Asymmetric Dimethylarginine Levels Are Associated with Elevated Pulmonary Artery Pressure in HIV+ Individuals
Rushi Parikh*, R Scherzer, E Nitta, A Leone, C Donovan, J Morelli, S Deeks, P Ganz, J Martin, and P Hsue
Univ of California, San Francisco, US
Background: HIV infection is an independent risk factor for pulmonary arterial hypertension (PAH), although the mechanism underlying this disease process remains unknown. Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and blocks the synthesis of nitric oxide (NO), a potent vasodilator formed in endothelial cells from arginine. NO play a key role in protecting against atherosclerosis by inhibiting thrombosis, inflammation, and smooth muscle proliferation. Among uninfected individuals, ADMA causes endothelial dysfunction and predicts cardiovascular events and mortality. The purpose of this study was to evaluate the association of ADMA and elevated pulmonary artery pressures in the setting of HIV infection.
Methods: We measured ADMA and arginine using HPLC in HIV+ individuals in the University of California–San Francisco SCOPE cohort. Pulmonary artery systolic pressure (PASP) was ascertained with Doppler echocardiography using the modified Bernoulli equation to measure the peak velocity of the TR jet and adding it to the right atrial pressure estimate. We used Poisson regression with a robust variance estimator to estimate the relative risk for factors associated with PASP ≥30 mmHg.
Results: We examined 162 HIV+ individuals; overall, the median age was 50 (IQR 42 to 56), 16% were female, 73% were on ARV, 75% had undetectable HIV RNA levels, and the median CD4+ T cell count was 576 cells/mm3 (IQR 376 to 771). The median ADMA was 0.48 µmol/L (IQR 0.43 to 0.54). The unadjusted rank correlation between levels of ADMA and PASP was r = 0.14 (p = 0.074). In contrast, there was no association between arginine and PASP (r = 0.013, p = 0.87). In unadjusted analysis, ADMA was associated with higher prevalence of elevated PASP (prevalence ratio = 1.23, 95%CI 1.01 to 1.51, p = 0.044, per 0.1 µmol/L increase in ADMA). The association was slightly attenuated after multivariable adjustment (prevalence ratio = 1.22, 95%CI 0.99 to 1.51, p = 0.063).
Conclusions: ADMA, a key marker of endothelial dysfunction, was associated with elevated pulmonary artery pressure among HIV+ individuals. As ADMA impairs the synthesis of NO, our findings suggest that reduced NO release resulting in impaired endothelial function may represent a potential mechanism for HIV-associated PAH.