Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection.
OBJECTIVE
To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH).


METHODS
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).


CONCLUSIONS
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.
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.
Rushi V
RV
Parikh
Rebecca
R
Scherzer
Elaine M
EM
Nitta
Anna
A
Leone
Sophia
S
Hur
Vanita
V
Mistry
John S
JS
Macgregor
Jeffrey N
JN
Martin
Steven G
SG
Deeks
Peter
P
Ganz
Priscilla Y
PY
Hsue
D000328:Adult; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D001794:Blood Pressure; D002407:Catheterization, Swan-Ganz; D015331:Cohort Studies; D004452:Echocardiography; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies
D015415:Biomarkers; C018524:N,N-dimethylarginine; D001120:Arginine