Abstract 15594: Renin Inhibition versus AT1 Receptor Blockade in Aneurysmal Fibulin-4 Mice: Unraveling the Importance of AT2 Receptor Stimulation in Aneurysm Progression and Cardiac Function
Increasing evidence supports a role for the angiotensin (Ang) II-Ang II type 1 receptor (AT1R)-TGFβ axis in aneurysm development. Counteracting this axis, e.g., by stimulating Ang II type 2 (AT2) R (which antagonize AT1R-mediated effects) may thus be beneficial. Such stimulation will occur during treatment with an AT1R blocker, since the elevated Ang II levels that accompany such blockade can only bind to the non-blocked AT2R. It will not occur during renin or ACE inhibition. To study the importance of AT2R stimulation, we treated aneurysmal homozygous Fibulin-4R/R mice with placebo, the AT1R blocker losartan or the renin inhibitor aliskiren (60 and 62.5 mg/kg p.o. per day, resp.). The β-blocker propranolol was used as control as it is the standard therapy in aneurysmal patients (50 mg/kg p.o. per day). Fibulin-4R/R mice display a 4-fold reduced fibulin-4 expression, which results in cystic media degeneration, aortic regurgitation, left ventricular dilation, a reduced ejection fraction, and fractional shortening. Treatment started postnatally at day 30 and lasted up to 100 days. Treatment with losartan, aliskiren or propranolol similarly reduced hemodynamic stress. Normally, ≈30% of Fibulin-4R/R mice survive until 100 days. Propranolol did not alter this, but losartan and aliskiren increased survival to 85 and 50%, respectively. Elastic fiber fragmentation was not rescued in established aneurysms by any drug, nor was a reduction in aneurysm size observed. Yet, treatment with losartan increased ejection fraction compared to placebo from 27 to 46% (p=0.06), and it decreased left ventricle diameter from 5.8 to 4.5 mm (p=0.03). Aliskiren and propranolol showed no effect on either heart function or structure. In conclusion, losartan and to a lesser degree aliskiren (but not propranolol) improved survival in Fibulin-4R/R mice, without affecting aortic media degeneration and aneurysm progression. The larger beneficial effects of losartan on survival may relate to its capacity to simultaneously improve cardiac function and structure. The absence of this effect during aliskiren treatment suggests that it is due to AT2R stimulation in the heart.
- © 2013 by American Heart Association, Inc.