An estimated 35.3 million people are living with HIV worldwide.1 An estimated 107,800 people in the United Kingdom were living with HIV in 2013, with one in 4 people living with HIV infection aged 50 years and over.2 The introduction of effective combination antiretroviral therapy (cART) in the mid 1990s has transformed HIV infection from a fatal to a chronic lifelong condition in the developed world. Increasingly, this is also the case in low-to-middle income countries as access to treatment improves.1 Despite this, mortality rates in HIV-infected patients are still higher than in the general population and non–AIDS-related morbidity and mortality is increasing.3,4 Cardiovascular disease, particularly ischemic heart disease, is an important cause of morbidity and mortality among HIV-infected individuals.3,5 Although traditional cardiovascular risk factors are highly prevalent and accepted to play a role in HIV-associated cardiovascular disease,6,7 the role of long-term cART and HIV infection itself remains controversial.
Atherosclerosis is a complex, active, and progressive disease with inflammation involved at every stage. Chronic inflammatory diseases, such as rheumatoid arthritis,8 and infections, such as Chlamydia pneumoniae and cytomegalovirus,9 have been shown to be associated with excess and premature cardiovascular risk. Assaults to the endothelium result in repair through upregulation of innate and adaptive immune systems.10 If the endothelial insult is repeated or continuous, the inflammatory process is continued, amplified, and becomes maladaptive, resulting in intimal proliferation11 and eventually in atheroma. HIV infection causes chronic inflammation with persistently increased inflammatory markers.12 These increase with increasing viremia13,14 and predict mortality.15 HIV infection is associated with raised markers of endothelial activation including vascular cell adhesion molecule-1, P-selectin, and monocyte chemoattractant protein-1, which decrease but may not normalize with antiretroviral treatment.14 Immune dysfunction may also contribute to the increased risk for atherosclerosis in HIV-infected individuals. Relative risk of ischemic heart disease among patients with a CD4+ cell count ≤200 cells per microliter was found to be greater than in those with a cell count >200 cells per microliter at antiretroviral therapy initiation.16 Activated T-lymphocytes in HIV-infected individuals have been found to be associated with subclinical carotid artery disease.17
Carotid artery intima-media thickness (C-IMT) assessed with B-mode ultrasound has been shown to be predictive of future cardiovascular events in HIV-uninfected individuals.18–20 C-IMT has been used in numerous studies to assess for the presence and rate of progression of subclinical atherosclerosis in HIV-infected individuals.21,22 Findings have been conflicting because of variation in study design and ultrasound methodology. The presence of confounding variables, such as a high burden of traditional cardiovascular risk factors in the HIV-infected groups, and exposure to antiretroviral therapy, has made the effect of HIV infection itself hard to ascertain.
Carotid vessel wall imaging by cardiovascular magnetic resonance (CMR) can overcome many of the limitations of C-IMT, which include one-dimensionality, variability of measurement site, and near field artifacts. It can be performed with constant resolution along the length of the artery and combined into a three-dimensional model giving the wall volume for the length of artery studied. CMR measurements of wall area and thickness have been shown to correlate well with measurements of C-IMT.23 Reproducibility is good with interstudy coefficients of variation of 4.4%,24 allowing for a greatly reduced sample size in clinical studies. Interrater variability is low, with interobserver intraclass correlation coefficient of 0.96 at 1.5T field strength25 and 0.90–0.99 at 3T.26
We report the first study using CMR to assess carotid wall thickness and determine the level of subclinical atherosclerosis in HIV-infected individuals with low cardiovascular risk, compared to a low cardiovascular risk, HIV-uninfected cohort.
