Prior to the widespread availability of combination antiretroviral therapy (cART), HIV-infected children demonstrated a high incidence (10–44%) of cardiomyopathy, and rates of cardiomyopathy tended to increase in proportion to time living with HIV infection [1,2]. These early studies defined cardiac dysfunction with traditional echocardiographic measures shortening fraction, left ventricular (LV) dimensions, and LV ejection fraction (LVEF). Studies since the introduction of cART have documented the general preservation of these measures in the fetus , during infancy [4,5], and after receiving long-term therapy [6,7].
Newer ultrasound-based cardiac imaging techniques (such as strain imaging and myocardial performance index – MPI) have increased sensitivity for detecting decreased myocardial function prior to changes in LVEF [8,9]. Strain (noted as LV GLS – LV global longitudinal strain to differentiate from other types of strain measurements) in its most basic form is the percentage change distance between two echo targets in diastole to systole . A more negative value indicates better function. Global refers to an average value across the entire LV and longitudinal refers to the direction of the distance change. In this case, longitudinal means in plane with the ventricular wall in the long axis. Strain measurements have been used in a few smaller studies (between 28 and 222 participants) of young adults and children living with HIV to demonstrate worse strain values compared with controls [11–14]. MPI, which measures the efficiency of cardiac contraction and relaxation, was used in the HIV-HEART study showing abnormal values in 19.4% of asymptomatic HIV-infected adults . Among children with other systemic illnesses, abnormal LV MPI has been shown to be predictive of cardiac injury and death [16,17]. However, we found no studies reporting on MPI among children living with HIV. Strain and MPI measurements represent promising means to identify early dysfunction, but to date there have been no large studies using these measures to assess cardiac function in children with HIV .
To address these gaps, we performed a comprehensive echocardiographic evaluation in a cohort of children and young adults living with HIV in Eldoret, Kenya. Further, we investigated circulating biomarkers that have been linked to HIV infection and associated comorbidities. Among these are Transforming growth factor β1 (TGF-β1), which is implicated in the pathogenesis of myocardial fibrosis , and together with IL-1β associated with chronic inflammation leading to end organ damage [19,20]. We also measured serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), which is linked to incident heart failure, as a tool for screening for myocyte stretching and heart failure in individuals living with HIV [21,22]. Our general hypothesis is that early cardiac dysfunction (abnormal changes in strain or MPI with normal LVEF) exists in some children and young adults living with HIV and is associated with HIV relevant indicators such as HIV viral burden, immune status, zidovudine-containing antiretroviral treatment (ART) regimens, and circulating inflammatory markers. The specific aims of the study were to describe the prevalence of early cardiac dysfunction using MPI and strain measurements; and to evaluate the association between echocardiographic measures of function and concurrent plasma HIV RNA levels and soluble inflammatory marker levels.
We performed a cross-sectional echocardiographic study on children and young adults attending the HIV care clinic at Moi Teaching and Referral Hospital and Academic Model Providing Access to Healthcare (AMPATH) in Eldoret, Kenya (approximately 2000 m above sea-level). The general characteristics of this clinic population have been previously published . All study procedures were approved by the ethical review boards of Moi University and Duke University.
Children and young adults attending their primary HIV care clinic (aged <26 years, based on local clinic designations) for routine follow-up were eligible for study inclusion. All clinic patients during the 8-month-study-period were offered study participation with the goal to census the clinic, purposive nonprobability sampling. Following introduction by clinical care providers, caregivers of children or patients older than 18 years attending their regularly scheduled HIV care clinic visit were approached by the research study team for detailed study description and to obtain informed written consent. Children aged 10 years and older provided written assent. Consented participants then underwent study procedures. Patients were excluded if they had significant congenital heart disease, were unable to tolerate study procedures or they or their caregivers were unable to give written informed consent in Kiswahili or English. All participants were determined to be highly likely to have perinatally acquired HIV given age of diagnosis (diagnosis <10 years), maternal HIV infection, and lack of additional identifiable risk factors for virus acquisition. All participants were on cART at the time of the study. Individual regimens were based on Kenya Ministry of Health recommendations for weight and disease status. Recruitment began in September 2017 and completed in April 2018.
