In the age of highly active antiretroviral therapy, children infected with human immunodeficiency virus (HIV) are reaching older ages. With this improved survival, deleterious outcomes in almost all organs, including the cardiovascular system, are being reported.1 The increased cardiovascular disease (CVD) is attributed to traditional risk factors2 and HIV-specific factors including direct effects of HIV, microbial translocation, immune activation, coinfections, and highly active antiretroviral therapy.3,4
Recent studies in HIV-infected adults have looked at early subclinical CVD. Lo et al5 found the rate of subclinical coronary artery atherosclerosis to be higher in HIV-infected men compared with age-matched controls. Data on the pediatric population are scant.1 Until recently, technology to evaluate this younger population consisted mainly in using echocardiograms6 or carotid ultrasound.7 Although coronary computed tomography has provided a noninvasive method of investigating early atherosclerotic lesions in the adult population, its use is limited in children because of concerns about radiation exposure. The introduction of high-field MR scanners (3 Tesla)8,9 provides an excellent opportunity to study the early cardiovascular changes in the younger population.
MATIERALS AND METHODS
Subjects and Data Collection.
We performed a cross-sectional analysis of 27 individuals who acquired HIV early in life and who are followed up longitudinally in an observational study at the National Institutes of Health (NIH). Enrollment for the cardiac imaging was between November 2008 and February 2009. The National Institute of Allergy and Infectious Diseases' institutional review board approved the protocol. Written informed consent was obtained from all patients, parents, or legal guardians. Assent was obtained from minors when developmentally appropriate.
Study participants completed a detailed clinical evaluation including medical history, history of antiretroviral (ARV) exposure, opportunistic infections, comorbidities, and smoking (past and current). Participants also had a physical examination including height, weight, and hip and waist circumference (obtained by registered dieticians using standardized techniques). Laboratory evaluation included fasting lipid profile, high sensitivity C-reactive protein (CRP), pro-brain natriuretic peptide, d-Dimer, homocysteine, lymphocyte phenotype, and HIV viral load.
All cardiac magnetic resonance imaging (MRI)/magnetic resonance angiography studies were performed at the NIH under the supervision of a single radiologist (AMG), using a commercial 3T MRI scanner. Subjects received up to 0.3 mmol/kg gadolinium-based contrast agent intravenously. MR images were evaluated using commercially available software (AZE, Tokyo, Japan). Each subject had 3 separate sequences to evaluate their coronary vessels. These included (1) targeted high resolution approach, (2) whole heart without and (3) with contrast. To ensure that the findings were not motion artifacts, only the lesions seen in the same location of the vessel on the 3 prescribed sequences were considered true findings. Coronary vessels were evaluated for abnormality on the basis of the following classification: 0 - normal coronaries without irregular wall; 1 - minimal coronary irregularity of the vessel wall without affecting the lumen diameter; 2 - mild coronary irregularity of the vessel wall, causing less than 25% narrowing of the vessel lumen; 3 - moderate irregularity of the vessel wall, causing 25% to 50% narrowing of the vessel lumen. MRIs classified as a 2 or 3 were considered abnormal. This classification scale is a minor modification from that used by Kim et al,8 which was chosen to capture all evidence of abnormality.
Two-dimensional echocardiogram and EKG were performed at the NIH and interpreted by NIH cardiologists. All echo, EKG, and MRI studies were confirmed by independent cardiologists from Children's National Medical Center (SC and RC).
General characteristics are summarized using mean and standard deviation. Comparisons between subjects with and without coronary artery abnormalities (CAA) were made using Kruskal-Wallis tests and χ2 statistics for noncontinuous variables. A multivariate regression model was used to identify possible independent predictors and included factors identified in univariate analysis as potentially important in CAA. All statistical analyses were performed using SAS JMP Statistical Software (Version 7.0, SAS Institute Cary, NC), and 2-tailed alpha level of 0.05 was used to determine statistical significance.
A total of 27 subjects were able to complete MRI. Their characteristics are shown in Table, Supplemental Digital Content 1, http://links.lww.com/INF/A751. The mean age was 18.9 ± 3.4 years, with a range from 13 to 29 years; 41% subjects were male, 37% subjects were white, 44% were African-American, 93% had acquired HIV perinatally, 100% had ARV exposure, 70% had undetectable HIV viral loads, and 18% had history of ever smoking. Mean CD4 count was 652 copies/mL. Mean duration of ARV exposure was 15.0 years.