Patients and Setting
HIV-infected individuals (n = 33) were recruited from the outpatient HIV unit at St Mary's Hospital, Imperial Healthcare NHS trust, London, United Kingdom. Inclusion criteria included HIV infection (known HIV antibody positive for at least 2 years as we wanted to selected patients who have been living with HIV for more than 2 years), male or female sex, 20–70 year old, stable on cART, and plasma HIV RNA <50 copies per milliliter (Quantiplex assay; Bayer, Emeryville, CA). Exclusion criteria were current or history of cardiovascular disease or positive family history of premature vascular disease, current, or history of major modifiable risk factors for atherosclerosis (current or former smoking, hypertension, hyperlipidemia, and diabetes), Framingham cardiovascular risk of more than 10% or DAD risk of more than 5%. The DAD risk equation is a cardiovascular risk score specifically developed for HIV-infected patients. It was based on the results of a large multicentre cohort study [The Data Collection on Adverse Effects on Anti-HIV Drugs (D:A:D) Cohort], conducted mainly in Europe and North America. Other exclusion criteria included taking any cardiovascular medication (eg, antiplatelet, antihypertensive, lipid-lowering medications), current alcohol abuse or recreational drug use of less than 6 months, or contraindication to CMR. The study was approved by the Imperial College London NHS health care trust Ethics Committee (reference number: 11/LO/1059) and all subjects provided written informed consent before enrollment. A control group comprising a historic cohort of HIV-uninfected healthy subjects (n = 35) with no known cardiovascular disease, no current or history of major modifiable risk factors for atherosclerosis, and low cardiovascular risk scores (<10%), matched for age, sex, and where possible, ethnicity (self-reported for both groups) was used.27 CMR was performed at the Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, United Kingdom. A single experienced investigator performed all HIV-infected subject analyses, blinded to all parameters other than HIV status. All the CMR images were analyzed using dedicated software (Atheroma Tools, a plug-in of CMR tools; Cardiovascular Imaging Solutions, London, United Kingdom).
A detailed assessment including age, height, weight, body mass index, ethnicity, HIV-disease history, and assessment of cardiac risk factors, including family history of coronary artery disease and Framingham and DAD cardiovascular risk scoring, was performed at a screening visit. Blood pressure, electrocardiography (ECG), and blood tests (CD4 lymphocyte count, plasma HIV RNA, fasting lipids, glucose, electrolytes, urea, and creatinine) were also performed. Subjects who reported no cardiovascular risk factors but were found to have elevated blood pressure (>140/90 mm Hg), elevated total cholesterol to HDL ratio (>5), triglycerides or glucose, or abnormal ECG were excluded from the study and referred to their physician for further management.
Carotid CMR was performed using a 3.0T scanner (Siemens Skyra, Erlangen, Germany) and a purpose-built bilateral 4-channel phased-array carotid surface coil (Machnet BV, Eelde, the Netherlands), with the head and neck immobilized. A contiguous stack of 20 high resolution T1-weighted fast spin echo images, centered on the carotid bifurcation bilaterally, was acquired approximately perpendicular to the longitudinal axis of both common carotid arteries, giving 40 mm of longitudinal coverage per artery. Slice thickness was 2 mm. Typical T1-weighted fast spin echo image sequence parameters were field of view read 110 mm, field of view phase 100%, echo time 11 milliseconds, echo train length 9, readout time 90 milliseconds, bandwidth 230 Hz/pixel, 3 averages, pixel size 0.43 × 0.43 mm (interpolated to 0.21 × 0.21 mm), ECG-gated to each cardiac cycle with end-diastolic triggering. Dark blood preparation was used with the inversion time determined by average R-R interval.
The internal and external carotid artery surfaces were manually traced giving luminal and total vessel areas for each slice. Two-dimensional semiautomated modeling by the software assisted where flow suppression was incomplete. The lumen and wall volumes were automatically calculated for each 2-mm slice and summated to create a three-dimensional model from which total lumen volume, wall volume, and vessel volume were derived. Total wall volume was expressed as a percentage of the total vessel volume (wall/outer-wall or W/OW ratio—an index of vascular thickening). A cine image perpendicular to the common carotid artery was manually contoured at end diastole and end systole for each side, and the percentage distensibility was calculated.
The historic non–HIV-infected cohort had been previously scanned on a 1.5T scanner using a similar protocol. Images had been previously analyzed using the same standard methods as used in this study to provide “normative” data and a control group for future studies.27 Previously, measures of carotid wall volume have been compared between 1.5T and 3.0T magnetic field strengths with no significant differences reported, allowing comparison between scans acquired at the different field strengths to be made.28
In a previous study by Keenan et al,27 the age group with the highest change in wall volume (60–69 year old) showed a mean wall volume of 1083 mm3 with an estimated SD of 189. Assuming an increase of 25% in wall volume among HIV-infected individuals, a sample size of 22 patients (11 cases and 11 controls) would be required, to detect differences between groups. We aimed to recruit an age- and sex-matched sample of 5 subjects per age group (20–39, 40–49, 50+ years) per sex.
