Abstract 2676: Doxycycline Is More Effective Than Atenolol To Prevent Thoracic Aortic Aneurysm In Marfan Syndrome By Improving Aortic Elastic Property And Attenuating Calcification Through The Inhibition Of Matrix Metalloproteinases
Introduction: Beta-blockers, such as atenolol, are the primary therapy for thoracic aortic aneurysm (TAA) in patients with Marfan syndrome (MFS). However, over 30% of patients do not respond to the treatment, and continued abnormal aortic growth has been reported. Degradation of medial elastic fibers and vessel calcification, the most prominent characteristics of TAA, are tightly regulated by matrix metalloproteinases (MMPs). We hypothesized that doxycycline, a nonspecific inhibitor of MMPs, prevents TAA in MFS by attenuating elastic fiber degeneration and calcification.
Methods and Results: Mice heterozygous for the Fbn1 allele encoding a cysteine substitution in FBN1 (Fbn1C1039G/+), the most common class of mutation in MFS, were untreated (n=20), given doxycycline (0.24g/1L, n=20) or atenolol (0.1g/1L, n=20) from drinking water at the age of 6 weeks. The littermate Fbn1+/+ mice served as control (n=20). Ascending thoracic aorta from each group at 6 months was studied. Mortality and TAA were not observed in the doxycycline-group, while mild aneurysm (diameter of aorta was increased by 15% compared with controls) was evident in 30% of the atenolol-group. From the aortic media of untreated and atenolol-groups, elastic fiber degeneration and calcification detected by Movat’s and von Kossa histology were pronounced, which accompanied with increased aortic stiffness. Doxycycline attenuated elastic fiber degradation and calcification, and normalized the aortic elasticity to the control level. The impairment of smooth muscle contraction and endothelial-dependent relaxation in the untreated group were improved by doxycycline by 100 and 55%, respectively. Only two-third of the atenolol-group showed improvement in contraction. Doxycycline reduced the enzymatic activities of MMP-2 and -9 in the aortic media by 40 – 60%. GM6001, a specific inhibitor of MMPs gave similar effects as doxycycline.
Conclusions: The oral treatment of doxycycline is more effective than atenolol to preserve elastic fiber integrity, attenuate vessel calcification, and normalize vasomotor function and elastic property in the thoracic aorta in MFS. The beneficial effects of doxycycline could be owing to the inhibition of MMPs, which might prevent the progression of TAA in MFS.