Increased systemic and pulmonary RAAS activity in patients with iPAH was associated with disease progression (P<0.05) and mortality (P<0.05).
Observational (n=72)
No
Does RAAS dysregulation contribute to iPAH progression, and does RAAS inhibition with losartan improve outcomes in experimental PAH?
Systemic and pulmonary RAAS activities are up-regulated in iPAH and associated with disease progression and mortality, while RAAS inhibition with losartan shows beneficial effects in experimental PAH models.
p-value: p=<0.05
RATIONALE: Patients with idiopathic pulmonary arterial hypertension (iPAH) often have a low cardiac output. To compensate, neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system are up-regulated, but this may have long-term negative effects on the progression of iPAH. OBJECTIVES: Assess systemic and pulmonary RAAS activity in patients with iPAH and determine the efficacy of chronic RAAS inhibition in experimental PAH. METHODS: We collected 79 blood samples from 58 patients with iPAH in the VU University Medical Center Amsterdam (between 2004 and 2010) to determine systemic RAAS activity. MEASUREMENTS AND MAIN RESULTS: We observed increased levels of renin, angiotensin (Ang)I, and AngII, which were associated with disease progression (P < 0.05) and mortality (P < 0.05). To determine pulmonary RAAS activity, lung specimens were obtained from patients with iPAH (during lung transplantation, n = 13) and control subjects (during lobectomy or pneumonectomy for cancer, n = 14). Local RAAS activity in pulmonary arteries of patients with iPAH was increased, demonstrated by elevated angiotensin-converting enzyme activity in pulmonary endothelial cells and increased AngII type 1 (AT(1)) receptor expression and signaling. In addition, local RAAS up-regulation was associated with increased pulmonary artery smooth muscle cell proliferation via enhanced AT(1) receptor signaling in patients with iPAH compared with control subjects. Finally, to determine the therapeutic potential of RAAS activity, we assessed the chronic effects of an AT(1) receptor antagonist (losartan) in the monocrotaline PAH rat model (60 mg/kg). Losartan delayed disease progression, decreased right ventricular afterload and pulmonary vascular remodeling, and restored right ventricular-arterial coupling in rats with PAH. CONCLUSIONS: Systemic and pulmonary RAAS activities are increased in patients with iPAH and are associated with increased pulmonary vascular remodeling. Chronic inhibition of RAAS by losartan is beneficial in experimental PAH.
Man et al. (Fri,) conducted a observational in idiopathic pulmonary arterial hypertension (iPAH) (n=72). Systemic and pulmonary RAAS activity vs. Control subjects was evaluated on Disease progression and mortality (p=<0.05). Increased systemic and pulmonary RAAS activity in patients with iPAH was associated with disease progression (P<0.05) and mortality (P<0.05).