Key result
Losartan therapy increased biventricular end-diastolic volume and stroke volume in Marfan patients with a haploinsufficient FBN1 mutation, but had no effect in those with a dominant negative mutation.
Why the study?
Does losartan improve ventricular volume and function in asymptomatic Marfan patients with haploinsufficient or dominant negative FBN1 mutations?
RCT (n=163)
Single-blind
1:1
Yes
Does losartan improve ventricular volume and function in asymptomatic Marfan patients with haploinsufficient or dominant negative FBN1 mutations?
Losartan therapy increases biventricular end-diastolic and stroke volumes in Marfan patients with haploinsufficient FBN1 mutations, suggesting improved filling properties, but has no effect in those with dominant-negative mutations.
Mutation type should guide losartan decisions in Marfan syndrome; extends randomized evidence for genotype-specific therapy.
BACKGROUND: Mild biventricular dysfunction is often present in patients with Marfan syndrome. Losartan has been shown to reduce aortic dilatation in patients with Marfan syndrome. This study assesses the effect of losartan on ventricular volume and function in genetically classified subgroups of asymptomatic Marfan patients without significant valvular regurgitation. METHODS: In this predefined substudy of the COMPARE study, Marfan patients were classified based on the effect of their FBN1 mutation on fibrillin-1 protein, categorised as haploinsufficient or dominant negative. Patients were randomised to a daily dose of losartan 100 mg or no additional treatment. Ventricular volumes and function were measured by magnetic resonance imaging at baseline and after 3 years of follow-up. RESULTS: Changes in biventricular dimensions were assessed in 163 Marfan patients (48 % female; mean age 38 ± 13 years). In patients with a haploinsufficient FBN1 mutation (n = 43), losartan therapy (n = 19) increased both biventricular end diastolic volume (EDV) and stroke volume (SV) when compared with no additional losartan (n = 24): left ventricular EDV: 9 ± 26 ml vs. -8 ± 24 ml, p = 0.035 and right ventricular EDV 12 ± 23 ml vs. -18 ± 24 ml; p < 0.001 and for left ventricle SV: 6 ± 16 ml vs. -8 ± 17 ml; p = 0.009 and right ventricle SV: 8 ± 16 ml vs. -7 ± 19 ml; p = 0.009, respectively. No effect was observed in patients with a dominant negative FBN1 mutation (n = 92), or without an FBN1 mutation (n = 28). CONCLUSION: Losartan therapy in haploinsufficient Marfan patients increases biventricular end diastolic volume and stroke volume, furthermore, losartan also appears to ameliorate biventricular filling properties.
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Hartog et al. (2016) conducted an RCT in Marfan syndrome (n=163). Losartan vs. No additional treatment was evaluated on Change in left ventricular end diastolic volume (LV-EDV) in patients with a haploinsufficient FBN1 mutation (p=0.035). Losartan therapy increased biventricular end-diastolic volume and stroke volume in Marfan patients with a haploinsufficient FBN1 mutation, but had no effect in those with a dominant negative mutation.
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