Imaging atherosclerosis in HIV: carotid intima-media thickness and beyond

REVIEW ARTICLES Imaging atherosclerosis in HIV: carotid intima-media thickness and beyond CHRIS T. LONGENECKER, and BRIAN D. HOIT CLEVELAND, OHIO

Chronic immune activation and inflammation are associated with an increased risk of atherosclerosis in HIV-infected patients. In this review, we discuss the role of established and novel imaging modalities to define more accurately the structure and function of inflammation-mediated atherosclerosis in the context of HIV. Historically, carotid ultrasound studies were the first to show higher rates of subclinical atherosclerosis in HIV-infected subjects versus uninfected controls. However, computed tomography is the noninvasive gold standard for imaging the coronary arteries, and studies in HIV suggest a higher prevalence of noncalcified plaque. Endothelial dysfunction can be quantified by measuring flow-mediated brachial artery dilation by ultrasound and has been used extensively in antiretroviral switching trials and small pilot trials of therapeutics to assess cardiovascular risk in this population. In the future, novel imaging modalities such as intracoronary optical coherence tomography, positron emission tomography imaging of 18F-fluorodeoxyglucose uptake, and molecular-targeted magnetic resonance imaging will characterize the burden of vulnerable plaque and other unique features of inflammatory atherosclerosis in HIV. (Translational Research 2012;159:127–139) Abbreviations: 2-D ¼ 2-dimensional; 3-D ¼ 3-dimensional; ART ¼ antiretroviral therapy; CIMT ¼ carotid intima-media thickness; CT ¼ computed tomography; CTA ¼ computed tomography angiography; FDG ¼ 18F-fluorodeoxyglucose; FMD ¼ flow mediated brachial artery dilation; IVUS ¼ intravascular ultrasound; MACS ¼ Multi-center AIDS Cohort Study; MRA ¼ magnetic resonance imaging angiography; MRI ¼ magnetic resonance imaging; OCT ¼ optical coherence tomography; PET ¼ positron emission tomography; PI ¼ protease inhibitor; SPECT ¼ single photon emission computed tomography; TCFA ¼ thin-capped fibroatheroma; USPIO ¼ ultrasmallsuperparamagnetic iron oxide; WIHS ¼ Women’s Interagency HIV Study

ince the introduction of combination antiretroviral therapy (ART) in the mid-1990s, the natural history of HIV infection and progression to AIDS has been altered dramatically. With the suppression of viral replication on ART, HIV-infected patients now successfully maintain or recover a high level of immune function, thus avoiding the severe opportunistic

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infections that characterize AIDS. However, a low level of chronic immune activation and inflammation persists, and it seems to be associated with the accelerated aging of multiple body systems and increased incidence of atherosclerotic cardiovascular disease, renal dysfunction, neurodegenerative disease, and cancer. Many mechanisms of immune activation and inflammation

From the Harrington-McLaughlin Heart and Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio; Case Western Reserve University, Cleveland, Ohio.

Reprint requests: Brian D. Hoit, MD, Division of Cardiology, University Hospitals Case Medical Center, 11100 Euclid Ave., Cleveland, OH 44106; e-mail: [email protected].

Supported by a research grant from Bristol-Myers Squibb (to C.T.L.).

1931-5244/$ - see front matter

Submitted for publication July 29, 2011; revision submitted October 17, 2011; accepted for publication October 19, 2011.

