P2.016: Recovery of Aortic Wall Structure in Mouse Models of Marfan Syndrome with Conditional Inactivation of ADAMTS6

Background: Marfan syndrome (MFS), a complex multisystem disorder most often characterized by cardiac, ocular, and skeletal manifestations, is caused by an autosomal dominant mutation in the FBN1 gene, leading to a deficiency in fibrillin-1 microfibrils, an extracellular matrix component critical for aortic wall structure and function. Recently, the ADAMTS6 gene was shown to co-localize, bind, and cleave fibrillin-1, leading to downregulation of fibrillin-1 microfibril quantity, and thus represents a potential therapeutic target for restoration of aortic wall structure, and prevention of aortic aneurysm formation, which if left untreated, can lead to aortic dissection, and ultimately, death.

Methods: We generated a conditional smooth muscle cell deletion of Adamts6 in a known chronic MFS mouse model. Sedated echocardiograms were completed in MFS mice with Adamts6 inactivation (“Rescue” mice), non-disease wild type controls (“WT” mice), and MFS mice. Using Vevo Lab, measurements of aortic root size, aortic outflow velocity, left ventricular function, and ejection fraction were completed to determine if Adamts6 inactivation in Rescue mice led to a cardiac phenotype comparable to WT controls.

Results: Echocardiography revealed a statistically significant difference in aortic root diameter between WT and MFS mice (Mean difference: 0.77 mm +/- 0.16 mm, p < 0.001) and between MFS and Rescue mice (Mean difference: 0.62 mm +/- 0.16 mm, p = 0.002) (Figure 1A-1C; Figure 2A). Importantly, there was no significant difference in aortic root size of WT and Rescue mice. Pulsed-wave doppler across the aortic valve also revealed outflow velocity in Rescue mice statistically indistinct from WT levels, but significantly reduced compared to velocity witnessed in MFS mice (Mean difference: 304.4 mm/sec +/- 103.2 mm/sec) (Figure 2B). There were no statistical differences among the end diastolic volumes and left ventricular ejection fraction among the three groups (Figure 1D-1F; 2C-2D).

Conclusion: Findings from this study suggest recovery of aortic wall strength and morphology in Rescue mice, consistent with the idea that Adamts6 inhibition may indeed present a possible target for MFS treatment. Ongoing studies include assessment and quantification of collagen, proteoglycan, and elastin structure by histology, with future work to include single-cell RNA sequencing of aortic tissue from across the three groups to discern changes at the cellular level. Ultimately, this study may help transition the standard of care in MFS from therapies aimed at limiting clinical sequelae, to interventions that focus on modifying the pathophysiology of the disease itself.