Elevated levels of asymmetric dimethylarginine are associated with lower CD4+ count and higher viral load in HIV-infected individuals

Abstract

Objectives: To compare asymmetric dimethylarginine (ADMA) among HIV-infected and uninfected individuals and to evaluate predictors of ADMA in HIV infection.

Background: HIV-infected individuals have high rates of atherosclerosis. Endothelial dysfunction is central to atherogenesis and is one possible mechanism underlying this increased cardiovascular risk. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, higher ADMA levels predict cardiovascular events and mortality. The association between HIV infection, HIV-related factors, and ADMA has not been well described.

Methods: We compared ADMA in 248 HIV-infected individuals and 50 uninfected controls. We performed multivariable analysis using traditional cardiovascular and HIV-specific factors as covariates to identify factors associated with ADMA.

Results: HIV-infected men were older, less often Caucasian, more hypertensive, and had lower HDL than uninfected men. The median duration of HIV infection was 13 years, median CD4+ count was 592 cells/μL, 76% had an undetectable viral load, and 76% were on antiretroviral therapy. ADMA levels were modestly higher in HIV-infected individuals than controls [median (IQR): 0.46 μM (0.41-0.52) vs. 0.44 μM (0.38-0.46), p = 0.019], but the association lost statistical significance after controlling for cardiovascular risk factors (+0.028 μM, p = 0.054). Lower CD4+ count and both detectable and higher viral load were independently associated with increased ADMA.

Conclusions: ADMA levels were modestly elevated in the setting of HIV infection. Notably, a greater HIV-associated inflammatory burden, as evidenced by lower CD4+ counts and higher viral loads, was associated with increased ADMA levels. Our findings suggest that HIV infection impairs endothelial function and predisposes to atherosclerosis through chronic inflammation and subsequent accumulation of ADMA.

Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Figures

Figure 1. Mechanism of ADMA Accumulation in HIV Infection

Solid line = primary pathway; Dashed line = secondary pathway; Red = inhibits. Abbreviations: O2 −, oxidative stress; DDAH, dimethylarginine dimethylaminohydrolase; ADMA, asymmetric dimethylarginine; NOS, nitric oxide synthase; NO, nitric oxide.