The effect of losartan therapy on ventricular function in Marfan patients with haploinsufficient or dominant negative FBN1 mutations

Abstract

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.

Keywords: Cardiac magnetic resonance imaging; FBN1 mutation classes; Losartan; Marfan syndrome; Ventricular function; Ventricular volumes.

Fig. 1

Randomisation and follow-up for ventricular function analysis. Abbreviations: CMR denotes cardiac magnetic resonance, FU denotes follow-up

Fig. 2

Box plot showing change in left and right ventricular stroke volume between control and losartan group in Marfan patients with a FBN1 mutation leading to haploinsufficiency (n = 43) or to a dominant-negative effect (n = 92). Abbreviations: SV denotes stroke volume, LV denotes left ventricle, RV denotes right ventricle. Boxes indicate median with interquartile range. Error bars indicate upper 90 percentile and lower 10 percentile limits