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Investigation of early effects of combination of mild aerobic exercise and angiotensin‐II type‐I receptor blocker losartan on aortic function in a mouse model of Marfan Syndrome.

Marfan syndrome (MFS) is a connective tissue disorder that causes complications throughout the body. However, the cardiovascular effects of MFS, specifically aortic aneurysms, are the leading cause of morbidity and mortality in patients. Both the transforming growth factor beta (TGF‐β) and angiotensin II type I receptor (AT1R) signaling pathways are known to contribute to the progression of MFS aneurysms. Recently, our laboratory reported that low‐intensity mild exercise could improve aortic function and structure in the mouse model of MFS. Losartan, an AT1R blocker, has been shown to slow down the progression of MFS aneurysms in both the mouse model and human patients. In this study, we have explored the potential of a combinational therapy of exercise and losartan in a well‐established mouse model of MFS associated aortic aneurysm in order to determine if there are additive protective and delaying effects on the progression of aortic aneurysm in the mouse model. Treatment consisted of 0.6 g/L (full dose) or 0.3 g/L (half dose) of losartan in drinking water combined with a 55% VO2 max exercise regimen (8 m/min, 30 min/day, 5 days/week). Mice were divided into experimental groups: control, MFS, MFS + exercise, MFS + 0.6 g/L losartan, MFS + 0.3 g/L losartan, MFS + exercise + 0.6 g/L losartan, and MFS + exercise + 0.3 g/L losartan. The biophysical properties of the aorta, such as the aortic diameter and pulse wave velocity (PWV), were determined by high resolution high frequency ultrasound imaging system (Vevo2100, FUJIFILM VisualSonics) in 3‐month‐old MFS and control mice. Aortic diameter measurements of the sinus of Valsalva were significantly higher in 3‐month‐old MFS mice as compared to control. However, losartan treatment, mild exercise, or combination of both had no effects on aortic root growth in MFS mice. In addition, measurements of the aortic annulus and sinotubular junction were not significantly different among experimental groups. MFS mice exhibited higher PWV as compared to control mice, indicating increased stiffness of aortic wall in these mice. Combination of mild aerobic exercise with full and half dose of losartan seems to have some effects on the aortic wall by decreasing the aortic diameter, although no statistical significant differences were observed among the treated and non‐treated groups. This study presents the effects of combination of mild exercise and losartan during the early stage of aneurysm progression in MFS mice. With the continuation of the longitudinal study at 6 and 9 months of age and as the aneurysm progresses, we will be able to continue our evaluation of aortic and cardiac function and structure in MFS mice subjected to exercise only, losartan only, or the combinational therapy. This study provides additional information on the most effective therapeutic approach to delay the progression of aneurysm in MFS.