Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension

Professor of Vascular Biology, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 12/2007; 176(11):1154-60. DOI: 10.1164/rccm.200702-278OC
Source: PubMed


Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase (NOS) inhibitor, is increased in idiopathic pulmonary arterial hypertension and associated with unfavorable outcome.
Chronic thromboembolic pulmonary hypertension (CTEPH), although principally amenable to surgical removal of major pulmonary arterial obstructions by pulmonary endarterectomy, may show a small-vessel pulmonary arteriopathy similar to idiopathic pulmonary arterial hypertension. We hypothesized that ADMA plasma levels are increased in patients with CTEPH.
We measured ADMA by high-performance liquid chromatography at the time of diagnosis in 135 patients with CTEPH. Inoperability in 66 patients was based on an imbalance between severity of pulmonary hypertension and morphologic lesions.
ADMA plasma levels were significantly elevated in patients, compared with 40 matched control subjects (0.62 [0.51-0.73] vs. 0.51 [0.45-0.6] micromol/L, P = 0.0002). At baseline, ADMA plasma concentrations correlated with mixed venous saturation (r = -0.25, P = 0.005), right atrial pressure (r = 0.35, P < 0.0001), and cardiac index (r = -0.21, P = 0.01). Patients who underwent surgery demonstrated lower ADMA levels at baseline than inoperable patients (0.60 [0.5-0.68] vs. 0.63 [0.53-0.85] micromol/L, P = 0.02), with a further decrease 12 +/- 1 months after pulmonary endarterectomy (P = 0.02). Endothelial NOS expression in endothelial cells was low in patients with elevated ADMA plasma levels. Survival of patients with ADMA plasma levels >/= 0.64 micromol/L was worse than in patients with ADMA plasma levels < 0.64 micromol/L.
ADMA plasma levels correlate with the severity of pulmonary vascular disease and predict outcome in patients with CTEPH. Measurement of ADMA plasma levels may be useful for estimating the degree of small-vessel arteriopathy in CTEPH.

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    • "c o m / l o c a t e / v p h significance of elevated circulating levels of ADMA in patients with PH has been demonstrated. Increased levels of ADMA have been associated with poor exercise capacity [15], unfavorable pulmonary hemodynamics and worse outcome [12] [14]. Phosphodiesterase-5 (PDE5) inhibitors represent a class of drugs that enhance the NO mediated pulmonary vasodilatation by promoting the accumulation of cyclic guanosine monophosphate (cGMP) [18]. "
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    ABSTRACT: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. ADMA, SDMA, and arginine were measured (0-540min) in twelve patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive haemodynamic data were collected at baseline and after 60min. A reduction in ADMA was observed at 30 and 45min with a median change of -11.1 % (P =0.021) and -12.5 % (P=0.002). SDMA decreased with a median -5.3 % change (P=0.032) at 45min. An increase in arginine, median 40.3 % (P=0.002), 45.0 % (P=0.010), and 77.1 % (P=0.008) was observed at 120, 300, and 540min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Vascular Pharmacology
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    • "Indeed, a distinct class of emerging therapies for PH is based upon the antagonistic actions of asymmetric dimethylarginine (ADMA) regulating NO production (137). Elevated plasma ADMA has been shown to correlate to severity of idiopathic (138) and chronic thromboembolic PH in adults (139), and in children with congenital heart disease (140) and sickle cell disease with PH (141). Moreover, in one study of systemic heart failure associated with pulmonary venous hypertension, exhaled NO levels were in higher in hypertensives, but NO did not correlate to increased plasma ADMA (142). "
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    ABSTRACT: Therapeutic approaches in pediatric pulmonary arterial hypertension (PAH) are based primarily on clinician experience, in contrast to the evidence-based approach in adults with pulmonary hypertension. There is a clear and present need for non-invasive and objective biomarkers to guide the accurate diagnosis, treatment, and prognosis of this disease in children. The multifaceted spectrum of disease, clinical presentation, and association with other diseases makes this a formidable challenge. However, as more progress is being made in the understanding and management of adult PAH, the potential to apply this knowledge to children has never been greater. This review explores the state of the art with regard to non-invasive biomarkers in PAH, with an eye toward those adult PAH biomarkers potentially suitable for application in pediatric PAH.
    Full-text · Article · Feb 2014 · Frontiers in Pediatrics
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    • "A product of protein arginine methylation, ADMA, is a naturally occurring nitric oxide synthase (NOS) inhibitor [49]. Elevated ADMA concentrations have been detected in the plasma of patients with idiopathic (i) PAH [109–111], CTEPH [112], PAH-related sickle cell disease [113] and systemic sclerosis [114], suggesting a strong association of circulating dimethylarginine levels with PH pathogenesis. It remains unclear which DDAH or PRMT isoforms control ADMA tissue and plasma levels under those pathological conditions. "
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    ABSTRACT: Protein arginine methylation is a novel posttranslational modification that plays a pivotal role in a variety of intracellular events, such as signal transduction, protein-protein interaction and transcriptional regulation, either by the direct regulation of protein function or by metabolic products originating from protein arginine methylation that influence nitric oxide (NO)-dependent processes. A growing body of evidence suggests that both mechanisms are implicated in cardiovascular and pulmonary diseases. This review will present and discuss recent research on PRMTs and the methylation of non-histone proteins and its consequences for the pathogenesis of various lung disorders, including lung cancer, pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease and asthma. This article will also highlight novel directions for possible future investigations to evaluate the functional contribution of arginine methylation in lung homeostasis and disease.
    Full-text · Article · Dec 2012 · International Journal of Molecular Sciences
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