High-resolution phenotyping of the hemodynamic consequences of thoracic aortic aneurysm repair

About This Grant

PROJECT SUMMARY In adults with descending thoracic aortic aneurysm (TAA), vascular repair (grafting) reduces the ~20% yearly rate of rupture and/or mortality but is associated with negative perioperative consequences. Currently, thoracic endovascular aortic repair (TEVAR) has become the standard treatment for descending TAA due its lower in and out of hospital morbidity and mortality. While repair is essential, there are known negative consequences of TEVAR related to the graft material’s stiffness. Notably, the non-physiological properties of the graft may attenuate the long-term benefit of TAA repair by reducing end-organ function. Indeed, age-related stiffening of the native aorta is known to increase arterial pressure, wave reflections and the associated adverse end-organ remodeling related to greater transmission of pressure and flow pulsatility in key pressure and flow sensitive organs, such as the heart, brain, and kidneys. Despite these well-known effects of native aortic stiffening, no study has comprehensively and directly assessed the hemodynamic consequences of descending TAA repair (i.e. stiffening) locally on the aorta or on the heart, brain and kidneys. It is known that placement of grafts in the ascending aorta elicits increased aortic flow velocity, local aortic stiffness, downstream descending aortic dilation, increased wall shear stress, and likely increases pressure and flow pulsatility, arterial wave reflections and aortic pressure that, together, elicit pathological vascular and end-organ remodeling associated with reductions in function and end-organ damage. Importantly, no study has performed high-resolution assessments of the hemodynamic (pressure, wave reflection and pulsatility) and end-organ consequences of descending TEVAR at rest, but also importantly not during exercise where the consequences of aortic grafting may be exaggerated. Thus, the overall aim of the K99/R00 proposal is to perform high-resolution phenotyping of the central hemodynamic consequences of TAA pre- and post-TEVAR at rest and during exercise and determine the magnitude of associated effects on end-organ structure and function. Our project will begin to fill the large unmet gap in understanding aortic and aortic aneurysmal physiology at rest and during exercise, the impact of the standard treatment for descending TAA, and point the way towards better recommendations in practice and for design of future therapies. Furthermore, these data will encourage medical device companies to design more compliant grafts so that the positive effects of aortic grafting in terms of reducing aortic rupture risk are not offset by inducing reductions in cardiac, brain and renal function. Completion of the proposed project will provide me with a unique skillset, different from that of my mentoring team, rendering me highly competitive for future NIH funding related to the study of hemodynamics and end-organ function in health and disease.