Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome. (April 2015)

• Record Type: Journal Article
• Authors: Franken, Romy; den Hartog, Alexander W.; Radonic, Teodora; Micha, Dimitra; Maugeri, Alessandra; van Dijk, Fleur S.; Meijers-Heijboer, Hanne E.; Timmermans, Janneke; Scholte, Arthur J.; van den Berg, Maarten P.; Groenink, Maarten; Mulder, Barbara J.M.; Zwinderman, Aeilko H.; de Waard, Vivian; Pals, Gerard
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.114.000950
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>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.</p> </sec> <sec> <title>Methods and Results—</title> <p>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. <italic>FBN1</italic> 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 <italic>FBN1</italic> 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; <italic>P</italic>=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; <italic>P</italic>=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; <italic>P</italic>=0.197).</p> </sec> <sec> <title>Conclusions—</title> <p>Marfan patients with haploinsufficient <italic>FBN1</italic> 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 <italic>FBN1</italic> mutations.</p> </sec> <sec> <title>Clinical Trial Registration—</title> <p> <ext-link ext-link-type="uri" xlink:href="http://www.trialregister.nl/trialreg/index.asp" xlink:type="simple" xmlns:xlink="http://www.w3.org/1999/xlink">http://www.trialregister.nl/trialreg/index.asp</ext-link>; Unique Identifier: NTR1423.</p> </sec> </abstract>