Categorical data were presented as number (percentage) and comparisons undertaken using the χ2 or Fisher Exact test. Numeric data were presented as a mean (SD) or 95% confidence interval if the data were normally distributed and analyzed using a 2-sample independent t test. Where data were not normally distributed normality was determined using visual inspection of graphical data and test for normality. Median (interquartile range) was presented and comparisons were done using the Mann–Whitney (Wilcoxon rank-sum) test. Linear regression analysis was performed to assess the strength of association between measured variables (W/OW, carotid artery wall volume, carotid artery lumen volume, total carotid artery volume) and age. The association of demographic and HIV-specific parameters with W/OW was analyzed using linear regression.
Demographics, blood pressure and laboratory values, and coronary risk scores in HIV-infected subjects and age- and sex-matched control subjects are shown in Table 1. Age, sex distribution, total cholesterol levels, blood pressure, body surface area, age, and 10-year coronary risk were similar between both groups.
HIV-infected subjects had a mean age of 45.2 ± 9.7 years. Mean duration of known HIV infection was 8.8 ± 4.4 years. All subjects were stable on cART with a median duration of treatment of 7 years (2–21 years); 24 were on a nonnucleoside reverse transcriptase inhibitors–based regimen and 9 on a protease inhibitor (PI)–based regimen. All subjects were receiving an NRTI backbone that comprised tenofovir, abacavir, and zidovudine in 24, 6, and 3 subjects, respectively. Of those on a PI-based regimen, 5 were on darunavir, 3 were on atazanavir, and 1 was on lopinavir. All patients on PIs were on a boosted combination with ritonavir.
Carotid CMR Measurements
Carotid artery walls were significantly thicker in HIV-infected individuals compared with controls (Table 2). W/OW was significantly greater (P < 0.0001) in HIV-infected subjects (36.7% ± 3.7%) compared with the control group (32.5% ± 2.8%); this was more marked in HIV-infected females (Table 3). There were no significant differences between total carotid lumen volume, total carotid artery volume, and total carotid wall volume between the study groups, although the total wall volume was increased in HIV-infected individuals (1712 ± 317 mm3) compared with the control group (1575 ± 418 mm3). There was no statistically significant difference in carotid artery distensibility between the 2 groups, although values were lower in HIV-infected patients (22.9% versus 24.2%, P = 0.35). Univariate regression analysis revealed HIV infection to be positively associated with W/OW (coefficient 5.28, P = 0.0001). Multivariate regression analyses were performed to assess the relationship between demographic and HIV-disease parameters and W/OW ratio. Parameters included are age, ethnicity, CD4 cell count, nadir CD4 cell count, years since HIV diagnosis, years on cART, and usage of NRTI or PIs—no significant associations were found other than a lower W/OW ratio of 5.48 (P = 0.038) when comparing the NRTI abacavir to zidovudine. In the multivariate analysis, W/OW remained significantly associated with HIV status, independently of age (r = 4.37, P = 0.001). There was no significant association between any other demographic or HIV-specific parameters and W/OW.
Carotid Artery Aging in HIV-Infected Individuals
Carotid artery lumen volume, total wall volume, total vessel volume, W/OW ratio, and average distensibility for all subjects according to age group and divided by sex are presented in Table 4. Wall volume, total vessel volume, and W/OW increased with age in both the HIV-infected and HIV-uninfected groups (Fig. 1). No carotid plaques were detected in either group.
As with the HIV-uninfected controls, predictors of increased W/OW, wall volume, and total vessel volume in the HIV-infected group were age and male sex. In HIV-infected males, wall volume and total vessel volume were positively associated with age. However, after the third decade, there is an accelerated increase of vessel wall thickening (W/OW ratio) compared with control group males (Fig. 1B). In HIV-infected females, a significantly increased WO/W was observed compared with female controls (36.4% versus 31.3%, P = 0.0002). The increase in W/OW was more marked in HIV-infected females than in HIV-infected males when compared with their respective controls (36.2% versus 33.4% P = 0.0019). Of note, in HIV-infected females, the increase in W/OW was present from the third decade, with very little change throughout. This trend is different from the one observed in the female control group where W/OW significantly increased with age (Fig. 1C).
