It has been shown that
losartan reduces aortic dilatation in patients with
Marfan syndrome. However, treatment response is highly variable. This study investigates
losartan effectiveness in genetically classified subgroups.
METHODS AND RESULTS: In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive
losartan 100 mg or no
losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on
fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal
fibrillin-1, or (2) dominant negative, normal
fibrillin-1 abundance with mutant
fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall,
losartan significantly reduced aortic root dilatation rate (no
losartan, 1.3±1.5 mm/3 years, n=59 versus
losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However,
losartan reduced only aortic root dilatation rate in haploinsufficient patients (no
losartan, 1.8±1.5 mm/3 years, n=21 versus
losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no
losartan, 1.2±1.7 mm/3 years, n=38 versus
losartan 0.8±1.3 mm/3 years, n=41; P=0.197).
CONCLUSIONS: Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to
losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations.
CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423.