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Original Research |

Associations Between HIV Infection and Subclinical Coronary AtherosclerosisAssociations Between HIV Infection and Subclinical Coronary Atherosclerosis

Wendy S. Post, MD, MS; Matthew Budoff, MD; Lawrence Kingsley, PhD; Frank J. Palella Jr., MD; Mallory D. Witt, MD; Xiuhong Li, MS; Richard T. George, MD; Todd T. Brown, MD, PhD; and Lisa P. Jacobson, ScD
[+] Article and Author Information

From Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California; University of Pittsburgh, Pittsburgh, Pennsylvania; and Northwestern University, Chicago, Illinois.

Note: Dr. Post had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Data were collected by the MACS centers at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (principal investigator, Joseph B. Margolick); Feinberg School of Medicine, Northwestern University, and Cook County Bureau of Health Services, Chicago, Illinois (principal investigator, Steven M. Wolinsky); University of California, Los Angeles, Los Angeles, California (principal investigator, Roger Detels); and University of Pittsburgh, Pittsburgh, Pennsylvania (principal investigator, Charles R. Rinaldo), as well as the data center at the Johns Hopkins Bloomberg School of Public Health (principal investigator, Lisa P. Jacobson).

Acknowledgment: The authors thank Andrea Stronski for administrative support for this study and Adrian Dobs, MD, MHS; Joseph Margolick, MD; and A. Richey Sharrett, MD, PhD, for their reviews of the manuscript draft and contributions to this study.

Grant Support: This study is funded by the National Heart, Lung, and Blood Institute (grant RO1 HL095129 to Dr. Post), with additional support from the National Center for Advancing Translational Sciences, a component of the National Institutes of Health and National Institutes of Health Roadmap for Medical Research (grant UL1 RR 025005). The MACS is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute (grants UO1-AI-35042, UL1-RR025005, UM1-AI-35043, UO1-AI-35039, UO1-AI-35040, and UO1-AI-35041).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1754.

Reproducible Research Statement: Study protocol and statistical code: Data collection forms used as part of the core MACS visit are available on the MACS Web site (www.statepi.jhsph.edu/macs/macs.html). The study protocol and the computer code used to generate results reported in this article are available on request. Data set: Individual-level MACS data are available from Dr. Post (e-mail, wpost@jhmi.edu) after review of a concept sheet by the MACS executive committee.

Requests for Single Reprints: Wendy S. Post, MD, MS, Johns Hopkins University School of Medicine, Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Carnegie 568, 600 North Wolfe Street, Baltimore, MD 21287; e-mail, wpost@jhmi.edu.

Current Author Addresses: Dr. Post: Johns Hopkins University School of Medicine, Ciccarone Center for the Prevention of Heart Disease, Division of Cardiology, Carnegie 568, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Budoff: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502.

Dr. Kingsley: University of Pittsburgh, Graduate School of Public Health, 418 Parran Hall, Fifth Avenue and Desoto Street, Pittsburgh, PA 15261.

Dr. Palella: Northwestern University, 645 North Michigan Avenue, Suite 900, Chicago, IL 60611.

Dr. Witt: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Chronic Disease Clinical Research Center, 1124 West Carson Street, Torrance, CA 90502.

Ms. Li: Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E7003, Baltimore, MD 21205.

Dr. George: Johns Hopkins University School of Medicine, 600 North Wolfe Street, Blalock 524D2, Baltimore, MD 21111.

Dr. Brown: Johns Hopkins University, Division of Endocrinology, Diabetes, and Metabolism, 1830 East Monument Street, Suite 333, Baltimore, MD 21287.

Dr. Jacobson: Johns Hopkins Bloomberg School of Public Health, Department of Epidemiology, 615 North Wolfe Street, Room E7646, Baltimore, MD 21205.

Author Contributions: Conception and design: W.S. Post, M. Budoff, L. Kingsley, R.T George, L.P. Jacobson.

Analysis and interpretation of the data: W.S. Post, L. Kingsley, F.J. Palella, X. Li, R.T George, T. Brown, L.P. Jacobson.

Drafting of the article: W.S. Post, L. Kingsley, F.J. Palella, R.T George, L.P. Jacobson.

Critical revision of the article for important intellectual content: W.S. Post, M. Budoff, L. Kingsley, F.J. Palella, M.D. Witt, X. Li, R.T George, T. Brown, L.P. Jacobson.

Final approval of the article: W.S. Post, M. Budoff, L. Kingsley, F.J. Palella, M.D. Witt, X. Li, R.T George, T. Brown, L.P. Jacobson.

Provision of study materials or patients: W.S. Post, M. Budoff, L. Kingsley, M.D. Witt, R.T George.

Statistical expertise: X. Li, L.P. Jacobson.

Obtaining of funding: W.S. Post, L. Kingsley, R.T George, L.P. Jacobson.