This carotid CMR study demonstrates that subjects with treated HIV infection and low cardiovascular risk exhibit early atherosclerosis at a younger age compared with controls. As increased C-IMT is an independent predictor of myocardial infarction and stroke,18–20 the rate of vascular events is therefore likely to remain elevated despite aggressive control of traditional cardiovascular risk factors in HIV-infected patients.
The antiretroviral agents indinavir, abacavir, and lopinavir are reported to be independently associated with increased cardiovascular disease risk in the DAD study.29 Other studies have produced conflicting results with regard to the contribution of HIV infection, type of antiretroviral therapy, and traditional risk factors to increased vascular wall thickening using a variety of US measurement techniques. Protease inhibitors have been associated with increased carotid plaques30 and C-IMT,31 but larger and more recent studies have found no association with increased C-IMT.32,33 Our study has not shown an association between PI-containing antiretroviral regimens and increased vascular wall thickness when compared with non–PI-containing antiretroviral regimens but was not powered to do so and contains few patients on PI-containing therapy. The lower W/OW ratio when comparing the NRTI abacavir to zidovudine in this study is contrary to the increased cardiovascular risk generally associated with abacavir.16 The large confidence interval (−10.63 to −0.34), low sample size (6 abacavir, 3 zidovudine), and overall poor fit of the model, with low R-squared of 0.14, make this finding unlikely to be of real significance. This result may also reflect a channeling bias whereby clinicians only use abacavir in subjects they consider to have very low cardiovascular risk.
Increased C-IMT and its progression over time have been shown to be associated with traditional cardiovascular risk factors.32 Our study included HIV-infected and HIV-uninfected cohorts with no traditional cardiovascular risk factors. Although our study has not followed up patients or controls longitudinally, the diverging lines between the groups with increasing age (Fig. 1A) suggests that HIV infection and/or its treatment may be associated with progression of vascular wall thickening beyond that normally seen with age.27 Moreover, risk does not seem to be abolished by viral suppression, although the virus is not eradicated: chronic, low-grade inflammation, and T-cell activation has been shown to persist.17,34,35 Exposure to HIV infection and/or the toxic effects of cART are possible causative factors in the increased cardiovascular disease risk seen in HIV. If the increased vascular thickening solely reflected a historic period of untreated HIV infection or suboptimal viral suppression, one might expect the difference between the groups would not increase with age. However, as a cross-sectional study, there may be unmeasured differences between the younger and older HIV-infected subjects, eg, immunosenescence in older subjects may allow the effects of HIV infection and/or the toxic effects of cART to be more marked, resulting in the observed divergence of the lines with age in Figure 1A.
Hsue et al33 found that, in their HIV-infected cohort, C-IMT was higher, progressed more rapidly, and was associated with a nadir CD4+ count <200 cells per microliter, suggesting that HIV infection itself is a predictor of increased C-IMT. A recent study following 2 large cohorts of HIV-infected and HIV-uninfected individuals using B-mode ultrasound, however, has found no association of increased C-IMT over time with HIV infection, beyond that seen with age.22 Carotid plaque development however, was significantly higher in the HIV-infected cohort when there was a CD4+ count <500 cells per microliter at baseline, the risk rising the lower the CD4+ count. No association of plaque formation and nadir CD4+ level was found. Our study measured wall volume, which would incorporate the various locations measured for C-IMT and the separate areas of thickening defined as plaques in the ultrasound studies. In our study, multivariate analysis showed a trend to increased wall volume and increased W/OW with baseline CD4+ counts <500 cells per microliter; no such trend was seen with nadir CD4+ counts. As our numbers are small and only 8 of our cohort had baseline CD4+ counts <500 cells per microliter, and none <200 cells per microliter, it is not however possible to draw any firm conclusions; indeed, our study was not powered to detect these.
