Graft Stiffness as a Substrate for Adverse Cardiovascular Remodeling and Clinical Outcomes in Genetically Triggered Aortic Aneurysms - PROJECT SUMMARY / ABSTRACT This K23 will provide Dr. Nupoor Narula with new skills critical for her to attain academic independence as an investigator focused on novel profiling approaches to improve therapy, risk stratification, and outcomes for patients with genetically triggered thoracic aortic aneurysms (gTAA). Extending logically on her prior track record, an integrated training plan has been developed focused on two key areas – cardiac magnetic resonance imaging (CMR) and advanced cardiovascular genetics. Applied training will be attained by leveraging an established R01, which will provide a rigorous framework in which to study impact of prosthetic aortic grafts (a cornerstone of therapy for gTAA known to be stiffer than native aortic tissue) on left ventricular (LV) and distal aortic remodeling, and whether gTAA etiology modifies impact of grafts. To test these concepts, at least 150 gTAA patients undergoing prosthetic graft replacement of the proximal aorta will be prospectively studied using cutting edge CMR methods pre- and (1 year) post-operatively, together with rigorous genotyping. LV tissue characterization will be performed using high resolution navigator and parametric mapping CMR technologies, and both 4D flow and dynamic (cine) CMR will be employed to quantify aortic vessel wall properties. In parallel, tailored genetic analyses will be performed to test if CMR-evidenced response to grafts is modified by genotypic characteristics of TAA, and validated survey methods will be used to assess outcomes. Aim 1 will test impact of native and graft-induced alterations of aortic stiffness on LV performance in gTAA, with focus on whether pre- and post- operative LV function and tissue characteristics (fibrosis) vary in relation to gTAA etiology; Aim 2 will employ innovative CMR approaches to assess distal aortic response to proximal graft implantation – including tortuosity, 4D flow derived wall shear stress, and pulse wave velocity; Aim 3 will explore phenotypic and genotypic modifiers of LV and distal aortic remodeling after proximal graft replacement, with focus on type and mechanism of pathogenic variants. Applied training will be complemented by didactic training enabled by graduate coursework in CMR physics, genetics, and translational research/statistics. K23 research and training will be attained at a leading institution for gTAA, and guided by mentors with complementary multidisciplinary expertise: Dr. Weinsaft is the principal investigator of the R01 to which this K23 is paired and has extensive experience in use of CMR in gTAA focused longitudinal outcomes studies; Dr. Wang is a co-mentor with an established track record in CMR pulse sequence development – including high resolution 3D CMR, as will be employed in the proposed research plan; Dr. Devereux is a co-mentor with longstanding expertise in gTAA – inclusive of translational genetics and LV remodeling. Findings from this K23 will address key knowledge gaps of broad significance to gTAA patients – including mechanism and patient profiles at greatest risk for adverse remodeling after prosthetic aortic graft implantation. Study results will directly inform future R01s focused genotype/CMR on use of integrated profiling to improve prediction of therapeutic response and clinical outcomes in gTAA.