Administrative, technical, or logistic support: M. Budoff, L. Kingsley.

Collection and assembly of data: W.S. Post, M. Budoff, L. Kingsley, M.D. Witt, R.T George, L.P. Jacobson.


Ann Intern Med. 2014;160(7):458-467. doi:10.7326/M13-1754
Text Size: A A A

Background: Coronary artery disease (CAD) has been associated with HIV infection, but data are not consistent.

Objective: To determine whether HIV-infected men have more coronary atherosclerosis than uninfected men.

Design: Cross-sectional study.

Setting: Multicenter AIDS Cohort Study.

Participants: HIV-infected (n = 618) and uninfected (n = 383) men who have sex with men who were aged 40 to 70 years, weighed less than 136 kg (200 lb), and had no history of coronary revascularization.

Measurements: Presence and extent of coronary artery calcium (CAC) on noncontrast cardiac computed tomography (CT) and of any plaque; noncalcified, mixed, or calcified plaque; or stenosis on coronary CT angiography.

Results: 1001 men had noncontrast CT, of whom 759 had coronary CT angiography. After adjustment for age, race, CT scanning center, and cohort, HIV-infected men had a greater prevalence of CAC (prevalence ratio [PR], 1.21 [95% CI, 1.08 to 1.35]; P = 0.001) and any plaque (PR, 1.14 [CI, 1.05 to 1.24]; P = 0.001), including noncalcified (PR, 1.28 [CI, 1.13 to 1.45]; P < 0.001) and mixed (PR, 1.35 [CI, 1.10 to 1.65]; P = 0.004) plaque, than uninfected men. Associations between HIV infection and any plaque or noncalcified plaque remained significant (P < 0.005) after CAD risk factor adjustment. HIV-infected men had a greater extent of noncalcified plaque after CAD risk factor adjustment (P = 0.026). They also had a greater prevalence of coronary artery stenosis greater than 50% (PR, 1.48 [CI, 1.06 to 2.07]; P = 0.020), but not after CAD risk factor adjustment. Longer duration of highly active antiretroviral therapy (PR, 1.09 [CI, 1.02 to 1.17]; P = 0.007) and lower nadir CD4+ T-cell count (PR, 0.80 [CI, 0.69 to 0.94]; P = 0.005) were associated with coronary stenosis greater than 50%.

Limitation: Cross-sectional observational study design and inclusion of only men.

Conclusion: Coronary artery plaque, especially noncalcified plaque, is more prevalent and extensive in HIV-infected men, independent of CAD risk factors.

Primary Funding Source: National Heart, Lung, and Blood Institute and National Institute of Allergy and Infectious Diseases.

Figures

Grahic Jump Location
Figure.

Unadjusted prevalence and 95% CI of plaque, stratified by HIV serostatus in 5-y age increments.

Interaction of age by HIV serostatus for the presence of noncalcified plaque was significant (P = 0.006). For the lines in each graph, the middle point is the point estimate and the 2 outer points are the 95% confidence limits for that point estimate.

Grahic Jump Location

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Noninvasive coronary artery plaque vulnerability assessment with computed tomography in HIV-infected patients
Posted on April 25, 2014
Carl Chartrand-Lefebvre MD (1); Madeleine Durand MD MSc (1); Cécile Tremblay MD (1,2)
1- University of Montreal Medical and Research Center; 2- Director, Immunology Laboratory at the Quebec Public Health Laboratory
Conflict of Interest: 1- Canadian Institutes of Health Research, Team Grant: HIV Comorbidity, PI C Tremblay, co-PI M Durand, co-applicant C Chartrand-Lefebvre;

2- RBIQ-FRSQ (Quebec Bio-Imaging Network), PI C Chartrand-Lefebvre, co-applicant M Durand, co-applicant C Tremblay
We read with great interest the article “Associations between HIV infection and subclinical coronary atherosclerosis” by Post et al. (1) in the April 2014 issue of the Annals of Internal Medicine. This is a multicenter cross-sectional study, including 618 HIV-infected and 383 noninfected men who have sex with men, with no history of previous surgical or percutaneous cardiac treatment. The 1001 patients had noncontrast computed tomography (CT) for coronary calcium scoring, and 759 of them had coronary CT angiography (CTA) for coronary plaque assessment. After adjustment for coronary artery disease (CAD) risk factors, the prevalence of coronary artery plaque at CTA was higher in HIV-infected men compared to noninfected men (prevalence ratio (PR) = 1.13, p = 0.004). When only noncalcified plaque was considered, association with HIV status was stronger (PR = 1.25, p = 0.001). In contrast, presence of calcified plaque at CTA was not significant (PR = 1.02, p = 0.88), although calcium score > 0 was higher in HIV-infected men (PR = 1.12, p = 0.07). Coronary artery stenoses were not more frequent in the HIV-infected patients, although advanced HIV infection (lower nadir CD4+ T-cell count, greater years of highly active antiretroviral therapy) was associated with greater prevalence of stenoses.