Ó 2012 Mosby, Inc. All rights reserved. doi:10.1016/j.trsl.2011.10.007

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in HIV have been proposed, including low-level ongoing HIV replication, chronic infections with other viruses such as cytomegalovirus, mucosal immune dysfunction and resultant microbial translocation, and immunosenescence. The role of inflammation in the development of atherosclerosis is increasingly recognized.1 Other chronic inflammatory diseases such as lupus erythematosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease have also been linked to early atherosclerosis and increased cardiovascular risk. Both the innate and adaptive immune systems (and the various proinflammatory cytokines they produce) have been implicated. The translation of this knowledge to the bedside assessment of cardiovascular risk has, in at least 1 example, led to the use of C-reactive protein to guide statin use in primary prevention.2 Imaging technology is rapidly evolving to meet the challenges of identifying both subclinical and symptomatic atherosclerosis. However, it is increasingly recognized that simply identifying the presence of atherosclerosis has limited prognostic value. Rather, recent research has focused on identifying individuals and plaque characteristics that are high risk for acute thrombotic events (ie, the so-called ‘‘vulnerable plaque’’). Indeed, considerable work in this area has focused on imaging the inflammation that may make plaques more prone to rupture and thrombosis. In this review, we will discuss the role of established and novel imaging modalities to define the structure and function of inflammation-mediated atherosclerosis more accurately in the context of HIV. It is apparent that the bulk of studies suggest an increased risk of atherosclerosis in HIV; however, we acknowledge many conflicting studies. The reasons for this are multifactorial but primarily may be the result a lack of standardized methodology for imaging protocols and geographical differences in baseline atherosclerotic risk factors among HIV-infected and uninfected controls. IMAGING THE STRUCTURE OF ATHEROSCLEROSIS IN HIV Summary. The first step in identifying individuals at risk for cardiovascular events such as myocardial infarction is defining the physical presence of atherosclerosis. Carotid ultrasound is the most widely used surrogate marker of cardiovascular risk in studies of HIVinfected individuals. It relies on the fact that the presence of subclinical atherosclerosis in one vascular bed (eg, carotid arteries) correlates with risk in another vascular bed (eg, coronary arteries). Computed tomography (CT) is the noninvasive gold standard for imaging the coronary arteries, and studies in HIV

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point to important differences between infected and noninfected populations. However, it is more expensive than ultrasound and exposes the patient to radiation and/or contrast dye. Magnetic resonance imaging (MRI) has important applications in imaging the structure of peripheral vascular atherosclerosis, although the experience in HIV is limited. Carotid ultrasound. The first reports of severe premature atherosclerosis among HIV-infected patients appeared in the literature in 1998.3 Investigators soon began adapting imaging technologies to identify subclinical atherosclerosis in this population. Highresolution, B-mode ultrasound of the carotid arteries, specifically measurement of carotid intima-media thickness (CIMT), has been well validated in the noninfected population as a surrogate marker of cardiovascular risk.4-6 The CIMT measurement correlates accurately with pathologic specimens.7 It is highly reproducibly measured over time, is relatively inexpensive, and does not expose the patient to radiation. For these reasons, the technology has been adapted widely as a research tool to compare HIVinfected populations with matched controls and to identify the predictors of atherosclerosis in HIV. The guidelines for carotid IMT imaging have been published by the American Society of Echocardiography and endorsed by the Society of Vascular Medicine.8 Studies are performed in a quiet, dark room with the patient lying supine and the neck tilted back slightly. An 8–12-MHz linear-array ultrasound transducer is then used to obtain images of the distal 1 cm of the common carotid artery (Fig 1). Image quality should be adjusted to visualize clearly the intima-media boundary and media-adventitia boundary. The American Society of Echo guidelines suggest obtaining images of the common carotid at 3 angles (anterior, lateral, and posterior) on both the left and right sides. The IMT is measured offline with semiautomated edge detection software to maximize reproducibility. A mean value for each segment is obtained, and an average of the segmental means is reported typically as the mean–mean CIMT. Atherosclerotic plaques should also be noted and reported separately. IMT is a 1-dimensional measurement that is well validated in large population-based cohorts; however, 3-dimensional (3-D) ultrasound techniques have been developed recently that allow volumetric assessment of carotid plaques.9 In patients with frank plaque, morphology (such as evidence of ulceration) and size may be important predictors of risk that are assessed more completely in 3 dimensions. In addition, 3-D ultrasound is more sensitive than IMT for following plaque progression and response to treatment.

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Fig 1. Carotid ultrasound showing a thickened IMT and the presence of atherosclerotic plaque. The carotid IMT is measured as the distance between the intima-media boundary and the media-adventitia boundary (designated here as the distance between the 2 white bars). Semiautomated edge-detection software is used to enhance reproducibility.

