Inhibition of Marfan‐associated Aortic Root Dilation by Angiotensin II Receptor Blockers May Be Independent of Blood Pressure Lowering

Abstract

BackgroundMarfan syndrome (MFS) is a connective tissue disorder resulting in accelerated vascular aging, aortic root widening and aneurysm if unmanaged. Despite encouraging pre‐clinical data, recent clinical trials have shown underwhelming efficacy of anti‐hypertensive angiotensin II receptor type 1 (ATR1) blocker (ARB) losartan in MFS patients. We have recently reported that losartan mediates its anti‐aortic root remodeling effects in blood pressure (BP)‐ and ATR1‐independent fashions, and instead acts by improving endothelial function and protective endothelial nitric oxide (NO) synthase‐mediated NO release. Considering the unique mechanism of action of losartan in MFS, whether other ARBs can provide greater protection against MFS aortic root widening is unknown.ObjectiveHere we compare the efficacy of other ARBs previously linked to endothelial function activity with losartan at blocking aortic root widening in MFS mice.Methods and ResultsAortic root dilation, aortic vessel remodeling, BP, and aortic contractility were compared between MFS and wild‐type (WT) mice after an 18‐week treatment with losartan, telmisartan, valsartan, or vehicle. Losartan and telmisartan doses were titrated to give similar hemodynamic effects in vivo, resulting in a 20–30% decrease in BP in both groups, while valsartan was chosen at a non‐BP lowering dose. Untreated MFS mice showed increased aortic root widening compared to WT controls (1.84 ± 0.05mm vs 1.52 ± 0.03mm; p<0.05) as assessed by high frequency ultrasound imaging. Despite differences in BP lowering, all ARBs significantly reduced aortic root widening in the MFS group by 10–16% (p<0.05). Histological assessment revealed a 26–37% (p<0.05) reduction in MFS aortic root medial thickening, and a 50% reduction in elastic fiber fragmentation (p<0.0001) in all treatment groups. Using ex vivo small chamber myography, we showed that all ARBs reduced phenylephrine‐induced aortic contractility by 60–80% (p<0.05) in both MFS and WT aortas in a NO‐dependent fashion.ConclusionThis is the first animal study to compare the effects of ARBs other than losartan in MFS. Despite differential BP effects, telmisartan and valsartan were effective at blocking MFS aortic root widening and activating endothelial function. This suggests BP lowering to be of minor therapeutic value in MFS management and thus aortic root protection could be achieved with lesser side effects for MFS patients. Future clinical trials should focus on other ARBs than losartan for the management of MFS.Support or Funding InformationSupported by CIHR, HSFC, BCKDF, Marfan Foundation, SPH Foundation and Rare Disease Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.