations than monotherapy.23–25,31
In contrast to nucleoside reverse transcriptase inhibitors, protease inhibitors in general do not cross the placenta suggesting the effects seen likely result from nucleoside reverse transcriptase inhibitor combinations rather than protease inhibitors. Combination ART compared with a nucleoside reverse transcriptase inhibitor alone in HIV-negative children was associated with more lymphocyte abnormalities.43
Other abnormalities in ART-exposed HIV-negative children include anemia, neutropenia, thrombocytopenia, lower CD4 and CD8-cell counts, and increased micronucleated erythrocytes.43–45
The P2C2-HIV study (1991–1996) and the CHAART-1 study (2003–2006) were performed in different eras (pre-HAART and HAART, respectively). This non-concurrent design was used for ethical reasons because ART therapy could not be withheld from pregnant women. However, the cardiac protocol, clinical sites, study personnel, and the person measuring echocardiograms were largely common to both studies.
As previously noted, a potential limitation of the use of Z-scores is if the study population differs significantly from the reference population in terms of anthropomorphic measures of exercise. We found no evidence of such differences between our study population and the reference group.
HIV virulence might have increased in the decade between the studies, causing CHAART-1 measurements to deviate more from normal than P2C2-HIV measurements. However, the CHAART-1 mothers had no evidence of more advanced disease.
Fetal exposure to ART is associated with reduced LV mass, dimension, and septal wall thickness and higher LV fractional shortening and contractility during the first 2 years of life. We speculate that in utero exposure to ART may impair myocardial growth while initially improving LV function, although LV function was less than normal. These effects are more pronounced in girls. In the U.S., with more than 100,000 HIV-negative infants exposed to ART, these findings clearly indicate a need for long-term monitoring of these infants to better define the mechanism of these effects and to evaluate their long-term clinical importance.