Data were collected during enrollment and extracted from the electronic medical record for key demographic and historical data including markers of HIV infection (e.g., CD4+ nadir and previous HIV RNA levels), date of initiation of cART, regimen, regimen changes, anthropomorphic data (age, weight, height, and sex), blood pressure measurements, and comorbidities. In addition, heart rate (HR) was captured from clinic triage prior to study introduction, and HR was captured at the time of strain image acquisition. A new variable was generated called HR gain, which is calculated as percentage change from triage HR to echocardiogram HR. This measure was a surrogate for anxiety-related tachycardia due to study echocardiogram which could influence LVEF and LV GLS.
All study participants underwent an echocardiogram with 2D, M-mode, color Doppler, spectral Doppler, and tissue Doppler imaging based on a study image acquisition and the reading protocol developed specifically for this project. The echocardiogram was performed using a General Electric Vivid iq (General Electric Healthcare, Little Chalfont, England) equipped with 6 and 12 MHz tissue-harmonic imaging probe and ECG-gating. Images were acquired with raw data and DICOM data at frame rates 60–100 frames/min. A standardized imaging protocol was utilized for image acquisition and image interpretation. All echocardiograms were interpreted by a single reader who was blinded to the clinical and laboratory data. A second reader blinded to first reader's measurements, interpretation and clinical data, measured tissue-Doppler-derived indices for interrater reliability comparisons. Echocardiographic measurements were made using American Society of Echocardiography standards [24,25]. Measured values were referenced to a BSA (Haycock formula) z-score calculator based on the Boston Children's Hospital database . All echocardiographic findings were discussed with the families by a pediatric cardiologist, and the children in need of continued cardiac care were referred to a local pediatric cardiology clinic.
LV size was measured from the parasternal short axis in end-systole and end-diastole by M-mode. LVEF was generated by General Electric's Auto-EF software utilizing the modified Simpson's method. Volumes were generated from apical 4-chamber and 2-chamber views of the LV.
Assessment of diastolic function was comprised of several measurements including Doppler measurements of pulmonary venous velocities, mitral valve inflow velocity, deceleration time, and from tissue Doppler imaging, e’ measurement for E/e’ ratio. If an echocardiogram had a mitral valve inflow E/A ratio of less than 1 or more than 2.8, the echocardiogram was determined to have evidence of diastolic dysfunction, according to published recommendations [27–29]. For echocardiograms not meeting this published criterion, we used composite score of published criteria whereby having three of the following criteria met the definition of diastolic dysfunction: E/A more than 2 or 2.8 or less, E deceleration time less than 140 ms, E/e′ more than 10, E′ velocity less than 0.1 m/s, and pulmonary venous peak velocity systole to diastole ratio 0.5 or less or at least 1.2 [24,29].
Measurements of right ventricular (RV) function, pulmonary artery pressures, septal geometry, chamber size and vessel size were assessed using standard criteria . Pulmonary hypertension by echocardiogram was defined as tricuspid regurgitation jet velocity of more than 2.5 m/s or in the absence of adequate tricuspid regurgitation jet, an eccentricity index more than 1.4 . Rheumatic heart disease by echocardiography was determined using the current World Heart Federation definitions .
LV GLS measurements were made using General Electric Vivid Automated Function Imaging software using the myocardial speckle tracking method. LV GLS was selected among other types of strain measurements due to its current clinical utility and its high inter and intra-observer reliability . The GLS-based criteria for early cardiac dysfunction was defined as LV GLS z-score of less than −2 and a LVEF at least 50% . Lateral mitral valve annulus velocity by tissue Doppler was used to measure MPI. MPI was measured in three separate beats, and the three-beat average is reported. MPI is given by the formula:
The MPI-based criteria for early cardiac dysfunction was an MPI of at least 0.5 and an LVEF at least 50% [34,35]. Since MPI required manual measurement of the tissue Doppler tracing, a random selection (10%) of tracings were read by a second pediatric cardiologist (PCAB) and compared with the primary reader using two-way Interclass Correlation Coefficient (ICC).
Participants provided whole blood samples collected by venipuncture in ethylenediaminetetraacetic acid-treated and plain tubes. Samples were transported to AMPATH Reference Laboratory [KENAS ISO 15189, accredited and good clinical laboratory practice compliant] located at Moi Teaching and Referral Hospital for processing within 1 h of blood collection. HIV RNA quantification was done using the Abbot Realtime HIV-1 assay (Abbott Park, Illinois, USA) according to manufacturer's protocol. In addition, a complete blood count was performed for a subset (n = 75) of consecutive participants, where hemoglobin (Hb) was measured. Circulating biomarker testing was done at Duke Molecular Physiology Institute. TGF-β1 and NT-proBNP were measured using R&D Systems Quantikine Elisas (Minneapolis, Minnesota, USA). IL1β and IL6 were measured with Meso Scale Diagnostics U-plex Assays (Rockville, Maryland, USA). These biomarkers were selected due to relevance to cardiac diseases in individuals living with HIV [18,21].