In a meta-analysis of 13 cross-sectional studies, HIV infection was associated with a thicker (0.04 mm) carotid IMT compared with the matched controls.10 HIV appears to be associated with a higher risk of progression of IMT over time,11 but this was not confirmed in another study.12 Traditional risk factors such as smoking and dyslipidemia are common in the HIV-infected populations studied, and HIV-specific risk factors such as low nadir CD4 T-cell count are associated with higher carotid IMT and progression.11-13 Increased levels of lymphocyte activation have also been associated with higher carotid IMT and plaque.14,15 To our knowledge, no studies have evaluated the use of 3-D ultrasound in HIV-infected populations. Generally, it is accepted that uncontrolled viremia raises cardiovascular risk in HIV16; however, the cardiovascular risk profiles of individual antiretroviral drugs and drug classes are controversial. In particular, protease inhibitors (PIs) have been associated with an increased risk of myocardial infarction in the large DAD study (Data Collection on Adverse Events of AntiHIV Drugs), which is mediated only partly by their effect on serum lipids.17 However, in most studies, PI use has not been associated with cross-sectional carotid IMT or progression.10 This illustrates the limited ability of anatomic imaging to define cardiovascular risk comprehensively. Computed tomography. CT is another useful modality for defining the structure of atherosclerosis in the coronary vascular bed. Coronary artery calcium scoring, which is obtained from non–contrast-enhanced conventional, multidetector, or electron beam CT scans of the chest, can identify the presence and overall burden of

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calcified coronary atherosclerosis. HIV-infected individuals have higher mean Agatston scores and proportion of scores .0 compared with noninfected controls.10,18-20 In HIV, higher coronary artery calcium has been associated with Framingham risk score21 and the metabolic syndrome,22 as well as higher levels of asymmetric dimethylarginine (an arginine analog and competitive inhibitor of nitric oxide synthase)18 and fatty liver disease.23 Contrast enhanced CT coronary angiography (CTA) provides additional value to calcium scoring by characterizing the degree of luminal stenoses and by identifying the presence of noncalcified plaque (Fig 2). HIV-infected subjects seem to be at higher risk of developing noncalcified plaques on CTA compared with controls.19,24 Furthermore, HIV-specific factors such as CD4/CD8 ratio and HIV duration independently predict plaque burden.19 A recent study using CT angiography provides additional evidence of inflammation and immune activation as a driver of atherosclerosis in HIV.24 The investigators describe a correlation of noncalcified plaque burden with soluble CD163, which is a marker of macrophage activation, that is stronger among HIV-infected individuals compared with noninfected controls. However, the ability of CTA to differentiate calcified from noncalcified plaque remains limited compared with invasive imaging modalities. This is illustrated clearly in the comparison of CTA and intravascular ultrasound in Fig 2, B and C. Disadvantages of cardiac CT include the need for stable, low heart rates (intravenous beta-blockers are frequently used to achieve this, but are contraindicated in some patients), an inability to visualize heavily calcified coronary segments, radiation exposure, and the use of contrast dye (with the risk of allergic reaction or contrast-induced nephropathy). Recent advances in CT technology such as prospective electrocardiogram triggering25 and high-pitch spiral CTA26 are lowering radiation doses levels under 1mSv and allow for higher heart rates, both of which may encourage more widespread use. Magnetic resonance imaging. MRI provides complimentary information to CT and ultrasound regarding the structure of atherosclerosis. Because of longer acquisition times and inferior spatial resolution compared with CTA, magnetic resonance angiography (MRA) is used less often to image the coronary arteries.27 However, time of flight angiography and first-pass MRA with gadolinium-based contrast have found extensive application in the cerebral and peripheral vascular beds.28 Time-resolved MRA is a technique that may use but does not require contrast enhancement to follow blood flow into and through

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Fig 2. (A) CTA of an HIV-infected person showing noncalcified plaque causing significant luminal stenosis. Ao, aorta; LV, left ventricle; RV, right ventricle; RCA, right coronary artery. Image (A) courtesy of Dr. Janet Lo, Massachusetts General Hospital, Boston, Mass. (B) Cross-sectional CTA of a soft, noncalcified plaque with corresponding intravascular ultrasound. The periadventitia boundary is traced in green. The blood–intima boundary is traced in red. (C) Cross-sectional CTA of a mixed calcified and noncalcified plaque with corresponding intravascular ultrasound. Images (B) and (C) courtesy of Dr. Hiram Bezerra, Cardiovascular Imaging Core Lab, University Hospitals Harrington-McLaughlin Heart and Vascular Institute, Cleveland, Ohio.

