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: 11.99). 12/2007; 176(11):1154-60. DOI: 10.1164/rccm.200702-278OC
Source: PubMed

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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    • "Skoro-Sajer et al. found that increased ADMA plasma levels were present in patients with CTEPH. ADMA levels were correlated with the severity of pulmonary vascular disease, and they decreased after pulmonary endarterectomy [15]. The purpose of our study was to analyze the preand posttreatment serum ADMA, NO 3 , vitamin B 12 , and homocysteine levels in PTE patients and to evaluate the predictive value of the variables for development of CTEPH. "
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    ABSTRACT: We aimed to analyze the pre- and posttreatment serum asymmetric dimethylarginine (ADMA), nitrate (NO(3)), vitamin B(12) and homocysteine levels in pulmonary embolism (PTE) patients and to determine the prognostic value of these variables in predicting chronic thromboembolic pulmonary hypertension (CTEPH). This study was conducted in 64 patients. The patients were classified into the two groups: patients with normal pulmonary artery pressure (PAP) (group I) and patients with high PAP with persistent lung perfusion defects or who died at the end of 3 months of therapy (group II). We found statistically significant differences between two groups with respect to the partial oxygen pressure, the oxygen saturation, and the PAP, but there was no difference between the two groups with respect to the pretreatment ADMA, NO(3), or homocysteine levels. The vitamin B(12) levels were higher in group II. The NO(3) levels increased and the ADMA and vitamin B(12) levels decreased with treatment in both groups. These results suggest that these parameters are not predictive of the development of CTEPH.
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    • "Elevated systemic levels of ADMA have been associated with atherosclerosis, particularly in patients with renal insufficiency (Boger and Zoccali, 2003). ADMA has been found at higher levels in idiopathic and chronic thromboembolic PH (Kielstein, et al, 2005, Skoro-Sajer, et al, 2007), PH related to congenital heart disease (Loukanov, et al, 2008), and in a rodent model of PH (Sasaki, et al, 2007), Elevation of ADMA in DDAH deficient mice is associated with endothelial dysfunction and elevated systemic and pulmonary blood pressure (Leiper, et al, 2007). ADMA has been found to be elevated in the plasma of patients with SCD, and associated with soluble vascular cell adhesion molecule-1 (sVCAM-1), a marker of endothelial activation normally suppressed by NO (Landburg, et al, 2008a, Schnog, et al, 2005). "
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