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

Abstract

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.

Figure 1. Mean Annual Rate of Change in Absolute and Normalized Aortic Diameters before and after Initiation of Therapy with an Angiotensin II–Receptor Blocker (ARB)

Panel A shows the rate of change in absolute aortic diameter, and Panel B shows the rate of change in aortic-diameter z scores for four aortic segments that were measured over time in patients with severe Marfan’s syndrome. All rates are expressed as means, with error bars representing standard errors. P values were calculated with the use of the Wilcoxon signed-rank test.

Figure 2. Change in Aortic-Root Diameter Standardized According to the Time of Initiation of Therapy with an Angiotensin II–Receptor Blocker (ARB)

Panel A represents the change over time in aortic-root diameter for each of the 18 patients in the analysis, with the solid trend line representing the overall mean change in aortic-root diameter before and after the initiation of ARB therapy. The time at which ARB therapy was started for all patients is standardized at year 0 and is represented by the vertical dashed line. The mean rate of change in aortic-root diameter was reduced among all 18 patients after ARB therapy was initiated (P<0.001, sign test). Panel B represents the change in aortic-root diameter in the one patient receiving irbesartan. The dashed line at year 0 represents the time of initiation of irbesartan and distinguishes the period during which beta-blocker therapy alone was administered from the period during which ARB therapy was added.