the extremity (Fig 3). Images obtained by this method compare favorably in spatial and temporal resolution with conventional angiography.29,30 In HIV, MRI has been used to show an association between HIV viremia and atherosclerotic plaque burden in the aorta.31 MRI plaque volume measurement may have application in HIV trials as an alternative ‘‘surrogate marker’’ to CIMT because its high reproducibility (ie, lower coefficient of variability) increases statistical power and allows smaller sample sizes. This has been demonstrated in trials of lipid-lowering therapy in the noninfected population.32,33 Epicardial adipose tissue. The unique physiologic roles of specific fat depots throughout the body are well recognized. Recently, epicardial adipose tissue has emerged as a potentially important mediator of coronary atherosclerosis through paracrine hormonal signaling, and it is a predictor of incident cardiovascular disease in the noninfected population.34 It can be measured volumetrically by CT scan or as the thickness of the epicardial fat pad above the right ventricle in the parasternal views of an echocardiogram. The first group to study epicardial adipose tissue in HIV using echocardiography described a strong correlation (r 5 0.92) with carotid IMT35 and found that epicardial adipose tissue is higher in patients with the metabolic syndrome.36 In the only study that had an uninfected control group, HIV infection was not independently associated with epicardial adipose tissue volume by CT scan.37 However, in a larger study of 876 patients, higher amounts of epicardial adipose tissue were associated with coronary calcium score .100 as well as current CD4 count and duration of antiretroviral therapy.20

It is questionable whether the quantification of epicardial adipose tissue adds additional prognostic value to a CT scan for coronary calcium; however, it may be a useful marker of coronary disease risk in patients who undergo an echocardiogram for other clinical indications. Structural imaging of vascular territories. Each imaging modality described has strengths and weaknesses that guide their practical application in the 3 main vascular territories (coronary, cerebral, and peripheral vasculature). The coronary arteries of a beating heart are best imaged by CTA because of more rapid acquisition times. The cerebral vasculature is best imaged with MRI, although ultrasound is more easily accessible and less expensive for the extracranial vessels. Ultrasound is the first-line modality for the diagnosis of peripheral atherosclerosis because of low cost and wide availability, although MRA can provide timeresolved images that rival conventional angiography in temporal and spatial resolution. FUNCTIONAL IMAGING OF ATHEROSCLEROSIS IN HIV Summary. The physical quantity of atherosclerosis in large arteries does not capture the functional aspects of atherosclerosis that also contribute to cardiovascular risk in HIV-infected patients. In addition, atherosclerotic plaques grow slowly over time, which limits the usefulness of anatomic measurements in testing the effect of an intervention on cardiovascular risk. In contrast, flow-mediated brachial artery dilation is an ultrasound measurement of endothelial function that is highly sensitive to environmental and drug interventions, and it has been a useful tool for testing the

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Fig 3. Contrast-enhanced time-resolved MR angiogram of a patient with peripheral vascular disease. (A–E) Coronal maximal intensity projections from consecutive 4.9-s time frames reveal asymmetric left/right filling and occlusion of the left popliteal artery. AT, anterior tibial artery; PT, posterior tibial artery. (F) Time-of-arrival map shows the late filling of the right side (arrow) compared with the left. Red-orange represents early filling and green-blue is later filling. Used with permission from Clinical Anatomy (John Wiley and Sons).29

risk profile of individual antiretroviral drugs or adjunctive therapies. Preliminary studies suggest that nuclear myocardial perfusion imaging may provide insight into the functional significance of atherosclerosis of both epicardial coronary arteries and the coronary microvasculature in HIV. Finally, arterial stiffness is another important functional consequence of atherosclerosis; however, studies in HIV are limited by the lack of uniform methods and outcome measures. Flow-mediated brachial artery dilation. The arterial endothelium is a complex organ that can respond to various physiologic stimuli or vessel injury by regulating vascular smooth muscle tone and by interacting with platelets and leukocytes. The normal vasodilatory response to shear stress is dependent on the local production of nitric oxide and prostaglandins by the endothelium; early in the pathogenesis of atherosclerosis, this pathway becomes dysfunctional.38 Brachial artery reactivity testing was developed to assess endothelial dependent flow-mediated vasodilation (FMD) noninvasively, and it has been shown to predict cardiovascular events in patients with established dis-

ease39 as well as incident cardiovascular events in asymptomatic patients.40 FMD has become a useful surrogate marker of cardiovascular risk in pilot trials of cardiovascular risk-reduction interventions. The technique is reproducible and highly sensitive to interventions, such that significant improvements can be observed in cross-over studies consisting of as few as 20–30 subjects. The International Brachial Artery Reactivity Task Force has published guidelines regarding its use.41 FMD studies should be performed in a quiet, temperature controlled room after an 8-12 hour fast. Subjects must also refrain from smoking 4-6 hours prior to the test. The subject lies supine with the arm in a comfortable position for imaging the brachial artery. A baseline high-resolution (2-dimensional) 2-D ultrasound image of the brachial artery in the longitudinal plane is then obtained at a location above the antecubital fossa that best visualizes the vessel intima (Fig 4). Veins and other soft-tissue landmarks are used to mark this location as the reference. A blood pressure cuff is placed on the upper arm or forearm and inflated to approximately 50 mm

