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Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Am+J+Respir+Crit+Care+Med 2012 ; 186 (8): 780-9 Nephropedia Template TP
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Dysregulated renin-angiotensin-aldosterone system contributes to pulmonary arterial hypertension #MMPMID22859525
De Man F; Tu L; Handoko L; Rain S; Ruiter G; François C; Schalij I; Dorfmüller P; Simonneau G; Fadel E; Perros F; Boonstra A; Postmus P; Van Der Velden J; Vonk-Noordegraaf A; Humbert M; Eddahibi S; Guignabert C
Am J Respir Crit Care Med 2012[Oct]; 186 (8): 780-9 PMID22859525show ga
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.
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Am+J+Respir+Crit+Care+Med 2012 ; 186 (8): 780-9
