The current study shows an increased prevalence and greater degree of subclinical CAD in asymptomatic young HIV-infected men without prior history of cardiovascular disease. The prevalence in the HIV-infected patients was significantly greater than that seen in concurrently recruited HIV-seronegative men with similar demographics, Framingham risk scores, and similar traditional risk factors (age, sex, family history, BMI, smoking, total cholesterol, and LDL).
Surprisingly and of important clinical relevance, even among asymptomatic young HIV-infected men, 6.5% had evidence of severe CAD defined as coronary artery stenosis more than 70% as compared with 0% in the control group. The information obtained from the coronary angiography led to further work-up confirming coronary disease and cardiac procedures that may have prevented major adverse cardiac events. The fact that 6.5% of the HIV patients, all without any known cardiac disease or symptoms, were found to have severe obstructive CAD is of potential clinical significance. In contrast, none of the controls had severe obstructive CAD.
We found increased prevalence of atherosclerosis and increased plaque burden by indices of plaque volume and number of coronary segments affected in the HIV vs. non-HIV participants. Prior studies to assess atherosclerotic vascular disease in the HIV population have used brachial artery flow-mediated vasodilation, carotid intima–media thickness (IMT), and electron beam computed tomography (EBCT) calcium score without CT coronary angiography [11
]. Despite evidence from data registry studies showing a greater prevalence of MIs in HIV vs. non-HIV-infected patients [22
], studies using surrogate markers show mixed results, though studies of Hsue et al.
] found carotid IMT to be higher in HIV patients than in age-matched controls and to progress at a more rapid rate than in noninfected controls. In a recent large study, carotid IMT was found to be higher in HIV patients from the study of Fat Redistribution and Metabolic Change in HIV (FRAM), compared with uninfected controls even after adjustment for traditional risk factors [23
Previous studies utilizing CT to assess CAD in HIV patients assessed only coronary calcifications by coronary calcium scoring, but did not investigate noncalcified plaques nor visualized lumen caliber [18
]. In a study by Kingsley et al.
], HIV infection and long-term HAART use increased the likelihood of coronary calcium being present; however, after adjustment for traditional cardiovascular risk factors, HAART had no significant association with presence or extent of coronary calcium.
Although coronary calcification is specific for atherosclerotic lesions and the Agatston calcium score has been associated with cardiac event risk in non-HIV populations [24
], atherosclerotic plaques can be present without detectable coronary calcium at the site. Coronary calcium score alone may not provide a true measure of early atherosclerosis in young HIV patients as plaque calcification usually occurs at a later stage and may not detect more vulnerable plaque lesions, which tend to be noncalcified or mixed calcified and noncalcified. In addition, the atherosclerotic disease process in HIV may be different from conventional atherosclerosis [25
]. No published studies to date have used coronary CTA to assess noncalcified plaques in HIV patients. Our data using CTA show that a significant proportion of patients with coronary atherosclerosis would have been missed if calcium score was used as the sole criterion for coronary atherosclerosis as 23.8% (95% confidence interval 13.5–38.5%) of HIV patients had evidence of noncalcified plaque seen on CTA among those with calcium score of zero. Moreover, the differences between the HIV and control groups were more consistent comparing indices of plaque that included noncalcified plaques beyond calcium score alone (e.g. presence of any plaque, segments with plaque, and plaque volume, all P
< 0.05). Thus, our data suggest that CTA gives different and potentially more sensitive information than the coronary calcium score alone.
Participants in our study were screened to exclude patients with known ischemic heart disease or any symptoms of CAD, and were, on average, young, with an estimated 10-year Framingham risk of only 4%, similar to that of the controls. Clinicians might not consider such patients at risk for CAD, yet 6.5% of these asymptomatic young patients had critical stenosis in at least one vessel. These patients with critical stenosis did, however, have the highest Framingham score and thus this score still appears to be useful to identify those with the greatest degree of subclinical coronary atherosclerosis, even among a population of young asymptomatic patients. Moreover, those HIV patients with plaque clearly had elevated traditional risk factors, including age, Framingham risk score, total cholesterol, and LDL.
Our data suggest relationships between traditional and nontraditional risk factors to indices of plaque burden. For example, traditional risk factors such as age, total cholesterol, and LDL were strongly related to all indices of plaque burden as is also evidenced in the strong relationship between the Framingham risk score and plaque burden. 2-h glucose and triglycerides were more strongly related to Agatston score than to plaque volume or segments with plaque.