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Fig 4. Ultrasound of a longitudinal brachial artery used to measure flow-mediated brachial artery dilation. Care must be taken to achieve a perpendicular angle of insonation through the center of the vessel so that the vessel diameter is not foreshortened. Typically, the diameter of the vessel is measured between the media-adventitia interface of the near and far vessel walls as shown here, although the intima-lumen interface may be used also.

Hg above the systolic pressure to occlude blood flow completely for 5 min (Fig 5). After release of the cuff, high-velocity hyperemic flow causes shear stress and vessel dilation. Repeated 2-D images of the artery at specified intervals after cuff release (typically 60 and 90 s) are then used to calculate the percent of vasodilation. Measurements are taken at the same time in the cardiac cycle using electrocardiographic gating. Automatic edge-detection software is used to improve accuracy and reproducibility. FMD is expressed as the change in diameter as a percentage of the baseline diameter. The baseline diameter can affect the results significantly and must always be reported. FMD is impaired in HIV-infected individuals compared with uninfected controls after adjustment for smoking, sex, and body mass index.42 Within the infected population, the degree of HIV viremia seems to be one of the most important independent predictors of FMD.42-44 In addition to traditional risk factors, other factors associated with impaired FMD in the HIV-infected population include injection drug use,42 periodontal disease,45 and vitamin D deficiency.46 Along with carotid IMT, brachial artery reactivity testing has been used to examine the cardiovascular risk profiles of ART. PIs were associated with impaired FMD in 1 study from early in the era of combination ART,47 although more recent studies have not confirmed this finding.42 Furthermore, in a randomized trial of ART initiation, equally significant improvements in FMD were found in both PI-containing and PI-sparing regimens.44 Atazanavir is a protease inhibitor with a more favorable effect on serum lipids; however, 2 trials that switched patients to an atazanavir-containing

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Fig 5. Schematic drawing of brachial artery ultrasound to measure flow-mediated dilation. This drawing shows upper vs lower cuff placement and transducer position above the antecubital fossa. BP, blood pressure.Used with permission from the Journal of the American College of Cardiology (Elsevier Science, Inc).41

regimen failed to show improvement in FMD.48,49 Abacavir, which is a nucleoside reverse transcriptase inhibitor that was associated with risk of myocardial infarction in the DAD study, has also been associated with impaired FMD, although its effect on cardiovascular risk remains controversial. Both statins50 and niacin51 seem to improve endothelial function in small studies of HIV-infected persons. Other small pilot studies have shown beneficial effects of anti-inflammatory agents such as pentoxifylline.52 Salsalate improved FMD in 1 study53 but was tolerated poorly and had no effect on FMD in another study.54 Myocardial perfusion imaging. Myocardial perfusion imaging with single-photon emission computed tomography (SPECT) or positron emission tomography (PET) is used commonly to assess the functional significance of coronary atherosclerosis. The added prognostic value of perfusion imaging in exercise and vasodilator stress testing is well established in a variety of clinical settings including subclinical disease, stable angina, and acute coronary syndrome.55 Perfusion defects are observed in the setting of obstructive epicardial disease but also can be found in microvascular dysfunction and impaired coronary flow reserve. Few studies have examined myocardial perfusion in HIV. A study of 105 HIV-infected adults and 105 matched controls in Mexico City found no difference in stress myocardial perfusion using gated-SPECT with technetium-99 sestamibi.56 Similarly, a Danish group found no difference in baseline myocardial perfusion or coronary flow reserve by PET in 25 HIV-infected subjects on stable ART with durable virologic suppression compared with 14 controls.57 However, the same group observed reductions in maximal myocardial perfusion and perfusion reserve in 12 treatment-na€ıve