Seven subjects had previous known cardiac conditions, including one subject each with tetralogy of fallot repaired in infancy, resolved aortic insufficiency, a history of aortic septal defect, a history of viral pericarditis, cardiomyopathy of unknown origin, and 2 subjects with Zidovudine-related cardiomyopathy that had resolved. None of the subjects had cardiac symptoms at the time of evaluation.
Similar to previous cohorts, the study revealed a high percentage of traditional cardiac risk factors, including 7.4% with high cholesterol (total fasting cholesterol >200 mg/dL), 26% with elevated triglycerides (total fasting triglycerides >150 mg/dL), and 37% with low high-density lipoprotein (<40 mg/dL). One subject was being treated for hypertension with medication and had controlled blood pressures during study visits.
More than half (14/27) of the subjects had CAA with luminal narrowing detected on magnetic resonance angiography; 13 classified as level 2 and 1 classified as level 3. Based on the cardiologists' clinical recommendation, the subject classified with a level 3 had a coronary computed tomography, which corroborated findings of atherosclerotic disease.
There was no association between previous cardiac conditions and CAA. Of the 14 patients with CAA, 2 had a history of cardiac complications including viral pericarditis and Zidovudine-related cardiomyopathy. The remaining 12 patients with CAA did not have previous cardiac conditions. Two of the subjects with CAA (and none of the patients without abnormalities) had ejection fraction abnormalities (<55%).
Interestingly, there was no increase in years of protease inhibitor or total ARV exposure in subjects with CAA. However, subjects with abnormalities had greater duration of exposure to tenofovir (2.3 vs. 0.84 years, P = 0.005) and emtricitabine (1.2 vs. 0.29 years, P = 0.01). Although not statistically significant, subjects with CAA tended to have higher low-density lipoprotein cholesterol (92 vs. 78 mg/dL, P = 0.24), higher CRP (0.29 vs. 0.12 mg/dL, P = 0.20), and were more likely to have a history of smoking (29% vs. 8%, P = 0.17). There was no difference in d-Dimer, homocysteine, pro-brain natriuretic peptide, HIV viral load, or CD4 count between those with and without CAA. In a multivariate regression analysis that included tenofovir years, emtricitabine years, low-density lipoprotein, CRP, and smoking, only history of smoking was a significant predictor of CAA (P = 0.03).
The high rate of CAA observed in adolescents and young adults who acquired HIV early in life suggests possible early atherosclerosis in this population. The advent of new, less invasive technology allows better understanding of early changes. Because of the novelty of the technology, normative values are unavailable. However, one would not expect a high rate of CAA in this population. Coronary artery calcium has been used as a measure of early, subclinical disease in a healthy young adult population with a similar age distribution (18–30 years), which identified an overall prevalence of 9.3% of patients with coronary artery calcium.10 MRI technology has been validated for detecting severe CAD, but has not been validated for detecting preclinical or minimal disease. We did an internal validation by requiring each lesion to be seen in 3 sequences in the same location.
The changes observed most probably signify vessel wall thickening as a result of early plaque development. Inflammation plays an important role in plaque development,11 especially at the early stages and in HIV-related vasculopathy. Therefore, the exact etiology of wall thickening cannot be determined in this small study and can represent either inflammation or CAD.
In this small cross-sectional study, causality cannot be established and interpretation of associations with individual ARV medications must be made with caution. Tenofovir DF and emtricitabine have not been previously reported as increasing the risk of CVD in HIV and their association does not persist in multivariate analyses. Smoking history, which has more physiologic relevance, appears to be a more relevant predictor of CAA. However, because of the small sample size, it is difficult to make conclusions about specific risk factors. These preliminary data do highlight the importance of examining subclinical disease. Studying early disease is critical in identifying modifiable risk factors and in understanding disease progression, which will aid in developing appropriate screening methods and interventions.
A considerable portion of the study participants had previous cardiac conditions. This may be related to the risk of acquiring HIV from surgery-related blood transfusions during the 1980s and the cardiotoxic effects of both untreated HIV and medications used in HIV treatment. However, the patients with prior cardiac conditions were not more likely to have CAA.
There are several limitations with the current study including a small sample size, lack of a control group, and the use of novel MR technology. Despite these limitations, the current report is among the first to identify early atherosclerosis in the population of young adults and adolescents with the greatest lifetime exposure to HIV and its therapy.
The authors thank the patients and their families for participation in the study. The authors also thank Jennifer Graf from the NIH dietary and nutrition department for performing anthropometric evaluations on patients.
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