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.
    Vascular Pharmacology 04/2015; 73. DOI:10.1016/j.vph.2015.04.010 · 3.64 Impact Factor
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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.
    Frontiers in Pediatrics 02/2014; 2:7. DOI:10.3389/fped.2014.00007
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    • "Abnormal NO metabolism accompanied by administration of ADMA has been described in patients with pulmonary hypertension associated with advanced systolic heart failure [112] and Down syndrome [113]. Elevated ADMA concentrations are also associated with hemodynamic parameters and prognosis in idiopathic [114] and chronic thromboembolic pulmonary hypertension [115]. With regards to SSc, it has been reported that ADMA is increased in patients with echocardiographically defined pulmonary hypertension [116] and it is correlated with systolic pulmonary artery pressure and functional capacity [117]. "
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    ABSTRACT: The last few decades have witnessed an increased life expectancy of patients suffering with systemic rheumatic diseases, mainly due to improved management, advanced therapies and preventative measures. However, autoimmune disorders are associated with significantly enhanced cardiovascular morbidity and mortality not fully explained by traditional cardiovascular disease (CVD) risk factors. It has been suggested that interactions between high-grade systemic inflammation and the vasculature lead to endothelial dysfunction and atherosclerosis, which may account for the excess risk for CVD events in this population. Diminished nitric oxide synthesis-due to down regulation of endothelial nitric oxide synthase-appears to play a prominent role in the imbalance between vasoactive factors, the consequent impairment of the endothelial hemostasis and the early development of atherosclerosis. Asymmetric dimethylarginine (ADMA) is one of the most potent endogenous inhibitors of the three isoforms of nitric oxide synthase and it is a newly discovered risk factor in the setting of diseases associated with endothelial dysfunction and adverse cardiovascular events. In the context of systemic inflammatory disorders there is increasing evidence that ADMA contributes to the vascular changes and to endothelial cell abnormalities, as several studies have revealed derangement of nitric oxide/ADMA pathway in different disease subsets. In this article we discuss the role of endothelial dysfunction in patients with rheumatic diseases, with a specific focus on the nitric oxide/ADMA system and we provide an overview on the literature pertaining to ADMA as a surrogate marker of subclinical vascular disease.
    International Journal of Molecular Sciences 12/2012; 13(10):12315-35. DOI:10.3390/ijms131012315 · 2.86 Impact Factor
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