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patients who were initiated on ART.58 These findings are unexpected in light of recent work associating biomarkers of inflammation (C-reactive protein, interleukin-6, and endothelial adhesion molecules) with impaired coronary flow reserve by PET,59 as well as a study showing a high prevalence of perfusion defects on stress cardiac MRI in lupus patients without obstructive coronary disease.60 Arterial stiffness. One of the earliest functional changes in the atherosclerotic process is a change in arterial distensibility. Multiple measures of arterial stiffness have been proposed using B-mode ultrasound (distensibility coefficient, compliance coefficient, and Young’s elastic modulus) and applanation tonometry (augmentation index, small and large artery elasticity, and pulse-wave velocity). In the noninfected population, measures of arterial stiffness predict risk of coronary artery disease61 and cardiovascular mortality.62 Most studies comparing HIV-infected and uninfected adults, including a large combined analysis of 2789 patients in the Women’s Interagency HIV Study (WIHS) and the male Multi-Center AIDS Cohort Study (MACS), have shown HIV infection to be an independent predictor of arterial stiffness.63-67 However, a study in Rwanda found no difference in augmentation index among 276 infected women and 67 negative controls.68 It is notable that in Rwanda, as in other African countries, the HIV- infected and uninfected populations are similar, and observational research in this setting is less likely to be affected by unknown confounding. In addition to traditional risk factors, HIV-specific factors associated with increased arterial stiffness include current CD4 count ,200,64 low nadir CD4 count,69 longer duration of HIV infection,70 and higher amounts of T-cell activation.71 The initiation of ART seems to be associated with impaired femoral distensibility, despite improvements in other markers of endothelial function.72 Current and cumulative protease inhibitor use has been associated with impaired pulse-wave velocity and augmentation index67,70,73; however, protease inhibitor use did not affect carotid distensibility in the large WIHS and MACS cohorts.64 It is evident that the literature on arterial stiffness in HIV is limited by the ability to compare the various outcome measures across studies. Thus, the lack of a well-validated, standardized outcome measure has limited the use of arterial stiffness as a surrogate marker of cardiovascular risk in HIV clinical trials. Functional imaging of vascular territories. The functional measures of atherosclerosis described are general measures of vascular health and are not specific to particular vascular beds. Nonetheless, nuclear myocardial perfusion imaging provides a well-validated measure

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of the functional significance of obstructive atherosclerosis in the coronary vascular bed. The tests of arterial stiffness and brachial artery reactivity are functional measures of atherosclerosis that are performed on peripheral vessels, but both methods predict strongly the coronary and cerebrovascular risk. Some functional tests such as stress testing for coronary disease or the ankle-brachial index for peripheral artery disease do not necessarily require imaging and are beyond the scope of this review.

IMAGING INFLAMMATION AND THE VULNERABLE PLAQUE Summary. Data from autopsy series suggest that atherosclerotic lesions in HIV may differ histologically from typical atherosclerosis. However, most of the structural and functional imaging modalities discussed thus far cannot visualize arteries (especially coronary arteries) with enough resolution to characterize these differences fully. Intravascular imaging with ultrasound (IVUS) and optical coherence tomography (OCT) can distinguish lipid laden from calcified plaque and detect the presence of thin-capped fibroatheromas which are more vulnerable to rupture. Because of its superior resolution, OCT is able to characterize the extent of inflammation and the presence of macrophages. However, the invasive nature of IVUS and OCT limit their use in sub-clinical disease. 18 F-fluorodeoxyglucose (FDG)-PET is a noninvasive modality that also identifies vessel wall inflammation, although currently its use is limited to larger vessels such as the carotid arteries and the aorta. Ultimately, these imaging tools will aid the search for therapies targeted at the reduction of vessel wall inflammation in HIV. Intravascular imaging: IVUS and OCT. Although the structure of atherosclerotic lesions in HIV patients is not understood fully, small autopsy series suggest that HIV patients may exhibit an intermediate phenotype that shares features common to both coronary atherosclerosis and transplant vasculopathy.74 In addition, HIV-infected subjects presenting with an acute coronary syndrome are younger and more commonly have single vessel disease,75 possibly suggesting that plaques rupture at an earlier stage of the disease process. Invasive methods of imaging atherosclerotic plaques such as IVUS and OCT have the potential to define more accurately the unique features of atherosclerosis in this population, including the prevalence of vulnerable plaque. These methods carry risks that limit their use in the detection of subclinical disease; however, they are useful in patients who are undergoing clinically indicated invasive angiography.

