Towards Personalized Prosthetic Graft Replacement for Genetically Triggered Thoracic Aortic Aneurysms

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PROJECT SUMMARY / ABSTRACT For patients with thoracic aortic aneurysms (TAA), replacement of the ascending aorta with a current standard of care prosthetic graft (polyethylene terephthalate) eliminates risk for dissection in graft-replaced regions and can thus be lifesaving. Nevertheless, accumulating evidence reveals that proximal aortic grafting can increase risk for downstream dissection, which is also life-threatening: Risk is greatest in patients with genetically triggered TAA, who undergo graft replacement at lower thresholds, higher frequency, and younger age - after which risk for dissection in graft-replaced regions is eliminated but possibility of distal complications increases. Up to two thirds of dissections in genetic TAA patients occur in the distal (arch or descending) aorta. We have also shown that over half of distal dissections with genetic TAA occur after graft surgery; proximal grafting has been linked to a >2-fold increase in risk for dissection independent of aortic size. Our clinical observations are consistent with experimental data: In pre-clinical and computational models, the dramatic increase in proximal aortic stiff- ness with grafting induces hemodynamic changes that exacerbate distal stiffening. Aortic stiffness is increased with genetic TAA - it is also known that mechanical loading forces drive adverse aortic remodeling. There is thus a critical need to identify markers of distal aortic disease progression after proximal grafting, with focus on altered hemodynamic loading in relation to graft characteristics (stiffness, length, enclosed volume). Our central hypoth- esis is that loss of proximal aortic compliance due to stiff prosthetic grafts induces adverse distal aortic remod- eling (driven by increased wall and wall shear stress) and predicts adverse prognosis. We also posit that adoption of grafts, for which compliance is tailored to compensate for patient-specific aortic stiffness, will attenuate ad- verse distal aortic remodeling. This will be tested in genetic TAA patients undergoing prosthetic graft replace- ment, via Aims integrated towards the goal of testing if graft implantation produces progressive increments in adverse remodeling (Aim 1A), identifying (native aortic and graft) features most responsible for adverse remod- eling (1B), testing if these features are modifiable via a new class of tailored grafts (Aim 2), and exploring if widely generalizable surrogates of graft-induced remodeling and native aortic stiffness predict clinical events (Aim 3). To do so, cardiac MRI will be integrated with computational modeling of fluid structure interactions and vascular remodeling - informed by material property testing of resected aortic tissue and simulations of tailored grafts for which compliance can be paired to patient-specific aortic features. Our team provides complementary expertise in cardiac imaging, aortic surgery, genetic TAA, computational modeling, and graft design - and a track record of productive collaboration. Results will yield key foundational insights as to mechanisms of adverse remodeling and events after grafting, transform risk stratification for current grafts and inform personalized therapy by guiding design and prototyping of a new class of tailored grafts - towards the goal of improved outcomes for TAA patients who benefit from proximal grafting but remain at risk for serious clinical events in the residual native aorta.