Atherosclerosis Is Evident in Treated HIV-infected Subjects With Low Cardiovascular Risk by Carotid Cardiovascular Magnetic Resonance

Kathleen A. M. Rose, MD, MRCP; Jaime H. Vera, MD, PhD, MRCP; Peter Drivas, MSc; Winston Banya, MSc; Niall Keenan, MD, MRCP, PhD; Dudley J. Pennell, MD, FRCP; Alan Winston, MD, MRCP


J Acquir Immune Defic Syndr. 2016;71(5):514-521. 

In This Article

Abstract and Introduction


Objective: Premature atherosclerosis has been observed among HIV-infected individuals with high cardiovascular risk using one-dimensional ultrasound carotid intima-media thickness. We evaluated the assessment of HIV-infected individuals with low traditional cardiovascular disease risk using cardiovascular magnetic resonance, which allows three-dimensional assessment of the carotid artery wall.

Methods: Carotid cardiovascular magnetic resonance was performed in 33 HIV-infected individuals (cases) (19 male, 14 female), and 35 HIV-negative controls (20 male, 15 female). Exclusion criteria included smoking, hypertension, hyperlipidemia (total cholesterol/HDL ratio > 5) or family history of premature atherosclerosis. Cases were stable on combination antiretroviral therapy with plasma HIV-1 RNA <50 copies per milliliter. Using computer modeling, the arterial wall, lumen, and total vessel volumes were calculated for a 4-cm length of each carotid artery centered on the bifurcation. The wall/outer-wall ratio (W/OW), an index of vascular thickening, was compared between the groups.

Results: Cases had a median CD4 cell count of 690 cells per microliter. Mean (±SD) age and 10-year Framingham coronary risk scores were similar for cases and controls (45.2 ± 9.7 years versus 46.9 ± 11.6 years and 3.97% ± 3.9% versus 3.72% ± 3.5%, respectively). W/OW was significantly increased in cases compared with controls (36.7% versus 32.5%, P < 0.0001); this was more marked in HIV-infected females. HIV status was significantly associated with increased W/OW after adjusting for age (P < 0.0001). No significant association between antiretroviral type and W/OW was found—W/OW lowered comparing abacavir to zidovudine (P = 0.038), but statistical model fits poorly.

Conclusions: In a cohort of treated HIV-infected individuals with low measurable cardiovascular risk, we have observed evidence of premature subclinical atherosclerosis.


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 proliferation[11] and eventually in atheroma. HIV infection causes chronic inflammation with persistently increased inflammatory markers.[12] These increase with increasing viremia[13,14] 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 strength[25] 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.