Background
Traditional measures of cardiac function are now often normal in adolescents and young adults treated with antiretroviral therapy for human immunodeficiency virus (HIV) infection. There is, however, evidence of myocardial abnormalities in adults with HIV. Cardiac strain analysis may detect impairment in cardiac function that may be missed by conventional measurements in this population.
Methods
This was a retrospective study in which echocardiograms of HIV-infected subjects ( n = 28) aged 7 to 29 years who participate in a natural history study of HIV acquired early in life were analyzed and compared with matched controls. Standard echocardiographic measures, along with speckle tracking–derived strain and strain rate, were assessed.
Results
Among the HIV-infected subjects, the median CD4 count was 667 cells/mm 3 , and the mean duration of antiretroviral therapy was 14.6 years. Ejection fractions and fractional shortening were normal. There were no significant differences in measures of systolic or diastolic function between the groups. The HIV-infected group had borderline increased left ventricular mass indices. Global longitudinal and circumferential strain and strain rate, as well as global radial strain rate, were significantly impaired in the HIV-infected group compared with controls. There were no associations identified between left ventricular mass index or strain indices and current CD4 count, CD4 nadir, HIV viral load, or duration of antiretroviral therapy.
Conclusions
HIV-infected participants demonstrated impaired strain and strain rate despite having normal systolic function and ejection fractions. Strain and strain rate may prove to be prognostic factors for long-term myocardial dysfunction. Therefore, asymptomatic children and young adults with long-standing HIV infection may benefit from these more sensitive measures.
It is known that people living with human immunodeficiency virus (HIV) have a high risk for cardiac disease, including pericarditis, myocarditis, cardiomyopathy, pulmonary hypertension, and valvular disease. Cardiac dysfunction has also been extensively described in children with HIV, but much of the cardiac dysfunction was described before the availability of highly active antiretroviral therapy (ART). Even asymptomatic children not on highly active ART have been shown to have cardiac abnormalities on echocardiography. In a study of 26 Indian children aged 1 to 9 years with perinatally acquired HIV not yet on highly active ART, Shah et al. found that 77% had evidence of cardiac abnormalities on echocardiography. The most common abnormalities found were left ventricular (LV) dilation and LV hypertrophy. Cunha et al. found that LV dysfunction was common in Brazilian children approximately 18 months after acquired immune deficiency syndrome diagnosis. Their data suggest a much lower incidence of LV dysfunction in patients treated with ART. They also suggest that the observed decreased in cardiac disease with ART may in fact be a delay in the onset of cardiovascular manifestations of HIV.
With the advent of potent ART, there has been a shift from significant cardiac disease thought to be a result of opportunistic infections or the HIV virus to seemingly few cardiac complications in the pediatric population. Adult studies have shown that asymptomatic HIV-infected patients do manifest mild functional and morphologic cardiac abnormalities. In addition, lipid and metabolic derange-ments have also been commonly found in the HIV-infected population, both with and without ART.
Echocardiographic measures of strain and strain rate are more sensitive indicators of function than the traditional measures of ejection fraction and shortening fraction and may provide a means for the early detection of cardiac dysfunction. Echocardiographic strain analysis uses speckle tracking to track the displacement and velocities of acoustic markers of individual segments of the myocardium as they move in different vectors. Speckles are areas of scattering, reflection, and interference in the myocardium caused by the ultrasound beam that can be tracked frame by frame through the cardiac cycle. Strain measures the regional fractional shortening of the myocardium, and strain rate is the integration of strain over time. Speckle tracking–derived strain rate is particularly useful because it is less likely to be preload and afterload dependent and is angle independent. Multiple studies have demonstrated the accuracy and reliability of strain and strain rate in the assessment of myocardial function. Global strain has been validated in the pediatric population using tagged magnetic resonance imaging as the gold standard.
In addition, strain and strain rate imaging can detect subclinical myocardial dysfunction at an earlier stage compared with conventional imaging. Intraobserver and interobserver variability in strain parameters has been measured and validated in previous studies.
We hypothesized that strain analysis may detect preclinical or asymptomatic cardiac abnormalities in pediatric HIV-infected populations. The aim of our study was to determine if there are differences in strain and strain rate between patients who acquired HIV in early life and matched controls. A secondary aim was to evaluate potential relationships between cardiac strain parameters and markers of immunologic status, inflammation, and cardiac dysfunction.
Methods
Echocardiograms were obtained from 28 children and young adults aged 7 to 29 years with known HIV disease and followed in a natural history protocol of HIV acquired in infancy or early childhood at the National Institutes of Health (NIH). Echocardiography was performed as part of an established research protocol, not because of symptoms or comorbidities. At the time this study was completed, 32 participants had echocardiograms available for analysis, but two studies were excluded for technical limitations and two for preexisting congenital heart defects. Because of the retrospective nature of the study, the use of M-mode echocardiography was not consistently collected for all patients.