Our data also support the hypothesis that there is a relationship between HIV infection and coronary artery atherosclerosis independent of traditional cardiovascular risk factors, as traditional risk factors were generally similar between the groups, yet significant differences in plaque prevalence and plaque burden were seen between the HIV and non-HIV groups. Age, smoking, family history and overall Framingham score, as well as LDL, HDL, and glucose parameters were similar between the groups. Triglyceride and insulin levels were higher among the HIV-infected group, but we performed sensitivity analyses excluding any patient in either group with hypertriglyceridemia and hyperinsulinemia, and found similar results. We also confirmed our results in regression analyses, controlling for traditional cardiovascular risk factors, as well as triglyceride and insulin levels.
Data from the Strategies for Management of Antiretroviral Therapy (SMART) study [26
] suggest that inflammatory, immune, or viral factors might contribute to increased CAD in the HIV population. We found that CD4/CD8 cell ratio was negatively associated with plaque volume and the relationship between CD4/CD8 ratio and plaque volume was stronger than that seen with CD4 cell count or viral load with plaque volume. Atherosclerosis is an inflammatory disease in which T lymphocytes can play a role in atheroma development [28
]. Activated T cells, including CD8 cells, are present in atherosclerotic plaques [30
] and may contribute to atherosclerosis [31
]. Hsue et al.
] have demonstrated increased carotid IMT in HIV-infected individuals who are able to maintain undetectable HIV RNA without ART, a group with heightened T-lymphocyte activation.
MCP-1 was significantly associated with the number of segments with plaque and with calcium score in our study. MCP-1 is a chemokine important for monocyte migration into the vascular intima during the development of atherogenesis [34
]. HIV-1 Tat
protein promotes MCP-1 secretion, leading to increased transmigration of monocytes across endothelium [35
]. Furthermore, HIV patients with the MCP-1 2518G allele were found to have an associated five-fold increased risk for atherosclerosis [36
] and this same polymorphism has also been associated with severity of CAD in non-HIV patients [37
In this study, we have also shown that CMV IgG antibody titers are positively associated with degree of coronary atherosclerosis, as measured by number of coronary segments with plaque and Agatston calcium score, suggesting that immune activation as well as CMV-specific immune response may also be contributory to atherosclerosis in HIV patients. CMV infection has been associated with cardiac transplant vasculopathy and also implicated in the pathogenesis of atherosclerosis in HIV [38
We found a significant and robust relationship between measures of coronary atherosclerosis and duration of known HIV infection. We controlled for duration of antiretroviral treatment and traditional cardiovascular risk factors in regression modeling. The relationship between duration of HIV and indices of coronary atherosclerosis (number of coronary segments with plaque, plaque volume, and calcium score) remained significant controlling for age, traditional cardiovascular risk factors, duration of ART, and specific HIV-related markers of disease and immune function. Duration of HIV disease may, therefore, reflect a relevant integrated measure of chronic subacute inflammation and altered immune function, processes that may contribute to increased CAD beyond the risk due to traditional risk factors. CRP and IL-6 were not increased in our participants; however, the participants in this study were specifically selected to have no history of CAD and were not acutely ill, in contrast to other studies investigating CRP in relationship to rates of MIs between HIV and non-HIV-infected patients [41
]. Taken together, our data suggest that both traditional and nontraditional HIV-specific risk factors contribute to increased CAD in young asymptomatic HIV-infected men.
The current study has limitations, including the cross-sectional design, from which causality cannot be inferred. Second, the study was performed in men only and thus results may not be generalizable to HIV-infected women. Our results also cannot be generalized to a more high-risk population of HIV-infected patients or to symptomatic patients, in whom traditional risk may dominate more and in whom an even greater prevalence of plaque and potentially calcified plaque might be seen. Based on the data in our study, further studies are now needed to investigate the clinical implications and clinical course of CAD in HIV-infected patients with subclinical coronary atherosclerosis.
Our findings suggest a high prevalence and significant degree of coronary atherosclerosis among young HIV-infected men with a long duration of HIV disease, without any symptoms of cardiac disease or a prior diagnosis of cardiac disease and with a generally low Framingham risk score. Participants were recruited with a goal to have a similar traditional cardiac risk profile in HIV and control participants, yet various measures of atherosclerosis, including unique indices of plaque volume and, the number of coronary segments of plaque were different between the groups. These data suggest that both traditional and nontraditional risk factors contribute to increase subclinical atherosclerosis in HIV-infected patients. The findings from the current study support the need for increased efforts and attention to reducing modifiable traditional and nontraditional cardiovascular risk factors in this patient population. Our data highlight the need to address cardiac risk reduction early on in the course of HIV disease, before significant subclinical disease accrues and before cardiac events occur.