Romy Franken1, Alexander W den Hartog1, Teodora Radonic1, Dimitra Micha1, Alessandra Maugeri1, Fleur S van Dijk1, Hanne E Meijers-Heijboer1, Janneke Timmermans1, Arthur J Scholte1, Maarten P van den Berg1, Maarten Groenink1, Barbara J M Mulder1, Aeilko H Zwinderman1, Vivian de Waard1, Gerard Pals2. 1. From the Departments of Cardiology (R.F., A.W.d.H., M.G., B.J.M.M.), Radiology (M.G.), Clinical Epidemiology and Biostatistics (A.H.Z.), and Medical Biochemistry (V.d.W.), Academic Medical Center Amsterdam, Amsterdam; Interuniversity Cardiology Institute of the Netherlands, Utrecht (R.F., A.W.d.H., M.G., B.J.M.M.); Departments of Pathology (T.R.) and Clinical Genetics (D.M., A.M., F.S.v.D., H.E.M.-H., G.P.), VU University Medical Center, Amsterdam; Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen (J.T.); Department of Cardiology, Leiden University Medical Center, Leiden (A.J.S.); and Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands (M.P.v.d.B.). 2. From the Departments of Cardiology (R.F., A.W.d.H., M.G., B.J.M.M.), Radiology (M.G.), Clinical Epidemiology and Biostatistics (A.H.Z.), and Medical Biochemistry (V.d.W.), Academic Medical Center Amsterdam, Amsterdam; Interuniversity Cardiology Institute of the Netherlands, Utrecht (R.F., A.W.d.H., M.G., B.J.M.M.); Departments of Pathology (T.R.) and Clinical Genetics (D.M., A.M., F.S.v.D., H.E.M.-H., G.P.), VU University Medical Center, Amsterdam; Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen (J.T.); Department of Cardiology, Leiden University Medical Center, Leiden (A.J.S.); and Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands (M.P.v.d.B.). g.pals@vumc.nl.
Abstract
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.
RCT Entities:
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 haploinsufficientpatients (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.
Authors: Syed Usman Bin Mahmood; Camilo A Velasquez; Mohammad A Zafar; Ayman A Saeyeldin; Adam J Brownstein; Bulat A Ziganshin; John A Elefteriades; Sandip K Mukherjee Journal: Ann Cardiothorac Surg Date: 2017-11