Abstract 14479: Abrupt Withdrawal of Losartan Therapy Increases Circulating Transforming Growth Factor Beta and Accelerates Aortic Root Growth in a Mouse Model of Marfan Syndrome
Objective: The AT1 receptor blocker losartan has shown the ability to attenuate TGFβ signaling and aneurysm progression in a mouse model of Marfan syndrome (MFS). Losartan is known to be teratogenic and can impair renal development through birth. Therefore therapy has to be discontinued at the onset of pregnancy. AT1 blockade has been shown to upregulate receptor expression. We assessed the hypothesis that abrupt withdrawal of losartan therapy would lead to excessive AT1 activity with a consequent elevation in circulating TGFβ and aortic root growth in a mouse model of MFS.
Subjects and Methods: Fbn1C1039G/+ (n=11) and wild-type mice (n=7) were randomly assigned to receive losartan therapy or placebo. Treatment in the losartan group was started at 4 months of age, continued for 2 months and then was abruptly withdrawn. Aortic root size was measured and serum samples were taken at 4, 6 and 8 months of age; serum samples were analyzed for levels of circulating TGFβ-1.
Results: In keeping with prior work, final aortic root size was larger in placebo treated Fbn1C1039G/+ mice than in wild-type mice (2.04±0.03mm vs. 1.74±0.06mm, respectively; p<0.005). Losartan-treated Fbn1C1039G/+ mice showed a significant reduction in aortic root growth rate compared to placebo (-0.062±0.04mm/2mo vs. +0.048±0.015mm/2mo, respectively; p<0.05). After abrupt withdrawal of losartan therapy in Fbn1C1039G/+ mice, aortic root growth was accelerated (-0.062±0.04mm/2mo vs. 0.34±0.54mm/2mo, respectively; p=0.06). This correlated with a decrease in circulating TGFβ levels after initiation of losartan therapy and an increase after therapy withdrawal (-22.7±10ng/ml vs. +32.6±7ng/ml, respectively; p<0.001).
Conclusion: Abrupt withdrawal of losartan therapy increases circulating levels of TGFβ-1 and initiates rapid acceleration of aortic root growth in a mouse model of MFS. These data suggest that abrupt discontinuation of losartan therapy should be avoided and tapering seems mandatory. Furthermore, circulating TGFβ serves as a sensitive surrogate marker to monitor disease activity in response to the initiation and modification of therapeutic protocols.
- © 2010 by American Heart Association, Inc.