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Grayscale IVUS was developed first over 20 years ago and is now used widely to guide percutaneous coronary interventions. It is useful in differentiating 4 categories of plaque: soft, fibrous, calcified, and mixed.76 Grayscale images enhanced with radiofrequency IVUS and virtual histology (Fig 6) have been used to detect thin-cap fibroatheroma (TCFA), which is one of the most important features of vulnerable plaque. TCFAs are characterized by necrotic lipid cores without detectable overlying fibrous tissue (ie, the cap is thinner than the resolution of IVUS). Investigators in PROSPECT77 examined the natural history of atherosclerotic lesions in a noninfected population by performing radiofrequency IVUS and virtual histology of all 3 major coronary arteries at the time of initial percutaneous coronary intervention. Total plaque burden, smaller luminal area, and TCFA were all predictive of future cardiac events including acute coronary syndrome over 3 years of follow-up. A similar study in HIV could define the unique natural history of atherosclerosis in this population. OCT uses light rather than sound to image the coronary vessel wall with axial and lateral resolution 10 times that of IVUS.78 Developed initially to image the retina, OCT has been adapted only recently to intracoronary imaging, and it gained approval from the U.S. Food and Drug Administration in 2010. Because of its higher resolution, OCT can assess the thickness of an atheroma’s fibrous cap more accurately. It is superior to IVUS in detecting thrombus and defining the extent of calcification; however, OCT light waves cannot penetrate more than 1–3 mm into the vessel wall, limiting the ability to define the extent of positive vessel remodeling and total plaque burden.78 In addition to fibrous cap size, additional OCT characteristics of ‘‘vulnerable plaque’’ such as the presence of thrombus,79 macrophage infiltration (Fig 7),80 and collagen and smooth muscle content of the fibrous plaque81 are being investigated. In addition to IVUS and OCT, a plethora of other intravascular imaging modalities has the potential to assess the characteristics of vulnerable plaques; however, the application of some of these techniques has been limited to animal models of atherosclerosis. Imaging the vasa vasorum with contrast-enhanced ultrasonography maps the amount of neovascularization in plaques.82 Thermography measures the temperature variations within the vessel, with the idea that macrophages in inflamed plaque produce more heat than fibrotic, calcified plaque.83 Near-infrared spectroscopy uses the differential absorption of light to distinguish fatty from fibrous tissue and can detect lipid-rich cores with high sensitivity.84,85 Similarly, intravascular MRI has been used in human iliac arteries to measure the

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Fig 6. Atherosclerotic lesion classification according to radiofrequency IVUS in the PROSPECT study. Fibroatheromas were defined by the presence of .10% confluent necrotic core (red color). If more than 30 of the necrotic core abutted the lumen in 3 or more consecutive frames, the fibroatheroma was classified as a TCFA; otherwise, it was categorized as a thick-cap fibroatheroma. Fibrotic plaque was defined as consisting mainly of fibrous tissue (dark green color) with ,10% confluent necrotic core, ,10% confluent dense calcium (white color), and ,15% of fibrofatty tissue (light green color). Fibrocalcific plaque was defined as mainly fibrous tissue with .10% of confluent dense calcium, with ,10% of confluent necrotic core. Pathologic intimal thickening was defined as $15% fibrofatty tissue, with ,10% confluent necrotic core and ,10% confluent dense calcium. Used with permission from the New England Journal of Medicine.77

lower water diffusion coefficient of lipid-rich plaques.86,87 Palpography measures the local elasticity of the vessel wall in response to pulse pressure and can differentiate stiff fibrous plaques from more distensible lipid-rich plaques.88 Finally, areas of locally high IVUS-derived shear stress have been shown at sites of plaque rupture in patients with acute coronary syndrome.89 To date, no studies outside of a single case report90 have used intravascular imaging to characterize the potentially unique features of HIV-associated atherosclerosis. Because of the inflammatory nature of the disease, future studies using intravascular imaging might examine whether HIV-infected subjects have more thin-capped fibroatheromas with large lipid cores or extensive macrophage infiltration to explain higher rates of acute coronary syndrome. Noninvasive imaging: FDG-PET and MRI. PET imaging of FDG uptake, which was developed initially as a highly sensitive imaging modality for tumors and infection, has been applied recently to the imaging of atherosclerosis.91 FDG is a glucose analog that accumulates within metabolically active tissues, primarily macrophages. Because of poor spatial resolution, PET-FDG is combined often with CT (less commonly MRI) to delineate the structural location of FDG uptake, and consequently, large arteries such as