The echocardiograms were obtained between September 2008 and August 2009, but were analyzed in a retrospective manner for this nested study. All NIH subjects and/or their guardians, as appropriate, completed written informed consent.
Control data were obtained by querying the echocardiographic database at the Children’s National Medical Center for “no cardiac disease identified.” From the list generated from the this query, control subjects ( n = 28) were age and gender matched to the HIV-infected participants. Control subjects were excluded if they had known exposure to chemotherapeutic medications, underwent more than one echocardiographic study, or had known genetic syndromes as the indications for study. The institutional review boards of Children’s National Medical Center and the National Institute of Allergy and Infectious Diseases approved this study.
Echocardiographic Measurements
Echocardiographic measurements were performed retrospectively on subject and control echocardiograms. Traditional measures of LV systolic function such as ejection fraction and fractional shortening, as well as indicators of diastolic function such as mitral inflow E/A ratio and tissue Doppler–derived E/E′ ratio, were evaluated. LV ejection fraction was calculated using the single-plane modified Simpson’s rule in the four-chamber view. LV mass was calculated from M-mode tracings using the method of the American Society of Echocardiography in the short-axis view. Tricuspid regurgitation velocity as an indicator of pulmonary artery pressure was also measured. Tissue Doppler velocities were measured from the septal annulus from a single representative beat. All measurements were performed by a pediatric cardiologist according to American Society of Echocardiography standards.
Strain measurements were performed using Syngo Velocity Vector Imaging software (Siemens Healthcare, Erlangen, Germany) on Digital Imaging and Communications in Medicine standard digital echocardiograms for each HIV and control subject. Measurements of strain by speckle-tracking imaging were recorded in all 56 patients (28 HIV-infected patients and 28 controls). Each study was analyzed from the parasternal short-axis and apical four-chamber views ( Figures 1 and 2 ). Each tracing was performed during end-systole, and the short-axis view was analyzed at the level of the papillary muscles. Each tracing was repeated twice, and measurements from the two best tracking images were averaged for each strain parameter. Six segments were used to calculate global strain from the short-axis and apical four-chamber views.
Traditional echocardiographic and strain measurements were performed by a single cardiologist on both the patients with HIV and the controls. The reader was blinded to the clinical characteristics of the study population but was not completely blinded to the study groups, because of technical differences in the acquisition of some of the studies. Although all of the studies were deidentified, some of the study echocardiograms obtained at the NIH did not apically invert the four-chamber view, whereas all of the four-chamber views of the control echocardiograms were apically inverted. Ten randomly selected echocardiograms (five from each group) were reanalyzed for interobserver variability. The second reader, who was blinded to study group, made independent measurements, which were then correlated with the initial reader’s analysis. Intraobserver variability was determined using the correlation coefficient between the first reader’s two analyses of each echocardiogram.
Short-axis measurements included circumferential strain (%), radial strain (%), circumferential strain rate (sec −1 ), and radial strain rate (sec −1 ). Longitudinal strain (%) and longitudinal strain rate (sec −1 ) were recorded from the apical four-chamber view (Figures 1 and 2 ).
Strain is the percentage of deformation of the myocardium. This percentage is measured by continuously tracking natural acoustic markers (speckles) frame by frame and calculating the end-systolic distance between two particles (or speckles) of tracked myocardium minus the original distance between those two particles all over the original length. In the longitudinal and circumferential directions, speckles of endocardium are tracked. The myocardium contracts in these directions during systole, so these values will be negative percentages. Radial strain measures the percentage of deformation in the radial direction, so both the endocardium and epicardium are tracked to calculate radial strain. The myocardium thickens in the radial direction during systole, so radial strain is measured as a positive percentage.
Laboratory Assays
Laboratory measurements were performed on the HIV-infected study patients as part of the NIH study protocol and analyzed at the central NIH laboratory in Bethesda, Maryland, and included CD4 T-cell count, HIV viral ribonucleic acid by reverse transcription polymerase chain reaction, fasting lipid panel, pro–brain natriuretic peptide, d -dimer, and high-sensitivity C-reactive protein.
Statistical Analysis
Direct group comparisons were performed using Wilcoxon’s rank-sum analyses. Correlations within the HIV-infected study group were found using Pearson’s coefficient of correlation analysis. A multivariate regression analysis was performed to evaluate the association between strain measures and age, race, sex, body mass index, blood pressure, lipids, and duration of ART. Intraobserver and interobserver variability was evaluated through intraclass correlation coefficients calculated from available measurements. Statistical significance was assumed for P values <.05.
