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.

Asymmetric dimethyl arginine induces pulmonary vascular dysfunction via activation of signal transducer and activator of transcription 3 and stabilization of hypoxia-inducible factor 1-alpha

“…Besides regulating the vasodilation, NO is able to suppress the proliferation of vascular smooth muscle cells and inhibit the interaction of circulating blood elements with the endothelial cells [10,12]. Importantly, the loss of NO production in PH patients is further associated with increased plasma levels of asymmetric dimethyl arginine (N G , N G -dimethyl-L-arginine, ADMA), an endogenous competitive inhibitor of eNOS enzyme [13][14][15][16][17].…”

Risk factors for chronic kidney disease do not influence the serum levels of asymmetric dimethylarginine in HIV-1-infected patients without significant renal disease

“…This impairment results in the development of subclinical atherosclerosis 24 and primary pulmonary hypertension. 21 It is believed that the accumulation of ADMA as a result of chronic immune activation is associated with a predisposition to atherosclerosis. 22 It is known that antiretroviral drugs, mainly PIs, are responsible for the development of lipodystrophy syndrome.…”

“…This marker has been studied in HIV-1-infected patients mainly in the context of cardiovascular disease and its diagnosis. [20][21][22][23][24][25][26] Due to the complex pathology of HIV-1 infection, which is associated with a higher number of kidney-damaging agents than that occuring in the general population, it is important to determine the prevalence of renal damage in HIV-1-infected population inhabiting a given region, as well as software for Windows (StatSoft Inc., Tulsa, Oklahoma, United States).…”

Human Immunodeficiency Virus–Associated Pulmonary Arterial Hypertension

“…60 Removal of apoptotic cells by neighboring viable cells, likely by phagocytosis intended to maintain tissue homeostasis, may in fact cause the release of growth factors and cytokines, which, consequently, could lead to the emergence of uncontrolled vascular cell proliferation, complex vascular remodeling, plexiform lesions, and PAH. [59][60][61][62] Inflammation, the release of cytokines and chemokines such as IL-6, or increased levels of vasoactive peptides that influence remodeling like asymmetrical dimethylarginine, 63,64 may also contribute to HIV-associated PAH. Observations suggest that chronic HIV-associated inflammation leads to an accumulation of asymmetrical dimethylarginine, which is a well-known endogenous inhibitor of endothelial nitric oxide synthase, and, thus, promotes endothelial dysfunction and vascular smooth muscle cell proliferation.…”

“…Observations suggest that chronic HIV-associated inflammation leads to an accumulation of asymmetrical dimethylarginine, which is a well-known endogenous inhibitor of endothelial nitric oxide synthase, and, thus, promotes endothelial dysfunction and vascular smooth muscle cell proliferation. [63][64][65] Additionally, Nef and Tat proteins modulate the release of IL-2 and monocyte chemotactic protein-1 (MCP-1, also known as CCL2), which stimulate pulmonary vascular remodeling, 66,67 particularly in Schistosomiasis infection 68,69 ( Figure 2). Whether overlap in cytokine activation patterns in Schistosomiasis and HIV is responsible for PAH in coinfected patients, however, requires further investigation.…”