Recent advances in understanding Marfan syndrome: Should we now treat surgical patients with losartan?
Recent advances in understanding Marfan syndrome: Should we now treat surgical patients with losartan?
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DOI：
10.1016/j.jtcvs.2007.08.047
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发表时间：
2008-02-01
影响因子：
6
通讯作者：
Dietz, Harry C.
中科院分区：
文献类型：
--
作者：
Matt, Peter;Habashi, Jennifer;Dietz, Harry C.
目的：马凡综合征是一种由β-淀粉样蛋白-1基因突变引起的全身性结缔组织疾病。最初认为，马凡氏综合征完全是由异常的结缔组织蛋白-1的产生引起的，该异常的结缔组织蛋白-1在掺入细胞外基质时导致结构较弱的结缔组织。这种效果似乎可以解释许多马凡氏综合征的临床特征，包括主动脉根部扩张和急性主动脉夹层，这是马凡氏综合征发病率和死亡率的主要原因。方法：最近的分子研究，大多数基于遗传定义的小鼠模型的马凡氏综合征，挑战了这种模式。这些研究建立了关键的贡献，haploinsufficiency和失调的转化生长因子-β信号转导疾病progress.Results：它似乎是马凡氏综合征的许多表现是不太相关的主要结构缺陷的组织比改变形态发生和稳态程序，诱导改变转化生长因子-β信号。最重要的是，通过转化生长因子β中和抗体或氯沙坦，（一种血管紧张素II 1型受体拮抗剂）已被证明可以预防并可能逆转马凡氏综合征小鼠模型中的主动脉根部扩张、二尖瓣脱垂、肺病和骨骼肌功能障碍。有迹象表明，氯沙坦，一种广泛用于治疗人类动脉高血压的药物，为马凡氏综合征临床表现的一级预防提供了第一个潜力。
Objective: Marfan syndrome is a systemic connective tissue disorder caused by mutations in the fibrillin-1 gene. It was originally believed that Marfan syndrome results exclusively from the production of abnormal fibrillin-1 that leads to structurally weaker connective tissue when incorporated into the extracellular matrix. This effect seemed to explain many of the clinical features of Marfan syndrome, including aortic root dilatation and acute aortic dissection, which represent the main causes of morbidity and mortality in Marfan syndrome.Methods: Recent molecular studies, most based on genetically defined mouse models of Marfan syndrome, have challenged this paradigm. These studies established the critical contribution of fibrillin-1 haploinsufficiency and dysregulated transforming growth factor-beta signaling to disease progression.Results: It seems that many manifestations of Marfan syndrome are less related to a primary structural deficiency of the tissues than to altered morphogenetic and homeostatic programs that are induced by altered transforming growth factor-beta signaling. Most important, transforming growth factor-beta antagonism, through transforming growth factor-beta neutralizing antibodies or losartan (an angiotensin II type 1 receptor antagonist), has been shown to prevent and possibly reverse aortic root dilatation, mitral valve prolapse, lung disease, and skeletal muscle dysfunction in a mouse model of Marfan syndrome.Conclusion: There are indicators that losartan, a drug widely used to treat arterial hypertension in humans, offers the first potential for primary prevention of clinical manifestations in Marfan syndrome.