Effectiveness of Combination of Losartan Potassium and Doxycycline versus Single-Drug Treatments in the Secondary Prevention of Thoracic Aortic Aneurysm in Marfan Syndrome

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Conclusion: The combination of losartan potassium and doxycycline synergistically offers better aneurysm-suppressing effect in a mouse model of Marfan syndrome than does either drug alone. Summary: Marfan syndrome is autosomal dominant and results from mutations in the gene encoding fibrillin-1. Abnormal aortic elastic fibers result in altered load-bearing capacity of the aorta with degeneration, fibrosis, and microdissection. Progression of thoracic aortic aneurysm in Marfan syndrome is associated with upregulation of matrix metalloproteinases (MMPs)-2 and MMP-9. Doxycycline inhibits MMP-2 and MMP-9 production and provides aneurysm suppressing effects in a mouse model of Marfan syndrome (Chung AW, Circ Res 2006;99:140-8). Perturbations of transforming growth factor (TGF)-β may also contribute to Marfan syndrome. TGF-β can be antagonized with losartan potassium, an angiotensin-2 type-1 receptor antagonist. The authors hypothesize a combination of losartan potassium and doxycycline would offer enhanced inhibition of aortic degeneration in Marfan syndrome. A mouse model of Marfan syndrome (Fbn1C1039G/+/L) was used in this study. Mice at 4 months of age, when aneurysm had been established, were given doxycycline alone (0.24 g/L), losartan potassium alone (0.6 g/L), or a combination of 0.12 g/L doxycycline and 0.3g/L losartan potassium in drinking water. Littermate Fbn1+/+ mice served as controls. Thoracic aortas were harvested and studied at 6 and 9 months. Aortic diameter at 9 months increased in the untreated group by 40% relative to controls. The aortic diameter was reduced by 10% in losartan potassium-treated mice and by 16% in doxycycline-treated mice compared with untreated aortas. Combination losartan potassium and doxycycline completely prevented thoracic aortic aneurysm in the mouse model. There was improvement in elastic fiber organization with downregulation of MMP-2 and MMP-9, as well as downregulation of TGF-β. Aortic contractile and relaxation functions also normalized compared with control values. Comment: Combination drug treatment in a mouse model of Marfan syndrome appears to offer potentially extraordinary secondary prevention benefits. Although the mouse model may not be representative of all cases of Marfan syndrome in humans, the mutation in the model is the most common mutation in classic Marfan syndrome. Both drugs used for secondary prevention in this study are readily available, and it seems a human study of combination therapy for prevention of aortic degeneration in patients with Marfan syndrome should not be long off.