The study design for participant recruitment was purposive nonprobability sampling. This strategy was employed with the goal to perform a census of the entire clinic. Political disruptions and echocardiographic availability limited the study recruitment period to 8 months, during which all clinic patients were offered study participation. Baseline characteristics were summarized for patients with normal cardiac dysfunction and those with early cardiac dysfunction. Group comparisons for categorical variables used the conventional chi-square test or Fisher's Exact Test, as appropriate. For continuous variables, the mean ± SD or median (25th percentile, 75th percentile), were provided depending on normality. The t test or Kruskall–Wallis test was used as appropriate for comparisons of treatment groups for continuous variables. Group comparisons were conducted with the compareGroups package in R version 3.5.1 (2018-07-02; Vienna, Austria). Ten percentage random interobserver read of MPI was performed by a senior PCAB blinded to all patient data and initial measurements.
Backward selection regression with selection based on Akaike information criterion (AIC) were performed to identify potential predictors of cardiac function. Cardiac function outcomes included LVEF (%), MPI, LV GLS (%), LV GLS z-score, shortening fraction, and diastolic dysfunction (yes/no). Predictor variables included HIV RNA level, age, sex, proportion of life on cART (years), azidothymidine or zidovudine (ZDV) exposure (yes/no), HR gain from clinic triage to echocardiogram (%), baseline HR, IL-6, IL-1β, TGR-β1, and NT-proBNP. Hypothesized interaction terms were also tested including proportion of life on cART and HIV RNA level; proportion of life on cART and ZDV exposure; age and ZDV exposure; and age and HIV RNA level. For HIV RNA level, results below the detectable level were imputed to half the detectable level (i.e. 20 copies/ml) prior to log-transformation. If backward selection retained HR gain in a model, then baseline HR was also included to control for this variable. To ensure all possible models in backward selection had equal numbers of observations, only records with complete data for all predictors were included. Backward selection was performed with the stepAIC function of the Mass package in R version 3.5.1 (2018-07-02). Missing data were not imputed in any of the models described above.
Six hundred and fifty-three of 1606 patients actively managed in clinic were approached for study participation during the recruitment period. Six families declined participation. Three consented patients were unable to tolerate the echocardiogram and thus were excluded. One participant was found to have significant congenital heart disease (intermediate atrioventricular septal defect) and was excluded from analysis. Remaining patients not approached did not present to clinic or were not available during the study period for recruitment. Table 1 displays the participants’ descriptive characteristics of the 643 study participants (40.0% of clinic patients). The mean age at enrollment was 14.1 ± 5.2 years (range 16–25 years). By WHO standard, 76.6% of the study participants were virally suppressed (<1000 copies/ml) compared with 82.1% of the remaining 953 clinic attendees not recruited.
Twenty-one participants of 643 (3.3%) were found to have LV ejections less than 50% and were deemed to have cardiac dysfunction. These patients were not included in the early cardiac dysfunction group, but were included in regression models. Three patients with cardiac dysfunction (or three of 643, 0.5%) had increased LV dimensions greater than a z-score of +2 for BSA and were diagnosed with HIV-associated cardiomyopathy. One hundred and seventy-eight participants of 643 were categorized as having early cardiac dysfunction (27.7%). Of those with early cardiac dysfunction, 176 of 178 (98.9%) had abnormal MPI and only two of 178 has LV GLS z-score less than −2 (1.1%). Among those with normal LVEF, Table 1 shows that early cardiac dysfunction was associated with older age, higher percentage of exposure to ZDV, lower CD4+ nadir, higher percentage of detectable HIV RNA, and higher median IL-6 levels. There was no difference in Hb levels among a subset with hemograms available. Overall, the HRs were lower by −7.14 ± 11.6% at time of echocardiogram from clinic check triage. In addition there was no difference in IL-1β, TGF-β1, and NT-proBNP levels between those with normal cardiac function and those with early cardiac dysfunction.