Acute coronary events often result from rupture and subsequent thrombosis of nonstenotic vulnerable plaques (2). Epidemiological studies have reported a higher rate of myocardial infarcts in HIV- infected patients compared to noninfected patients (3). The results of the large study of Post et al. seem to support the hypothesis that CT plaque vulnerability data obtained in the general population could also apply in HIV-infected patients, and that plaque vulnerability mechanisms may contribute to the premature CAD in HIV-infected individuals. Recent technological development of CT scanners and 3D image postprocessing have allowed the assessment of more sophisticated CT markers of plaque vulnerability, such as positive-remodeling, and especially low-attenuation plaque foci (lipid-rich) in the plaque. Both have been recently assessed in HIV-infected patients using a 2D strategy (4). In an ongoing CTA substudy, nested in the Canadian Aging and HIV Cohort Study (5), we started to quantitatively evaluate these CT markers of plaque vulnerability, using 3D volumetric postprocessing tools. Noninvasive coronary artery plaque vulnerability assessment may be a promising paradigm for the assessment of the increased cardiovascular risk in the HIV-infected patients, and could help elucidate how CAD may differ in this specific population.


References:
1. Post WS, Budoff M, Kingsley L, Palella FJ Jr, Witt MD, Li X, George RT, Brown TT, Jacobson LP. Associations Between HIV Infection and Subclinical Coronary Atherosclerosis. Ann Intern Med. 2014;160:458-67.

2. Virmani R, Burke A, Kolodgie FD, et al. Vulnerable plaque: the pathology of unstable coronary lesions. J Interven Cardiol, 2002. 15: p. 439-446.

3. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Québec's public health insurance database. J Acquir Immune Defic Syndr, 2011 57: p. 245-53.

4. Zanni MV, A.S., Lo J, Wai B, Hark D, Marmarelis E, Grinspoon SK Increased coronary atherosclerotic plaque vulnerability by coronary computed tomography angiography in HIV-infected men. AIDS, 2013 27: p. 1263-72.

5. Durand M, Rau, P, Cyr L, Matte S, Chamberland A, Mansour S, Chartrand-Lefebvre C, Tremblay C. The Montreal HIV and Aging Cohort: Results from a Pilot Study of Coronary Calcium Measurement. 22nd Annual Canadian Conference on HIV/AIDS Research, CAHR (Canadian Association of HIV Research) 2013, Vancouver, avril 2013
Author's Response
Posted on October 15, 2014
Wendy S. Post, MD, Richard George, MD, Matthew Budoff, MD
Johns Hopkins University
Conflict of Interest: None Declared
Dear Drs. Chartrand-Lefebvre, Durand and Tremblay,
Thank you for your very insightful comments regarding our recent publication demonstrating a greater prevalence and extent of non-calcified plaque in HIV-infected men compared with uninfected men in the Multicenter AIDS Cohort Study (MACS). We agree that noninvasive plaque vulnerability assessment with CT imaging has the potential to further elucidate potential mechanisms whereby HIV infected individuals may be at increased risk for acute myocardial infarction. Prior to plaque rupture, the degree of luminal stenosis is frequently less than 50% and therefore would not lead to symptoms or to an abnormal stress test.(1) Recent advances in coronary CT image analysis have led to the ability to identify potentially high-risk, vulnerable plaques among asymptomatic individuals. (2) Plaque characteristics identified on coronary CT angiography that have been associated with acute coronary syndromes include low attenuation (Hounsfield Units < 30), spotty calcification and outward remodeling (expansion of arterial diameter with plaque growing outward, rather than only encroaching on the lumen).(3)
As you mentioned, previous studies from Massachusetts General Hospital demonstrated that HIV infected persons have a greater prevalence of high risk vulnerable plaques than uninfected people.(4) We also found a greater prevalence of coronary artery outward remodeling in our MACS cohort (manuscript in progress). We are repeating coronary CT angiography in our cohort and will identify all these high-risk plaque features from baseline and follow-up CT scans in our progression study using advanced image analyses techniques. We look forward to also seeing the results of your Canadian studies.

1. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et al. A prospective natural-history study of coronary atherosclerosis. The New England journal of medicine. 2011;364(3):226-35.
2. Nakazato R, Shalev A, Doh JH, Koo BK, Dey D, Berman DS, et al. Quantification and characterisation of coronary artery plaque volume and adverse plaque features by coronary computed tomographic angiography: a direct comparison to intravascular ultrasound. European radiology. 2013; 23(8):2109-17.
3. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol. 2009;54(1):49-57.
4. Zanni MV, Abbara S, Lo J, Wai B, Hark D, Marmarelis E, et al. Increased Coronary Atherosclerotic Plaque Vulnerability by Coronary Computed Tomography Angiography in HIV-Infected Men. AIDS. 2013.
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