Medical treatment of aortic aneurysms in Marfan syndrome and other heritable conditions

Abstract

Thoracic aortic aneurysms can be triggered by genetic disorders such as Marfan syndrome (MFS) and related aortic diseases as well as by inflammatory disorders such as giant cell arteritis or atherosclerosis. In all these conditions, cardiovascular risk factors, such as systemic arterial hypertension, may contribute to faster rate of aneurysm progression. Optimal medical management to prevent progressive aortic dilatation and aortic dissection is unknown. β-blockers have been the mainstay of medical treatment for many years despite limited evidence of beneficial effects. Recently, losartan, an angiotensin II type I receptor antagonist (ARB), has shown promising results in a mouse model of MFS and subsequently in humans with MFS and hence is increasingly used. Several ongoing trials comparing losartan to β-blockers and/or placebo will better define the role of ARBs in the near future. In addition, other medications, such as statins and tetracyclines have demonstrated potential benefit in experimental aortic aneurysm studies. Given the advances in our understanding of molecular mechanisms triggering aortic dilatation and dissection, individualized management tailored to the underlying genetic defect may be on the horizon of individualized medicine. We anticipate that ongoing research will address the question whether such genotype/pathogenesis-driven treatments can replace current phenotype/syndrome-driven strategies and whether other forms of aortopathies should be treated similarly. In this work, we review currently used and promising medical treatment options for patients with heritable aortic aneurysmal disorders.

Fig. (1)

Canonical (green) and non-canonical (blue) TGF-β signaling cascades as well as intracellular proteins implicated in the TGF-β signaling (red) of Marfan syndrome and related disorders (adapted and modified from Doyle et al. [69], Lee et al. [70], and Willaert et al. [71]). Disorders caused by a mutated gene product are indicated in parentheses next to the corresponding protein. Drugs have been tested in Marfan mice and/or patients (green) and untested but may have hypothetical benefit based on disease pathogenesis (red) are illustrated accordingly. MFS: Marfan syndrome; SSS: Stiff skin syndrome; WMS: Weill-Marchesani syndrome; ELS: Ectopia lentis syndrome; AD: Acromelic dysplasia; GD: Geophysic dysplasia; CCA: Congenital contractural arachnodactyly; CAEND: Camurati-Engelmann disease; HHT1: Hereditary hemorrhagic telangiectasia type 1; HHT2: Hereditary hemorrhagic telangiectasia type 2; LDS1/2/3/4: Loeys Dietz syndrome types 1, 2, 3, 4; ATS: Arterial tortuosity syndrome; PVNH: Periventricular nodular heterotopia; iFTAA: Isolated familial thoracic aortic aneurysm; FSS: Ferguson Smith syndrome; SGS: Shprintzen-Goldberg syndrome; AOS: Aneurysms-osteoarthritis syndrome; MYHRS: Myhre syndrome; JP/HHT: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. NAb: neutralizing antibody; ARB: Angiotensin II type I receptor blocker; ACEi: Angiotensin converting enzyme inhibitor; SLC2A10*: SLC2A10/GLUT10 is mainly localized to the mitochondria of aortic smooth muscle cells.