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Fig 7. OCT images of 2 lipid-rich plaques with differing amounts of inflammatory macrophage infiltration. The lipid pool absorbs most of the light emitted by the catheter and thus appears as a low-intensity signal region (asterisks). Macrophage/foam cells in atherosclerotic plaques are relatively large (20–30 mm) and may contain multiple intracellular, lipid-rich phagolysosomes. As a function of their size and the refractive index difference, the macrophages might have a higher OCT signal than the surrounding tissue and appear as high-signal dots within the fibrous cap. A high concentration of macrophages is observed in (B) compared with (A). Figure courtesy of Dr. Hiram Bezerra and Dr. Daniel Chamie, Cardiovascular Imaging Core Laboratory, University Hospitals Harrington-McLaughlin Heart and Vascular Institute, Cleveland, Ohio.

the aorta and carotids tend to produce the best images. The high reproducibility of combined PET-CT images over time allows it to measure the effect of interventions in clinical trials accurately (Fig 8). In the noninfected population, FDG uptake in these vascular beds has been linked to higher circulating biomarkers including matrix metalloproteinases, interleukin-18, C-reactive protein, and fibrinogen,93 as well as to clinical inflammatory phenotypes such as the metabolic syndrome94 and periodontal disease.93 FDG-PET detected vascular inflammation decreases with statin therapy.95 The BioImage study of the High-Risk Plaque Initiative will test the prognostic value of FDG-PET in combination with other biomarkers of inflammation in more than 7000 subjects.95 Preliminary studies in HIV suggest that FDG-PET uptake is high in atherosclerotic lesions compared with HIV-negative controls96; however, larger studies are needed to confirm this finding. Inflammatory plaque can also be imaged noninvasively with molecular targeted MRI. Ultrasmallsuperparamagnetic iron oxide (USPIO) particles are taken up by macrophages and can be detected as signal voids on T2*-weighted images.97 USPIO was used to show that high-dose atorvastatin decreases inflammation in carotid plaque in the ATHEROMA study.98 Endothelial-targeted peptides grafted to gadolinium99 have also been used as contrast agents. Imaging inflammation in vascular territories. Vascular inflammation is sometimes a generalized process but often is confined to local vascular beds. FDG-PET and

MRI are well suited to imaging inflammation in the aorta and peripheral vasculature; however, the lack of resolution limits their use in the coronaries. Coronary artery inflammation is better imaged with invasive percutaneous methods such as IVUS and OCT. Generally, it has been assumed that OCT will not find application in the periphery because of the large imaging radius required in these vessels, although newer techniques may challenge this assumption. CONCLUSIONS AND NEW HORIZONS

During the past 15 years, the field of HIV-medicine has transitioned rapidly from a focus exclusively on an AIDS-defining illness toward a better understanding of the complications of accelerated aging and chronic inflammation. Cardiovascular disease has now become a leading cause of morbidity and mortality; however, many questions remain regarding the pathophysiology and natural history of atherosclerosisin this population. The science behind vascular imaging technology is evolving rapidly, particularly in regard to the molecular imaging techniques discussed previously. However, more translational work is needed to bring these technologies into wider clinical application. Wellvalidated, inexpensive, and widely available imaging tools such as carotid ultrasound and brachial artery reactivity testing will continue to have their place as surrogate markers of cardiovascular risk; however, newer, more powerful technologies such as CT and MRI likely will find a broader clinical application. Finally, intracoronary modalities such as OCT and molecular

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Fig 8. PET/CT images of inflammatory carotid and aortic plaque. (A) Axial images of a subject’s carotid artery obtained 2 weeks apart. CT (right), PET (center), and combined images (left). Arrows point to similar FDG uptake in the carotid artery on both scans. (B) Sagittal images of a subject’s aorta obtained 2 weeks apart. CT (right), PET (center), and combined images (left). The arrows point to similar FDG uptake in the aorta on both scans. Reprinted with permission from the Journal of the American College of Cardiology (Elsevier Science, Inc.).92

imaging probes have great potential to clarify the unique features of inflammatory atherosclerosis in HIV. We acknowledge Dr. Janet Lo, Dr. Hiram Bezerra, and Dr. Chamie for the permission to use images.

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