Published ahead of print on September 13, 2007, doi:10.1164/rccm.200702-278OC Am. J. Respir. Crit. Care Med., Volume 176, Number 11, December 2007, 1154-1160 A more recent version of this article appeared on December 1, 2007
Submitted on February 18, 2007 Asymmetric Dimethylarginine is Increased in Chronic Thromboembolic Pulmonary HypertensionNika Skoro-Sajer1,1 Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria, 2 Department of Clinical Pharmacology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria, 3 Department of Cardiothoracic Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria, 4 Wilhelminenspital der Stadt Wien, Vienna, Austria * To whom correspondence should be addressed. E-mail: irene.lang{at}meduniwien.ac.at.
Rationale: Asymmetric dimethylarginine (ADMA), a potent endogenous nitric oxide synthase (NOS) inhibitor, is increased in idiopathic pulmonary arterial hypertension (iPAH) and associated with unfavorable outcome.
Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH), though principally amenable to surgical removal of major pulmonary arterial obstructions by pulmonary endarterectomy (PEA), may show a small-vessel pulmonary arteriopathy similar to iPAH. We hypothesized that ADMA plasma levels are increased in patients with CTEPH.
Methods: 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. Measurements and Main results:
ADMA plasma levels were significantly elevated in patients, compared with 40 matched controls (0.62 (0.51-0.73) vs. 0.51 (0.45-0.6 µmol/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 were operated demonstrated lower ADMA levels at baseline than inoperable patients (0.60 (0.5-0.68) vs. 0.63 (0.53-0.85 µmol/l); p=0.02), with a further decrease 12±1 months after PEA (p=0.02). Endothelial nitric oxide synthase expression in endothelial cells was low in patients with elevated ADMA plasma levels. Survival of patients with ADMA plasma levels Key words: chronic thromboembolic pulmonary hypertension, nitric oxide, nitric oxide synthase
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0.64 µmol/l was worse than in patients with ADMA plasma levels <0.64 µmol/l.
Conclusions: ADMA plasma levels correlate with the severity of pulmonary vascular disease and predict outcome in CTEPH patients. Measurement of ADMA plasma levels may be useful for estimating the degree of small-vessel arteriopathy in CTEPH.
