Angiotensin II blockade and aortic-root dilation in Marfan's syndrome

Background: Progressive enlargement of the aortic root, leading to dissection, is the main cause of premature death in patients with Marfan's syndrome. Recent data from mouse models of Marfan's syndrome suggest that aortic-root enlargement is caused by excessive signaling by transforming growth factor (beta) (TGF-(beta)) that can be mitigated by treatment with TGF-(beta) antagonists, including angiotensin II-receptor blockers (ARBs). We evaluated the clinical response to ARBs in pediatric patients with Marfan's syndrome who had severe aortic-root enlargement. Methods: We identified 18 pediatric patients with Marfan's syndrome who had been followed during 12 to 47 months of therapy with ARBs after other medical therapy had failed to prevent progressive aortic-root enlargement. The ARB was losartan in 17 patients and irbesartan in 1 patient. We evaluated the efficacy of ARB therapy by comparing the rates of change in aortic-root diameter before and after the initiation of treatment with ARBs. Results: The mean (+/-SD) rate of change in aortic-root diameter decreased significantly from 3.54+/-2.87 mm per year during previous medical therapy to 0.46+/-0.62 mm per year during ARB therapy (P<0.001). The deviation of aortic-root enlargement from normal, as expressed by the rate of change in z scores, was reduced by a mean difference of 1.47 z scores per year (95% confidence interval, 0.70 to 2.24; P<0.001) after the initiation of ARB therapy. The sinotubular junction, which is prone to dilation in Marfan's syndrome as well, also showed a reduced rate of change in diameter during ARB therapy (P<0.05), whereas the distal ascending aorta, which does not normally become dilated in Marfan's syndrome, was not affected by ARB therapy. Conclusions: In a small cohort study, the use of ARB therapy in patients with Marfan's syndrome significantly slowed the rate of progressive aortic-root dilation. These findings require confirmation in a randomized trial

A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome

Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents. DOI: http://dx.doi.org/10.7554/eLife.08648.00

Angiotensin II type 2 receptor signaling attenuates aortic aneurysm in mice through ERK antagonism

Angiotensin II (AngII) mediates progression of aortic aneurysm, but the relative contribution of its type 1 (AT1) and type 2 (AT2) receptors remains unknown. We show that loss of AT2 expression accelerates the aberrant growth and rupture of the aorta in a mouse model of Marfan syndrome (MFS). The selective AT1 receptor blocker (ARB) losartan abrogated aneurysm progression in the mice; full protection required intact AT2 signaling. The angiotensin-converting enzyme inhibitor (ACEi) enalapril, which limits signaling through both receptors, was less effective. Both drugs attenuated canonical transforming growth factor-β? (TGFβ) signaling in the aorta, but losartan uniquely inhibited TGFβ-mediated activation of extracellular signal-regulated kinase (ERK), by allowing continued signaling through AT2. These data highlight the protective nature of AT2 signaling and potentially inform the choice of therapies in MFS and related disorders.5 page(s