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Asymmetric Dimethylarginine Is Increased in Chronic Thromboembolic Pulmonary Hypertension

¹ Division of Cardiology, Department of Internal Medicine II, ² Department of Clinical Pharmacology, and ³ Department of Cardiothoracic Surgery, Vienna General Hospital, Medical University of Vienna, Vienna, Austria; and ⁴ Wilhelminenspital der Stadt Wien, Vienna, Austria

Correspondence and requests for reprints should be addressed to Irene M. Lang, M.D., Professor of Vascular Biology, Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. 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 and associated with unfavorable outcome.

Objectives: 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.

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 control subjects (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 underwent surgery 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 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 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 patients with CTEPH. Measurement of ADMA plasma levels may be useful for estimating the degree of small-vessel arteriopathy in CTEPH.

Key Words: chronic thromboembolic pulmonary hypertension • nitric oxide • nitric oxide synthase

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Asymmetric dimethylarginine (ADMA) is a potent endogenous nitric oxide synthase inhibitor that is increased in plasma from patients with idiopathic pulmonary arterial hypertension, and pulmonary arterial hypertension associated with congenital heart disease. Small-vessel pulmonary vasculopathy that is typical for idiopathic pulmonary arterial hypertension may also be a feature of chronic thromboembolic pulmonary hypertension (CTEPH). What This Study Adds to the Field Increased ADMA plasma levels are present in patients with CTEPH. ADMA correlated with the severity of pulmonary vascular disease. ADMA concentrations of 0.64 µmol/L or greater predict worse prognosis, and could serve as a surrogate marker for small-vessel arteriopathy in CTEPH.

 

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