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

Abstract

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.

Fig. 1. Association of asymmetric dimethylarginine with pulmonary artery systolic pressure and mean pulmonary artery pressure in HIV infection

Pulmonary artery systolic pressure (PASP) analysis (left-side scatterplot) comprises all 214 HIV-infected participants; mean pulmonary artery pressure (mPAP) analysis (right-side scatterplot) only includes subset of 85 HIV-infected participants with right heart catheterization (RHC). Solid lines denote predicted level of PASP and mPAP (with dotted 95% confidence intervals) calculated from unadjusted generalized additive models. Linear and spline P values indicate whether the linear and nonlinear curved associations, respectively, are statistically significant. ADMA, asymmetric dimethylarginine.

Fig. 2. Asymmetric dimethylarginine-dimethylarginine dimethylaminohydrolase-nitric oxide axis in pathogenesis of HIV-associated pulmonary arterial hypertension

Solid line = primary pathway; dashed line = secondary pathway; Red = inhibits. ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; NO, nitric oxide; NOS, nitric oxide synthase; O₂⁻, oxidative stress; PAH, pulmonary arterial hypertension.