Abstract 11748: Prophylactic Aortic Arch Replacement in Patients With Loeys-Dietz Syndrome: Surgical Outcomes and Molecular Rationale

Abstract

Introduction: Loeys-Dietz syndrome (LDS) patients typically develop focal aortic root aneurysm but have substantial risk of distal aortic events (arch aneurysm and type B dissection) after root replacement. We offer prophylactic arch replacement to LDS patients of all genotypes undergoing elective valve-sparing aortic root replacement (VSARR) to prevent late aortic events. We hypothesized that non-dilated LDS aortic arch tissue demonstrates ongoing deterioration at the time of VSARR. Methods: Aortic tissue was anatomically segmented (root, ascending, arch) then examined via histology and single-cell RNA sequencing (‘scRNAseq’, n=4 patients) to comprehensively profile cellular phenotypes. Results: LDS patients (n=8, mean age 37.9 years, 87.5% male) had root aneurysm (mean 45.1 ± 8.9mm) without ascending (35.1± 7.8mm) or arch dilation (28.7 ± 2.8mm) and underwent concurrent VSARR and branched graft total arch replacement. There were no perioperative deaths or strokes and no distal aortic events or reoperations after median 1.26 years follow-up. Histologically, elastin fragmentation and collagen deposition were detectable in each aortic segment (n=4). scRNAseq identified a continuum of smooth muscle cell (SMC) phenotype modulation associated with progressively reduced contractile gene expression. Pathway analysis of 260 genes enriched during SMC modulation identified heightened integrin signaling, transforming growth factor-beta-responsiveness, cell adhesion, and extracellular matrix remodeling. Histologic confirmation using RNA probes specific for modulated SMCs (TGF-beta responsive gene SERPINE1 and glycoprotein TNFRSF11B ) identified these cells in the tunica media layer of each aortic segment, with greatest density in the root aneurysm but extending to the arch. In age-matched donor aortas, TNFRSF11B + cells were restricted to the atherosclerotic tunica intima, confirming specificity of medial SMC modulation in aneurysm. Conclusions: Total arch replacement during elective VSARR is feasible without substantial morbidity. In LDS patients with root aneurysm, matrix deterioration and SMC phenotype modulation are present in the non-dilated aortic arch, providing molecular rationale for aggressive arch replacement.