Abstract 14647: Calcium Channel Blockers Exacerbate Aortic Disease and Cause Premature Lethality in Marfan Syndrome
Aortic root dilatation and dissection is the leading cause of death in Marfan syndrome (MFS). We previously showed that excessive TGFβ-dependent activation of ERK signaling drives aneurysm progression in MFS. TGFβ neutralizing antibody, selective inhibitors of ERK activation, or the AT1R blocker losartan abrogate aneurysm growth in MFS mice by antagonizing TGFβ-dependent ERK activation. Pending the results of clinical trials of losartan, calcium channel blockers (CCBs, e.g. amlodipine) are currently used as second-line therapy for MFS in patients intolerant of beta-blockers, largely on theoretic grounds due to their blood pressure-lowering effect. To interrogate this practice, wild-type (WT) and MFS (C1039G/+) mice were treated with amlodipine or placebo from 2 months of age. Baseline echocardiography was performed at 2 months, and every 2 months thereafter. Placebo-treated C1039G/+ mice had larger aortic roots at 4 months (p<0.001) and more rapid growth from 2 to 4 months (p=0.04), compared to WT littermates. Amlodipine-treated C1039G/+ mice showed no improvement in either parameter, compared to placebo-treated counterparts (p=1.0; p=0.95). There was no difference in the more distal ascending aortic (AscAo) diameter at 4 months (p=0.51) or growth from 2 to 4 months (p=0.87), between C1039G/+ and WT mice. In contrast, both AscAo size and growth were increased in amlodipine-treated WT (p=0.002; p=0.025) and C1039G/+ (p<0.0001; p<0.0005) mice, compared to genotype-matched placebo controls, with a greatly amplified growth effect in C1039G/+ mice (p=0.007). Amlodipine-treated C1039G/+ mice uniquely showed early mortality, with 30% dead from aortic dissection after 3 months of treatment. Accelerated AscAo growth and dissection correlated with increased ERK activation. In a retrospective analysis, 2 of 6 MFS patients treated with CCBs showed aortic dissection in childhood, one of whom dissected at unusually small aortic dimensions. Use of CCBs requires more study, but should be done with caution in MFS. In an era of expanding tension between concepts in evidence-based and personalized medicine (where the generation of evidence for small groups is inherently constrained), this study demonstrates how animal models can be used to fill the void.
- © 2010 by American Heart Association, Inc.