Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome

Circ Cardiovasc Genet. 2015 Jan 22. pii: CIRCGENETICS.114.000950. [Epub ahead of print]

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

Franken R1den Hartog A1Radonic T2Micha D3Maugeri A3van Dijk FS3Meijers-Heijboer HE3Timmermans J4Scholte AJ5van den Berg MP6Groenink M7Mulder BJ1Zwinderman AH8de Waard V9Pals G10.

Comment: The previously reported COMPARE study was a multicenter, open label, randomized controlled trial in adults with Marfan syndrome, which demonstrated that adding losartan (goal dosage 100 mg daily) to patients’ existing medical therapy effectively reduced the rate of aortic root dilation measured over a 3 year time period.  Despite the study’s positive result among the cohort collectively, the investigators recognized significant inter-individual variability in the response to losartan.  This provided the rationale for evaluating whether an individual’s response to losartan is impacted by carrying a dominant negative FBN1 mutation versus a FBN1 mutation that leads to haploinsufficiency.

With this study Franken et al selected the 117 trial participants who were confirmed to have FBN1 mutation and did not require aortic replacement surgery before or during the trial period.  Among these patients, 79 (68%) were reported to have a dominant negative mutation versus 38 (32%) reported to have a mutation leading to haploinsufficiency.  The study’s major finding was that losartan effectively reduced the rate of aortic root dilation in subjects with FBN1 haploinsufficiency (1.8 mm per 3 years in controls vs. 0.5 mm per 3 years on losartan, p=0.001) but did not impact the rate of dilation in subjects with dominant negative mutations (1.2 mm per 3 years in controls vs. 0.8 mm per 3 years on losartan, p=0.197).  The authors speculate that the preferential effect may relate to increased local angiotensin II production in the context of FBN1 haploinsufficiency and that dominant negative mechanisms are likely to manifest greater phenotypic variability than haploinsufficiency.  Another noteworthy observation was that while all trial participants met clinical criteria for Marfan syndrome, only 80% were found to have FBN1 mutation by DNA sequencing.  Overall, this study highlights the heterogeneity that can exist even among patients who have a well characterized syndrome and carry mutations within the same gene, which may significantly impact pathophysiological processes and ultimately the patient’s clinical course including response to therapies.