Inflammatory biomarkers associated with coronary artery stenosis in HIV+ menBahrami H et al., J Am Heart Assoc. 2016
Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study
Bahrami H, Budoff M, Haverlen SA, et al.,
J Am Heart Assoc. 2016; 5: e003371. doi: 10.1161/JAHA.116.003371
BackgroundThanks to successful control of viremia with antiretroviral therapy (ART), HIV infection can now be considered a chronic medical condition. As a consequence, cardiovascular disease, among other disease, is becoming a major health concern for HIV-infected (HIV+) persons. Higher rates of CV abnormalities, including coronary artery disease (CAD) have been noted in HIV+ patients [1-7], with an estimated 1.5- to 2-fold higher risk of CAD as compared to HIV- individuals [8,9].
The mechanisms underlying the increased CV risk are poorly understood. While earlier research mainly investigated prevalence of traditional risk factors and ART, more recent evidence suggests that HIV-related inflammation may play a central role [10-12]. ART initiation reduces inflammation, but virologically suppressed HIV+ patients still have higher levels of inflammation than those without HIV [13,14].
Because it is challenging to enrol the large number of subjects required to study mechanisms involved in CAD in HIV+ individuals, research now focusses on subclinical atherosclerosis, as a surrogate for clinical events (with CAC as proxy measure). Contrast-enhanced coronary CT angiography (CTA) provides detailed information of subclinical CAD, by imaging noncalcified plaques.
This study aimed to determine the associations of biomarkers of systemic inflammation and coagulation with subclinical CAD in HIV+ and HIV- participants (aged 40-70 years, no prior history of cardiac surgery or PCI) of the Multicenter AIDS Cohort Study (MACS). 923 (575 HIV+ and 384 HIV-) men underwent noncontrast coronary CT scans, of whom 411 HIV+ and 281 HIV- individuals underwent CTA. 96% of HIV+ participants had been on ART at some point, and 83% were virologically suppressed (average current CD4+ T-cell count of 703 cells/mm3).
- Levels of inflammatory biomarkers IL-6 (median (IQR): 1.5 (1.0-2.5) vs. 1.3 (0.9-2.1) pg/mL, ICAM-1 (257.8 (214.7-3.15.0) vs. 228.6 (193.1-273.5 ng/mL), hs-CRP 1.24 (0.64-2.76) vs. 0.95 (0.52-1.92) mg/dL), sTNFαR II (6622 (5390-8285) vs. 5844 (4961-6902) pg/mL) were significantly higher in HIV+ as compared to HIV- men (all P<0.01), while fibrinogen and D-dimer did not differ between groups. Only analysing HIV+ men with undetectable viral load did not significantly alter these findings.
- HIV+ men had a higher prevalence of noncalcified plaques (62.8% vs. 53.7%, P=0.02) on CTA and greater extent of noncalcified plaque (<0.01).
- CAC score or the prevalence of CAC, mixed or calcified plaques or coronary artery stenosis did not differ between HIV+ and HIV- men.
- In HIV+ men, higher levels of IL-6 and ICAM-1 were significantly associated with greater prevalence of >50% coronary artery stenosis on CTA, also after adjustment for traditional CV risk factors and HIV clinical factors. Every SD increase in log-IL-6 or log-ICAM-1 was associated with 30% or 60% increase in prevalence of >50% stenosis, respectively.
- Every SD increase in log sTNFαR I and sTNFαR II were associated with higher prevalence ratios for >70% stenosis (2.3, 95%CI: 1.3-4.2, P=0.006 and 1.7, 95%CI: 1.1-2.7, P=0.02 respectively, after correction for traditional risk factors and HIV clinical factors.
- Higher serum levels of IL-6, sTNFαR I and sTNFαR II were associated with a greater CAC score in HIV+ men (each SD increase in log levels was associated with 0.3, 0.2 and 0.2 units log-CAC score respectively, adjusted for traditional risk factors and HIV clinical factors), which corresponds to about 22 and 35% higher CAC score.
- In HIV- men, IL-6 was the only inflammatory biomarker associated with CAC score, but it did not remain significant in adjusted models.
- The studied inflammatory biomarkers were not significant determinants of plaque composition and extent on CTA.
ConclusionElevated levels of several inflammatory biomarkers were significantly associated with a higher prevalence of clinically relevant coronary artery stenosis in HIV+ men as compared with men without HIV, independently of traditional risk factors and HIV clinical factors. To a lesser extent, IL-6, sTNFαR I and sTNFαR II independently correlated with the extent of coronary artery calcification in HIV-infected men.
Thus, these findings provide evidence for the relationship between inflammatory biomarkers and coronary plaque characteristics. The studied biomarkers do not seem to mediate the presence and extent of the predominantly noncalcified coronary artery plaques as seen on CTA.
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1. Grunfeld C, Delaney JA, Wanke C et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009;23:1841–1849.
2. Holloway CJ, Ntusi N, Suttie J, et al. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients.
3. Hsue PY, Hunt PW, Ho JE, et al Impact of HIV infection on diastolic function and left ventricular mass. Circ Heart Fail. 2010;3:132–139.
4. Hsue PY, Lo JC, Franklin A, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation. 2004;109:1603–1608.
5. Lai H, Redheuil A, Tong W, et al. HIV infection and abnormal regional ventricular function. Int J Cardiovasc Imaging. 2009;25:809–817.
6. Sims A, Frank L, Cross R, et al. Abnormal cardiac strain in children and young adults with HIV acquired in early life. J Am Soc Echocardiogr. 2012;25:741–748.
7. Bahrami H, Fonarow G, Heidenreich P. Heart failure admission in HIV-infected patients. J Am Coll Cardiol. 2014;63:(12_s).
8. Ho JE, Hsue PY. Cardiovascular manifestations of HIV infection. Heart. 2009;95:1193–1202
9. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation. 2008;118:198–210.
10. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART study. J Infect Dis. 2008;197:1133–1144.
11. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5:e203.
12. Hunt PW, Landay AL, Sinclair E, et al. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One. 2011;6:e15924.
13. Jain V, Hartogensis W, Bacchetti P, et al. Antiretroviral therapy initiated within 6 months of HIV infection is associated with lower T-cell activation and smaller HIV reservoir size. J Infect Dis. 2013;208:1202–1211.
14. Hunt PW, Martin JN, Sinclair E, et al. T cell activation is associated with lower CD4+ T cell gains in human immunodeficiency virus-infected patients with sustained viral suppression during antiretroviral therapy. J Infect Dis. 2003;187:1534–1543.