Results
HIV-infected subjects ranged in age from 7 to 29 years. All HIV-infected study participants acquired HIV from mother-to-child transmission, except for two participants who acquired HIV from blood transfusions performed in infancy. Control participants ranged from 7 to 32 years of age. There were no significant differences between the percentage of Caucasian and non-Caucasian subjects and the percentage of African American subjects between the HIV and control groups. There were more Hispanic subjects in the control group than in the HIV-infected group. In addition, there was a trend toward statistical significance in blood pressure between groups ( Table 1 ), with the HIV-infected group having higher blood pressures. All HIV-infected participants were asymptomatic from a cardiovascular standpoint. The primary indications for control echocardiographic studies were chest pain ( n = 13) or syncope ( n = 10) in the outpatient clinic setting. Other indications included abnormal chest x-ray ( n = 2), murmur ( n = 2), abnormal electrocardiographic findings ( n = 1), palpitations ( n = 1), and headaches ( n = 1). Some participants had two indications for echocardiography.
| Variable | HIV positive ( n = 28) | Control ( n = 28) | P |
|---|---|---|---|
| Age (y) | 18 ± 4 | 19 ± 5 | .80 |
| Male/female | 12/16 | 12/16 | 1.00 |
| African American | 46% | 39% | .60 |
| BMI (kg/m 2 ) | 23 ± 4 | 23 ± 4 | .30 |
| BSA (m 2 ) | 1.6 ± 0.2 | 1.7 ± 0.2 | .40 |
| Systolic BP (mm Hg) | 121 ± 12 | 116 ± 11 | .07 |
| Diastolic BP (mm Hg) | 72 ± 8 | 67 ± 2 | .06 |
| Echocardiography | |||
| Ejection fraction (%) | 61 ± 4 | 62 ± 4 | .30 |
| Shortening fraction (%) ∗ | 36.7 ± 4.1 | 34 ± 3.8 | .06 |
| LVMI (g/m 2 ) ∗ | 81.6 ± 17.1 | 73.3 ± 12.3 | .06 |
| LV mass Z score ∗ | −0.51 ± 1.11 | −1.04 ± 0.61 | .046 |
| E/A ratio | 2 ± 0.5 | 1.8 ± 0.5 | .20 |
| E/E′ ratio (lateral) | 5 ± 1.2 | 5.2 ± 1.8 | .80 |
| E/E′ ratio (septal) | 6.5 ± 2.1 | 7.2 ± 1.9 | .30 |
| Tricuspid regurgitation velocity (m/sec) | 2.1 ± 0.3 | 2.1 ± 0.2 | .80 |
| LV dimension (mm) | 4.6 ± 0.5 | 4.7 ± 0.5 | .50 |
| HIV characteristics and lipids | |||
| Cumulative ARV exposure (y) | 14.6 ± 3.1 | — | — |
| Cumulative PI exposure (y) | 9.9 ± 2.8 | — | — |
| Cumulative NRTI exposure (y) | 3.7 ± 3.7 | — | — |
| Median CD4 count (cells/mm 3 ) | 667 | — | — |
| Viral load < 50 copies/mL | 71% | — | — |
| HDL cholesterol (mg/dL) | 45 ± 13 | — | — |
| Triglycerides (mg/dL) | 150 ± 170 | — | — |
| Total cholesterol (mg/dL) | 156 ± 36 | — | — |
∗ For the HIV-positive and control groups, n = 15 and n = 25, respectively.
Echocardiographic Findings
Echocardiographic parameters are summarized in Table 1 . Echocardiographic measurements of chamber size, systolic and diastolic function, and estimated pulmonary artery systolic pressure were within normal limits in control and HIV subjects. Ejection fraction and measures of diastolic function were not significantly different between the HIV-infected and control groups. Fifteen of the 28 HIV-infected participants underwent M-mode echocardiography as part of their routine studies. There was a trend toward higher shortening fractions ( P = .06) and higher LV mass indices (LVMIs) ( P = .06) in HIV-infected subjects. In addition, mean LV mass Z scores were significantly different between groups, with the HIV-infected subjects having greater LV mass Z scores (−0.51 ± 1.11 vs 1.04 ± 0.61, P = .046) than control subjects ( Table 1 ).
The HIV-infected group had significantly impaired strain indices compared with controls ( Figure 3 ). Longitudinal strain ( P < .001), longitudinal strain rate ( P < .001), circumferential strain ( P < .001), circumferential strain rate ( P < .001), and global radial strain rate ( P = .001) were significantly decreased compared with controls. Radial strain was not found to be different between the groups. The strain measurements in both the study and control population were less than reported normal ranges. For longitudinal strain, 96% of the HIV-infected participants had abnormal values (below the fifth percentile), and 55% of the control participants were below the fifth percentile. For radial strain, 92% of the HIV-infected and 80% of the control participants had values below the fifth percentile. For circumferential strain, 37% of the HIV-infected and 4% of the control participants had values below the fifth percentile, whereas 4% of the HIV-infected and 15% of controls were greater than 95th percentile.
