Sex, pregnancy and aortic disease in Marfan syndrome

BackgroundSex-related differences as well as the adverse effect of pregnancy on aortic disease outcome are well-established phenomena in humans with Marfan syndrome (MFS). The underlying mechanisms of these observations are largely unknown.ObjectivesIn an initial (pilot) step we aimed to confirm the differences between male and female MFS patients as well as between females with and without previous pregnancy. We then sought to evaluate whether these findings are recapitulated in a pre-clinical model and performed in-depth cardiovascular phenotyping of mutant male and both nulliparous and multiparous female Marfan mice. The effect of 17β-estradiol on fibrillin-1 protein synthesis was compared in vitro using human aortic smooth muscle cells and fibroblasts.ResultsOur small retrospective study of aortic dimensions in a cohort of 10 men and 20 women with MFS (10 pregnant and 10 non-pregnant) confirmed that aortic root growth was significantly increased in the pregnant group compared to the non-pregnant group (0.64mm/year vs. 0.12mm/year, p = 0.018). Male MFS patients had significantly larger aortic root diameters compared to the non-pregnant and pregnant females at baseline and follow-up (p = 0.002 and p = 0.007, respectively), but no significant increase in aortic root growth was observed compared to the females after follow-up (p = 0.559 and p = 0.352). In the GT-8/+ MFS mouse model, multiparous female Marfan mice showed increased aortic diameters when compared to nulliparous females. Aortic dilatation in multiparous females was comparable to Marfan male mice. Moreover, increased aortic diameters were associated with more severe fragmentation of the elastic lamellae. In addition, 17β-estradiol was found to promote fibrillin-1 production by human aortic smooth muscle cells.ConclusionsPregnancy-related changes influence aortic disease severity in otherwise protected female MFS mice and patients. There may be a role for estrogen in the female sex protective effect.

背景：马凡综合征（Marfan syndrome, MFS）患者群体中，性别差异及妊娠对主动脉疾病预后的不良影响已得到广泛证实，但其潜在机制仍未完全阐明。
研究目的：本研究首先通过初步（先导）阶段，旨在验证男性与女性MFS患者之间，以及有妊娠史与无妊娠史女性患者之间的临床差异。随后，我们旨在评估上述发现能否在临床前模型中重现，并对突变型雄性马凡小鼠以及未产、经产雌性马凡小鼠开展了深入的心血管表型分析。此外，我们采用人主动脉平滑肌细胞与成纤维细胞开展体外实验，对比了17β-雌二醇对原纤维蛋白-1（fibrillin-1）蛋白合成的影响。
结果：我们针对由10名男性、20名女性MFS患者（其中10名有妊娠史，10名无妊娠史）组成的队列开展的小型回顾性研究证实：与无妊娠史组相比，妊娠组的主动脉根部年增长率显著更高（0.64mm/年 vs 0.12mm/年，p=0.018）。基线及随访阶段，男性MFS患者的主动脉根部直径均显著大于无妊娠史及妊娠女性组（分别为p=0.002与p=0.007）；但随访期间的主动脉根部年增长率与女性组相比无显著差异（分别为p=0.559与p=0.352）。在GT-8/+马凡综合征小鼠模型中，经产雌性马凡小鼠的主动脉直径显著大于未产雌性小鼠，其主动脉扩张程度与雄性马凡小鼠相当。此外，主动脉直径增大与弹性板层碎裂程度加重显著相关。进一步实验发现，17β-雌二醇可促进人主动脉平滑肌细胞合成原纤维蛋白-1。
结论：妊娠相关的生理变化会加重原本存在性别保护效应的雌性MFS患者与小鼠的主动脉疾病严重程度。雌激素或许在女性的性别保护效应中发挥了一定作用。