We observed a markedly increased W/OW in HIV-infected females. A possible explanation for this finding may be related to sex hormones. Estrogen and androgen receptors are found in vascular tissue, with androgens mediating a variety of actions on endothelial and smooth muscle cells.36
Estrogen's cardioprotective role is well established. Estrogen has been shown to protect against HIV Tat protein-induced inflammatory reactions in human vascular endothelium.37 Progesterone, used in many hormonal contraceptives, exerts an immunosuppressive effect that may result in susceptibility to HIV progression38 and hence possible vascular damage. HIV infection can also cause premature ovarian insufficiency and menopause,35 reducing estrogen levels. Therefore, HIV infection may cause excess atherosclerosis in HIV-infected females through changes in sex hormones relative to controls. However, information about contraception method, levels of sex hormones, and numbers of females who were perimenopausal or postmenopausal in our study are unknown.
The assessment of carotid vascular wall thickening and plaque quantification using CMR has been studied in a variety of patient groups including those at high risk of and with known cardiovascular disease,23,25 and also in those with chronic inflammatory diseases associated with accelerated atherosclerosis.39 CMR has also been used in longitudinal studies to assess the effect of drugs, such as the cholesterol-lowering statins40 or immunomodulatory drugs,41 on carotid vascular disease progression/regression. Carotid CMR would therefore also be applicable in the study of HIV-infected individuals with traditional CVD risk factors, such as hypertension, hyperlipidemia, or smoking, or in those with markers of suboptimally treated HIV infection, treated with either established cardiovascular or antiretroviral drugs, or with novel treatments. It is likely that the degree of atherosclerosis is greater in individuals with CVD risk factors. The results of this study may provide a baseline against which the contribution of other risk factors and their treatments can be measured.
This study has a number of limitations. Although adequately powered overall, the low numbers of older female HIV-infected subjects may be a reason why we observed a less marked difference in W/OW in older females compared with controls (Fig. 1C). The HIV-infected group had a higher proportion of black individuals than the control group (Table 1) so possible racial variation in W/OW cannot be excluded. Previous studies have shown that in adults of black ethnicity, C-IMT is higher than in white adults at the level of the common carotid, but not the internal carotid arteries.42,43 However, the results in those studies could have been affected by differences in traditional cardiovascular risk factor profiles between the racial groups (despite being adjusted for statistically).42 The use of a length of the common and internal carotid arteries in our study should reduce the effect of race in our results. In view of this, we believe that the increased W/OW in HIV-infected subjects in our study is unlikely due solely to the different racial profile between the groups.
No significant association between W/OW and the use of abacavir or PIs has been found in our study. This may be due to the study not being powered to detect this effect or the exclusion of patients who are susceptible to and clinically manifesting the deleterious metabolic effects of cART, namely, abnormal lipid profile and hyperglycemia.
As a cross-sectional cohort study, it is not possible to attribute the observed carotid vascular thickening to HIV infection itself, as all the individuals were on cART.
CLINICAL IMPLICATIONS AND CONCLUSION
This carotid CMR study has shown evidence of premature subclinical atherosclerosis in a cohort of treated HIV-infected individuals with low measurable cardiovascular risk factors. Despite being stable on cART with good viral suppression, they still exhibit early and greater carotid vascular thickening compared with HIV-uninfected controls. As increasing C-IMT has been found to be independently predictive of future stroke and myocardial infarction in HIV-uninfected populations,18–20 the findings of this study suggest that the rate of vascular events is likely to remain elevated in HIV-patients despite aggressive treatment of cardiovascular risk factors, highlighting the need for improved patient and health care provider education to detect and manage aggressively early signs of cardiovascular disease. Given the known low-grade inflammation and immune activation associated with HIV infection12 and the known deleterious metabolic effects of existing cART regimens,28 the presence of premature subclinical atherosclerosis despite the exclusion of all traditional cardiovascular risk factors highlights the need for the development of novel antiretroviral treatments.
The authors are grateful to the staff of the CMR Unit and the Cardiovascular BRU, Royal Brompton Hospital for their support with this work and the medical and administrative staff at St Mary's Hospital who assisted with data collection.
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