Am J Respir Crit Care Med. 2012 Aug 2. [Epub ahead of print]
Dysregulated Renin-Angiotensin-Aldosterone System Contributes to Pulmonary Arterial Hypertension.
de Man FS, Tu L, Handoko ML, Rain S, Ruiter G, François C, Schalij I, Dorfmüller P, Simonneau G, Fadel E, Perros F, Boonstra A, Postmus PE, van der Velden J, Vonk-Noordegraaf A, Humbert M, Eddahibi S, Guignabert C.
Pulmonology, VU University Medical Center, Amsterdam, Netherlands.
Rationale - Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems like renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system are upregulated but this may have long-term negative effects on the progression of iPAH.
Objectives - Assess systemic and pulmonary RAAS-activity in iPAH-patients and determine the efficacy of chronic RAAS-inhibition in experimental PAH.
Measurements and Main Results - We collected 79 blood samples from 58 iPAH-patients in the VU University Medical Center Amsterdam (between 2004-2010), to determine systemic RAAS-activity. We observed increased levels of renin, angiotensin (Ang) I and AngII, which was associated with disease progression (p<0.05) and mortality (p<0.05). To determine pulmonary RAAS-activity, lung specimens were obtained from iPAH-patients (during lung transplantation, n=13) and controls (during lobectomy or pneumonectomy for cancer, n=14). Local RAAS-activity in pulmonary arteries of iPAH-patients was increased, demonstrated by elevated ACE-activity in pulmonary endothelial cells and increased AngII type 1 (AT1) receptor expression and signaling. In addition, local RAAS-upregulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT1-receptor signaling in iPAH-patients compared to controls. Finally, to determine the therapeutic potential of RAAS-activity, we assessed the chronic effects of an AT1-receptor antagonist (losartan) in the monocrotaline PAH-rat model (60 mg/kg). Losartan delayed disease progression, decreased RV afterload and pulmonary vascular remodeling and restored right ventricular-arterial coupling in PAH-rats.
Conclusions - Systemic and pulmonary RAAS-activities are increased in iPAH-patients and associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.