Key result
Losartan slows aortic root dilatation by ~0.5 mm over 3 years, driven by haploinsufficient FBN1 variants.
Why the study?
Losartan reduces aortic dilatation in Marfan syndrome but treatment response varies and effectiveness in genetically classified subgroups is unclear.
Does losartan reduce aortic root dilatation rate in patients with Marfan syndrome based on FBN1 mutation type?
RCT (n=117)
randomized
Does losartan reduce aortic root dilatation rate in patients with Marfan syndrome based on FBN1 mutation type?
Absolute Event Rate: 0.8% vs 1.3%
p-value: p=0.009
Losartan therapy significantly reduces aortic root dilatation in Marfan syndrome patients with haploinsufficient FBN1 mutations, but not in those with dominant negative mutations, suggesting a genotype-specific treatment response.
Supports genotype-guided losartan use in Marfan syndrome; extends prior RCTs by identifying FBN1 mutation-specific responses.
Background— 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.
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Franken et al. (2015) conducted an RCT in Marfan syndrome (n=117). Losartan vs. no losartan was evaluated on Aortic root dilatation rate (p=0.009). Losartan therapy reduced aortic root dilatation rate overall (0.8 vs 1.3 mm/3 years; P=0.009), with significant benefit in patients with haploinsufficient but not dominant negative FBN1 mutations.
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