Table 2 displays the summary of the echocardiography measurements obtained. There was no evidence of pericardial effusion greater than trace in any participant. Thirty-five patients (5.4%) were defined as having evidence of diastolic dysfunction by the study definition. No patients had evidence of elevated RV systolic pressures. Four patients (0.01%) met criteria for rheumatic heart disease of the mitral valve. Early cardiac dysfunction was associated with lower fractional shortening percentage, lower ejection fractions, and lower E/A ratios. MPI interrater reliability of 70 randomly selected patients was very high with a two-way ICC of 0.87 (95% confidence interval: 0.79, 0.92).
Multivariable regression modeling of associations with cardiac function
Table 3 displays the final models selected for measure of cardiac function by step-wise AIC selection. The range of incomplete data per model, thus excluded from the models, was 6.2–7.6%. LV ejection fraction was negatively associated with HIV RNA levels and history of ZDV exposure, but positively associated with proportion of life on cART and HR gain. MPI was positively associated with IL-6. Strain (LV GLS and LV GLS z-score) and shortening fraction were not significantly associated with HIV RNA levels or levels of inflammatory markers.
In the current era of highly effective ART, the historical high prevalence of overt cardiac dysfunction has diminished . Given the predicted near-normal life expectancy for many people living with HIV, the focus is now on mitigating cardiovascular disease risk and detecting signs of early cardiac dysfunction for possible intervention. In the current study, over one-quarter of children and young adults with perinatally acquired HIV demonstrated echocardiographic evidence of early cardiac dysfunction-based primarily on abnormal MPI measurements. This is the largest reported prevalence of abnormal MPI measurements in pediatric patients with structurally normal hearts . MPI was positively associated (worse) with an elevated marker of systemic inflammation, specifically IL-6. LVEF was negatively associated (worse) with same-day HIV RNA level and history of ZDV exposure, but was better in patients with higher proportion of life on cART.
Although we did not observe a high prevalence of HIV-associated cardiomyopathy in children with perinatally acquired HIV, a large proportion of participants had elevated MPI measurements and these measurements correlated with elevated markers of inflammation. Tissue Doppler-derived MPI has been shown to be predictive of morbidity and mortality in patients at risk for heart failure . While relatively few studies assess clinical outcome among children with elevated MPI, increases in MPI have been observed with dose-related exposure to anthracyclines [16,17]. A modest increase in MPI is expected with age,  however, a large portion of measurements in these children and young adults exceed adult abnormal cutoffs . This study therefore suggests a large proportion of children and young adults with perinatally acquired HIV are living with unrecognized cardiac dysfunction.
As this study showed no apparent association between MPI and same-day plasma HIV RNA levels, we next attempted to discern the underlying processes driving these abnormal values. Current HIV comorbidities research has largely focused on systemic immune activation as a potential source of end-organ sequelae, such as cardiac dysfunction. This includes investigating the association between inflammatory markers and risk of cardiovascular disease and events in adults with HIV . Mediated by chronic inflammation, other cardiac disease states such as heart failure with preserved ejection fraction (HFpEF) and hypertrophic cardiomyopathy may provide insight into understanding HIV-associated cardiac dysfunction . In HFpEF, for example, systemic inflammation signals a cascade that results in induction of reactive myocardial fibrosis . In addition, in hypertrophic cardiomyopathy associated with familial genetic mutations, the degree of fibrosis and ultimate severity of myocardial hypertrophy is directly related to the degree of systemic inflammation present . MPI is abnormal in both HFpEF and hypertrophic cardiomyopathy even when LVEF is normal and may be predictive of important clinical outcomes . These cardiac diseases may parallel HIV-associated cardiac injury as high levels of residual immune activation and evidence of myocardial fibrosis are noted . MPI may serve as a readily available and noninvasive clinical measurement that could be used to monitor this disease process.
