We studied a unique population of children and young adults with HIV acquired at a young age. This population has not previously been extensively studied in terms of echocardiographic findings in the era of effective HIV therapy. Deterioration of standard echocardiographic measures of ejection fraction and fractional shortening is often a late measure of cardiac dysfunction. Strain and strain rate are sensitive new measures of function that can give us insight into whether these patients are at higher risk for cardiovascular disease than their uninfected peers, despite being adequately treated with antiretroviral medications and clinically asymptomatic.
Compared with their uninfected peers in our study, however, HIV-infected participants demonstrated impaired (less negative) longitudinal and circumferential strain and strain rate and impaired (less positive) radial strain rate despite normal measures of systolic and diastolic function. No significant difference was found between HIV-infected participants and controls in radial strain. Radial strain measurement has more sources of error and is less validated than strain measurements in the other directions, because it incorporates measurements from the endocardium and epicardium. Because two surfaces are traced, and the true epicardium may be cut off in some studies, radial strain is not as reproducible a measure as strain measured in other vectors.23
Because it is a relatively new technology, there are limited established normal range values for strain and strain rate in this age group. The strain measurements in both the study and control populations were less than reported normal ranges.13
This may be due to differences between the various systems used to generate strain data from one study to the next.13,23
Frame rate differences may have the potential to alter strain results at very low or high frame rates, but all studies were performed within a range such that this was unlikely to happen (25–60 frames/sec).24
Strain and strain rate are relatively new measures of cardiac function, and the exact clinical implications of decreased strain and strain rate are unknown. Previous studies have demonstrated that in certain populations, impaired strain and strain rate do carry a higher rate of mortality.25
Therefore, strain and strain rate may be prognostic factors for myocardial dysfunction. Impaired strain and strain rate may indicate early cardiovascular dysfunction and may represent premature aging in this population. Strain rate is a particularly useful and sensitive measure of function because it is likely less preload and afterload dependent and is angle independent.
Further study is warranted to determine the etiology of the difference in myocardial strain between the HIV-infected study population and control subjects. It is difficult to determine the exact etiology of possible subclinical myocardial dysfunction in our study population. The cause of subtle myocardial damage may be multifactorial. Causes may include metabolic disturbances observed in this population, such as hyperlipidemia and insulin resistance, antiretroviral medication toxicity including in utero exposure, chemotherapy, or myocardial invasion of the HIV virus itself. Many of the HIV-infected study subjects had abnormal lipid profiles, which have the potential contribute to the difference in strain parameters. Elevated lipids levels are a well-known characteristic of HIV-infected populations. Before the introduction of antiretroviral agents, elevated triglyceride and low-density lipoprotein cholesterol levels were reported with HIV in adults. After the initiation of ART including protease inhibitors, lipid levels may increase by 20% to 50% in HIV-infected children.7
Because the control population for this study was a retrospective procurement of normal echocardiograms in healthy children, lipid levels and other risk factors were not available for comparison.
In addition to difference in strain, LV mass as measured by LVMI and LV mass Z
score tended to be increased in patients with HIV compared with control subjects. Increased LVMI has been demonstrated in previous studies of cardiac features in asymptomatic adults and children with HIV.5
Prior studies have shown higher rates of diastolic dysfunction among adults with HIV,5,6
which was not replicated in our study. This may be related to the relative young age of our study group or to our limited sample size. Decreased function has been noted in children exposed to ART in utero.26
It is unlikely that our population was exposed to ART prenatally, given that most were born before the widespread use of ART in pregnancy or were infected by transfusions during the first year of life.
It is important to consider why our HIV-infected study group had slightly higher LVMIs and LV mass Z
scores than controls and whether this could explain the impaired strain indices we observed. Even though not statistically significant, HIV-infected participants tended to have higher blood pressures. It is possible that early coronary artery disease, which is increased or accelerated in HIV,27
may contribute to both increased LVMI and impaired strain indices in this population. Alternatively, children and young adults with lifelong HIV infection may have experienced myocardial insults earlier in life that resulted in subtle scarring and subsequent impaired strain indices. It is important to also note that increased LVMI has been associated with increased mortality in HIV-infected children.28
One may expect that with impaired global strain in both the longitudinal and circumferential directions, a decrease in ejection fraction would be observed. This was likely not the case, however, because strain measurements derived from speckle tracking of the myocardium are able to detect much more subtle changes in myocardial function than ejection fraction and shortening fraction. Both ejection fraction and shortening fraction rely on geometric assumptions and are more prone to human error than speckle tracking, thus making strain measurements derived from speckle tracking a more accurate measure of function.
In this relatively small group of subjects, impaired strain and strain rate did not appear to be directly correlated with immunologic measures such as CD4 count or viral load, nor did we see any correlation between certain biomarkers such as lipids, C-reactive protein, and brain natriuretic peptide. There was a correlation between higher pulmonary artery pressure as estimated by tricuspid regurgitation velocity and time on zidovudine. A recent study demonstrated a link between zidovudine and other antiretroviral medications and pulmonary artery endothelial abnormalities in animal and in vitro assays, suggesting that zidovudine and other ART agents may contribute to the high incidence of pulmonary artery hypertension in HIV-infected patients.29
The estimated pulmonary pressures of all of the HIV-infected subjects were normal, so the significance of this observation is unclear. We also found that increased exposure to tenofovir was associated with more favorable strain indices. Associations such as these cannot be used to presume causality and must be interpreted with caution given the small sample size. Indeed, in a large adult cohort study, recent tenofovir exposure was related to an increased risk for heart failure, which is contradictory to our findings.30
The question of whether tenofovir provides a cardiotoxic or cardioprotective effect warrants further in-depth study.
Limitations of the current study included the limited sample size and the relatively wide age range of the HIV-infected participants. The study was completed by performing retrospective strain analysis on a convenience sample. Therefore, the echocardiograms were not acquired for this particular study, and some echocardiograms were missing M-mode views. In addition, the reader was not completely blinded, as some of the echocardiograms of HIV-positive patients obtained at the NIH did not apically invert the study, whereas all of the four-chamber views performed at the Children’s National Medical Center were apically inverted. Another limitation is the difference in Hispanic ethnicity between the groups, although both groups were similar with regard to African American race. Prospective studies with larger sample sizes are needed to confirm our conclusions.
In addition, limited data were available for the control group, and it is possible that controls may not represent a completely healthy population. Another potential limitation is that echocardiograms for the HIV-infected participants and the controls were obtained at different centers. However, all echocardiograms were performed by trained echocardiographic technicians, and all strain analysis was centralized. Strain analysis software has a sophisticated algorithm, which limits observer bias, and we were able to demonstrate high intraobserver and inter observer correlations. Radial strain was not different between our two populations, but radial strain is the least validated strain measure and requires the tracing of both the endocardium and the epicardium, so more sources of error are introduced. Prior studies have shown minimal intraobserver and interobserver variability in the measurement of strain.31
Finally, strain technology is novel, and the clinical implications of these results are not yet completely known. We have observed a difference in strain, which has been shown in several populations to detect patients at risk for subsequent cardiac morbidity and mortality. Further study is needed to determine the significance of our findings in HIV-infected patients, but strain abnormalities may be an important preclinical precursor to cardiac disease in this population.