HIV-infected persons have a heightened risk for coronary artery disease (CAD), and abdominal visceral adipose tissue is a described risk factor [1,2]. Another type of visceral fat, epicardial adipose tissue (EAT), may promote a local proatherogenic environment resulting in the development of CAD [3,4]. Studies in the general population have shown that EAT corresponds to the severity of CAD and predicts future cardiovascular events [3,4], but little data exist among HIV-infected persons [5,6], especially regarding the role of antiretroviral agents.
We conducted a cross-sectional study of factors associated with coronary artery calcium (CAC) among adult HIV-infected men , including a substudy on the role of EAT. Data on demographics, substance use, medical conditions and HIV-specific factors (including antiretroviral agents) were collected. Body measurements included BMI, waist circumference and skin-fold thickness (subscapular, suprailiac, biceps and triceps using a standardized Lange skin-fold calipers) to calculate the percentage body fat . Fat gain in the abdominal, breast and/or neck areas by visual assessment was considered lipohypertrophy; weight loss in the cheeks, buttocks and/or legs was considered as lipoatrophy . A fasting blood specimen was also collected.
All participants underwent a computed tomography (CT) scan on the same day as clinical and laboratory data collection to determine the CAC score and EAT volume. All imaging was performed on a single, multidetector 64-slice CT scanner (Siemens Definition Dual Source CT Scanner, Siemens Medical Solutions, Forsheim, Germany). Contrast media was not administered, and the estimated total radiation dose was 1.0 mSv. EAT was measured using the same images for CAC and defined as the hypodense rim surrounding the myocardium and limited by the pericardium as previously described [10,11]; tissue was measured that was −190 to −30 Hounsfield units, thus excluding any contribution from the coronary arteries, coronary calcium, blood or aorta (Fig. 1a).
Statistics included linear regression analyses to examine factors associated with EAT volume, and logistic regression models examining factors associated with a CAC greater than 100. Factors significantly associated in the univariate models were placed into a multivariate model, and the final model was derived using a backward stepwise approach. Data are presented as odds ratios (ORs) with 95% confidence intervals (CIs) (StataCorp, College Station, Texas, USA).
A total of 213 HIV-infected men were evaluated with baseline characteristics shown in Table 1. Eight percent (n = 16) had a positive CAC score greater than 100. EAT volume was a median of 96 cm3 [interquartile range (IQR) 65–134] for HIV-infected persons with a CAC score 0–100 and 154 cm3 (IQR 109–206) for CAC of more than 100 (P = 0.001) (Fig. 1b).
Factors independently associated with EAT in the final multivariate model included increasing age (β 1.48, 95% CI 0.75–2.21, P < 0.001), longer duration of protease inhibitor use (β 0.16, 95% CI 0.02–0.31, P = 0.028), increasing waist circumference (β 1.18, 95% CI 0.67–1.69, P < 0.001), triglyceride level more than 200 mg/dl (β 22.24, 95% CI 9.38–35.11, P = 0.001) and CAC more than 100 (β 24.98, 95% CI 0.79–49.17, P = 0.043).
Factors independently associated with CAC more than 100 in the multivariate model included age (OR 2.92 per 10 years, 95% CI 1.44–5.96, P = 0.003) and EAT volume (OR 1.12 per 10 cm3, 95% CI 1.02–1.22, P = 0.017). No other factors were significant, including traditional measures of body weight/fat including visual assessment of lipohypertrophy, BMI, percentage body fat or waist circumference. Further, addition of these measures did not significantly increase the predictiveness (R 2) of the final model.
We also found that the odds of CAC more than 100 increased with each quartile of EAT, with the highest quartile (>140 cm3) being associated with a 10-fold higher odds (OR 10.4, 95% CI 1.27–85.28, P = 0.03). We also examined the relationship of having multivessel disease (among those with a CAC >0) and EAT volume, and found a significant association (OR 1.12 per 10 cm3, 95% CI 1.02–1.23, P = 0.02).
In summary, EAT has rarely been considered in the pathogenesis of CAD among HIV-infected persons, but they may be at particular risk for excessive regional fat deposition due to antiretroviral therapy and inflammation. We found a novel association between protease inhibitor use and increasing EAT volume. Further, our study showed that increasing EAT volume was significantly associated with CAC scores more than 100, and that EAT was more strongly associated with CAC than traditional measures of fat.
The pathogenesis of EAT with positive CAC scores is likely several-fold. First, EAT is a type of visceral fat which is embryologically related to intra-abdominal fat, both are derived from brown adipose tissue in infancy . Second, deposition of adipose tissue around the coronary vessels and the resultant proatherogenic milieu may contribute to CAD. For example, EAT may exert local toxic effects on the vasculature via production of inflammatory cytokines (e.g. tumor necrosis factor, interleukin 1, and interleukin 6) and inhibition of anti-inflammatory adipokines (e.g. adiponectin) . An outside-to-inside mechanism has been proposed in which EAT leads to adventitial inflammation (with vaso vasorum neovascularization) and subsequent endothelial dysfunction, thrombogenesis and plaque formation . This hypothesis is supported by studies demonstrating that segments of coronary arteries lacking epicardial fat are typically without atherosclerotic lesions .
