Asymmetric dimethylarginine is increased in chronic thromboembolic pulmonary hypertension.
ABSTRACT 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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ABSTRACT: Hyperhomocysteinemia is a putative risk factor for cardiovascular disease, which also impairs endothelium-dependent vasodilatation. A number of other risk factors for cardiovascular disease may exert their adverse vascular effects in part by elevating plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Accordingly, we determined if homocysteine could increase ADMA levels. When endothelial or nonvascular cells were exposed to DL-homocysteine or to its precursor L-methionine, ADMA concentration in the cell culture medium increased in a dose- and time-dependent fashion. This effect was associated with the reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Furthermore, homocysteine-induced accumulation of ADMA was associated with reduced nitric oxide synthesis by endothelial cells and segments of pig aorta. The antioxidant pyrrollidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation. Moreover, homocysteine dose-dependently reduced the activity of recombinant human DDAH in a cell free system, an effect that was due to a direct interaction between homocysteine and DDAH. Homocysteine post-translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium-mediated nitric oxide-dependent vasodilatation.Circulation 12/2001; 104(21):2569-75. · 15.20 Impact Factor
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ABSTRACT: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, causes vasoconstriction, impairs cardiac function, and may predict cardiovascular risk. The prognostic value of plasma ADMA concentrations in acute vascular situations may be confounded by concomitant factors such as clot formation. In an effort to address the effect of hemostatic system activation, the authors have measured plasma concentrations of ADMA, its stereoisomer symmetrical dimethylarginine (SDMA), and L-arginine in 74 patients with suspected deep vein thrombosis (DVT). DVT was confirmed by sonography or venography in 39 subjects. There was no difference of L-arginine, ADMA, or SDMA (all P > 0.05) between subjects with or without DVT. ADMA correlated with SDMA, L-arginine, and plasma creatinine (all P < 0.05) but not with age, body mass index, D-dimer, thrombus extension, or history of symptoms. Venous thrombembolism does not influence circulating ADMA concentrations. The lack of association between ADMA and DVT argues against a contribution of endogenous NO synthase inhibition in hemostatic systemic activation.Translational Research 07/2006; 148(1):26-9. · 3.49 Impact Factor
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ABSTRACT: Pulmonary arterial hypertension is a severe disease that has been ignored for a long time. However, over the past 20 yrs chest physicians, cardiologists and thoracic,surgeons,have,shown,increasing interest in this disease because,of the development of new therapies, that have improved both the outcome and quality of life of patients, including pulmonary transplantation and prostacyclin therapy. Chronic thromboembolic,pulmonary,arterial hypertension,(CTEPH) can be cured surgically through,a complex,surgical procedure: the pulmonary,thromboendarter- ectomy. Pulmonary thromboendarterectomy is performed,under hypothermia,and total circulatory arrest. Due to clinically evident acute-pulmonary,embolism,episodes being absent in w50% of patients, the diagnosis of CTEPH can be difficult. Lung scintiscan showing segmental,mismatched,perfusion defects is the best diagnostic tool to detect CTEPH. Pulmonary,angiography,confirms,the diagnosis and determines,the feasability of endarterectomy according to the location of the disease, proximal versus distal. The technique of angiography,must be perfect with the whole arterial tree captured on the same picture for each lung. The lesions must start at the level of the pulmonary,artery trunk, or at the level of the lobar arteries, in order to find a plan for the endarterectomy. When the haemodynamic gravity corresponds to the degree of obliteration, pulmonary,thromboendarterectomy,can,be performed,with minimal,perioperative mortality, providing definitive, excellent functional results in almost all cases. Eur Respir J 2004; 23: 637–648. *Dept of Thoracic and Vascular Surgery and Heart-Lung Transplantation, Marie Lannelongue Hospital, Paris-Sud University, Le Plessis Robinson,and,,Service de Pneumologie,et Re ´animation Respiratoire, Ho ˆ pital AntoineVnitr̆ní lékar̆ství 02/2011; 57(2):129.