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Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection

Parikh, Rushi V.a; Scherzer, Rebeccaa,b; Nitta, Elaine M.c; Leone, Annad; Hur, Sophiac; Mistry, Vanitac; Macgregor, John S.c; Martin, Jeffrey N.e; Deeks, Steven G.e; Ganz, Peterc; Hsue, Priscilla Y.c

doi: 10.1097/QAD.0000000000000124
Clinical Science

Objective: To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH).

Design: HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality.

Methods: We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL-6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC.

Results: Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 μmol/l, P = 0.0049 and 3.9% per doubling, P = 0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 μmol/l, P = 0.0014 and 5.8% per doubling, P = 0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio = 1.74, P = 0.029).

Conclusion: Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH.

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aDepartment of Medicine, University of California San Francisco

bDivision of Endocrinology and Metabolism, San Francisco VA Medical Center

cSan Francisco General Hospital Cardiology Division, University of California San Francisco, San Francisco

dOxonon BioAnalysis, Emeryville

eSan Francisco General Hospital Positive Health Program, University of California San Francisco, San Francisco, California, USA.

Correspondence to Priscilla Hsue, MD, Room 5G1 Cardiology SFGH, 1001 Potrero Avenue, San Francisco, CA 94110, USA. Tel: +1 415 206 8257; fax: +1 415 206 5447; e-mail:

Received 30 June, 2013

Revised 21 October, 2013

Accepted 21 October, 2013

This work was presented in part at the Conference on Retroviruses and Opportunistic Infections, 5–8 March 2012, Seattle, WA, USA.

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