This is the first study to show a relationship between EAT volume and duration of protease inhibitor use, and suggests that these medications may not only lead to abdominal visceral fat deposition, but also to fatty deposition in the epicardium. This study may provide an additional potential mechanism for the link between protease inhibitor use and CAD beyond that explained by dyslipidemia and abdominal fat accumulation.
Limitations include its cross-sectional design and that we did not study clinical cardiac events. We relied on visual assessments and abdominal measurements to define lipodystrophy rather than dual-energy X-ray absorptiometry scans. Additionally, an HIV-negative comparison group was not utilized. Finally, the number of patients with CAC was small, and further studies are warranted.
In summary, increasing EAT volume is associated with CAD as measured by CAC scores among HIV-infected persons. Understanding the precise role of HIV and antiretroviral therapy (especially protease inhibitors) on EAT deposition as well as the role of EAT progression on cardiac events should be the subject of future studies among HIV-infected persons.
All authors contributed to the content of the manuscript and concurred with the decision to submit it for publication. Study concept: N.-C.C., G.B.
Study supervision: N.-C.C.
Data collection: N.-C.C., N.K., K.L., G.B.
Data analysis: N.-C.C.
Writing of manuscript: N.-C.C. Critical review of manuscript: N.K., K.L., G.B.
The content and views expressed in this publication are the sole responsibility of the authors and do not necessarily reflect the views or policies of the DoD or the Departments of the Army, Navy, Air Force, Department of Defense, nor the US Government. Mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
Conflicts of interest
There are no conflicts of interest.
Support for this work (IDCRP-018) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense (DoD) program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), under Inter-Agency Agreement Y1-AI-5072.
This work is original and has not been published elsewhere.
1. Lake JE, Wohl D, Scherzer R, Grunfeld C, Tien PC, Sidney S, Currier JS. Regional fat deposition and cardiovascular risk in HIV infection: the FRAM study
. AIDS Care
2. Hadigan C, Meigs JB, Wilson PW, D’Agostino RB, Davis B, Basgoz N, et al. Prediction of coronary heart disease risk in HIV-infected patients with fat redistribution
. Clin Infect Dis
3. Ding J, Hsu FC, Harris TB, Liu Y, Kritchevsky SB, Szklo M, et al. The association of pericardial fat with incident coronary heart disease: the Multi-Ethnic Study of Atherosclerosis (MESA)
. Am J Clin Nutr
4. Ahn SG, Lim HS, Joe DY, Kang SJ, Choi BJ, Choi SY, et al. Relationship of epicardial adipose tissue by echocardiography to coronary artery disease
5. Lo J, Abbara S, Rocha-Filho JA, Shturman L, Wei J, Grinspoon SK. Increased epicardial adipose tissue volume in HIV-infected men and relationships to body composition and metabolic parameters
6. Guaraldi G, Scaglioni R, Zona S, Orlando G, Carli F, Ligabue G, et al. Epicardial adipose tissue is an independent marker of cardiovascular risk in HIV-infected patients
7. Crum-Cianflone N, Krause D, Wessman D, Medina S, Stepenosky J, Brandt C, Boswell G. Fatty liver disease is associated with underlying cardiovascular disease in HIV-infected persons
. HIV Med
8. Durnin JV, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 1 to 72 years
. Br J Nutr
9. Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ JR, et al. HIV Outpatient Study InvestigatorsHIV outpatient study investigators. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population
10. Gorter PM, van Lindert AS, de Vos AM, Meijs MF, van der Graaf Y, Doevendans PA, et al. Quantification of epicardial and peri-coronary fat using cardiac computed tomography; reproducibility and relation with obesity and metabolic syndrome in patients suspected of coronary artery disease
11. Nichols JH, Samy B, Nasir K, Fox CS, Schulze PC, Bamberg F, Hoffmann U. Volumetric measurement of pericardial adipose tissue from contrast-enhanced coronary computed tomography angiography: a reproducibility study
. J Cardiovasc Comput Tomogr
12. Jeong JW, Jeong MH, Yun KH, Oh SK, Park EM, Kim YK, et al. Echocardiographic epicardial fat thickness and coronary artery disease
. Circ J
13. Baker AR, Silva NF, Quinn DW, Harte AL, Pagano D, Bonser RS, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease
. Cardiovasc Diabetol
14. Herrmann J, Lerman LO, Rodriguez-Porcel M, Holmes DR Jr, Richardson DM, Ritman EL, Lerman A. Coronary vasa vasorum neovascularization precedes epicardial endothelial dysfunction in experimental hypercholesterolemia
. Cardiovasc Res
15. Ishikawa Y, Ishii T, Asuwa N, Masuda S. Absence of atherosclerosis evolution in the coronary arterial segment covered by myocardial tissue in cholesterol-fed rabbits
. Virchows Arch