In addition, LV GLS was not as useful in demonstrating patterns of early cardiac dysfunction in this population. In fact, LVEF detected more abnormal findings than LV GLS. Values for LV GLS in this study were mostly normal, consistent with previous work in sub-Saharan Africa utilizing different ultrasound equipment and software . Our study reports increased magnitude of the LV GLS values with z-score average of +1.4. This is correlated with hyperdynamic function in LVEF and relative baseline tachycardia of patients. LV GLS only assesses peak systolic contraction inplane with the myocardium. MPI on the other hand is a combined measure of systolic and diastolic function and may be capturing abnormality not represented in LV GLS measurements. Limited previous work has suggested that there is only a weak correlation between LV GLS and MPI in preserved ejection fraction, despite cardiovascular compromise . In addition, tachycardia, increased LV shortening fraction (hyperdynamic), and abnormal diastolic indices have been reported in children with hypertension suggesting these findings co-vary in diastolic impairment . While children and young adults in this study were not hypertensive, abnormal MPI may be capturing diastolic dysfunction. For the participants in this study with early cardiac dysfunction, there was a concerning combination of tachycardia, hyperdynamic LV function (elevated LVEF and LV GLS), and decreasing LV efficiency (worse MPI). These findings suggest that these patients may not have subclinical cardiac dysfunction but rather previously unrecognized overt dysfunction with unrecognized functional limitations .
Surprisingly, NT-proBNP was not associated with continuous measures of cardiac function or with the study definition of early cardiac dysfunction. If the early cardiac dysfunction definition were predominantly capturing early diastolic dysfunction, then an association would have been expected. In adults with diastolic dysfunction, NT-proBNP has been used to distinguish between mild and more severe diastolic dysfunction . Thus NT-proBNP performs less well with discriminating normal from mild dysfunction. In HIV literature, higher levels of NT-proBNP in adults living with HIV were associated with increased risk of cardiovascular events after controlling for known cardiovascular risks . However, these patients were categorized by presence of cardiovascular event. Despite statistical significance, the biomarker level ranges between the groups overlapped and only a very few would have been captured by the suggested cut point of 100 pg/ml. In children with systolic dysfunction, ejection fraction is negatively correlated with NT-proBNP . However, there has been very little work with NT-proBNP and diastolic dysfunction. Overall, NT-proBNP test failure in this study may have been due to difficulty with detecting mild diastolic dysfunction and possible differences in pediatric cohort levels.
We note several limitations. First, the cross-sectional design does not allow for understanding changes in the measurements over time in the same patient. Cross-sectional studies are at risk for participant selection bias. The biggest concern would be if our cohort were less well and presented to clinic more frequently, thus having more opportunity to participant than healthier patients. However, we are able to compare our sample with the reported metrics (WHO viral suppression rates) for the entire clinic and found our cohort was similar to the entire clinic not. The comparability for our cohort to the rest of the clinic was aided sampling 40% of the actively managed patients in this clinic. The results specifically relate to children and young adults on cART that are actively engaged in clinical care. Next, the echocardiographic measures of this study could be subject to measurement error. Measurement error was mitigated by a single reviewer of all images and a selection of comparison measurements between reviewers on the primary outcome measurement. Finally, there was no control group for general comparison. The focus of the results is the associations between continuous measurements of cardiac function and clinical and serologic indicators. While widely accepted cut-offs for normal MPI values were used, this measurement has not been reported for HIV uninfected children in sub-Saharan Africa and at this altitude (2000 m above sea level). Future work should include age-matched healthy controls.
Over one-quarter of children and young adults with perinatally acquired HIV engaged in care in Western Kenya demonstrated echocardiographic evidence of early cardiac dysfunction, based primarily on abnormal MPI measurements. This finding was associated with increased levels of systemic inflammation, but not same-day HIV RNA levels or other clinically relevant variables. Further investigation into the clinical significance of this finding is urgently needed as abnormal MPI measurements have been shown to be predictive of heart failure in at-risk populations.
The authors would like to acknowledge and thank children and adolescents living with HIV in western Kenya for their participation and clinic providers for their inspirational care.
Author's contributions: A.W.M., W.N., A.M.E., H.C., M.K., N.M.T., J.A.K., P.C.A.B., and G.S.B. developed the study protocol and statistical plan. A.W.M. performed all echocardiograms. E.B. performed participant recruitment, specimen and data management. M.J.M. and I.D. performed and oversaw laboratory testing. All authors contributed to manuscript preparation and revision.
Financial support: This project was supported by grants from the International AIDS Society CIPHER grant programme, a Duke University Center for AIDS Research small grant, National Heart, Lung and Blood Institute, and Fogarty International Center's Global Health Fellowship administered by the Vanderbilt, Emory, Cornell, And Duke (VECD) consortium. Additionally, AWM received support from the Hubert-Yeargan Global Health Center at Duke University Global Health Institute through the global health-training pathway. Lastly, there was in kind support from GE Healthcare.
Conflicts of interest
The authors report no conflicts of interests.
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