Loeys-Dietz syndrome subtypes exhibit distinct clinical behavior and aortic cellular transcriptomic profiles

Loeys-Dietz syndrome comprises genetically discrete subtypes of varying clinical severity. This study integrates longitudinal Loeys-Dietz syndrome clinical outcomes after aortic root replacement with transcriptomic analysis of aortic smooth muscle cell dysregulation to investigate mechanisms governing this subtype-specific aortic vulnerability.

Single institutional experience with aortic root replacement for nondissected aneurysm in patients with Loeys-Dietz syndrome was reviewed for midterm survival and distal aortic events (subsequent aortic intervention, aneurysm, or dissection). Single-cell RNA sequencing was performed using fresh aortic aneurysm tissue to compare smooth muscle cell phenotypes between patients with TGFBR1/2 and SMAD3 variants.

A total of 62 patients with Loeys-Dietz syndrome were identified, including 59 genetically confirmed (n = 36 TGFBR1/2, n = 16 SMAD3, and n = 7 TGFB2/TGFB3). Valve-sparing operations were performed in 54 patients, 8 patients underwent composite root replacement operations, and 19 patients underwent concomitant arch replacement. Median follow-up was 6.16 years (interquartile range, 2.88-10.82). Estimated 5- and 10-year survivals for TGFBR1/2 patients were 97% (99%-82%) and 86% (96%-61%), respectively, and estimated incidence of aortic events at 5- and 10-year follow-up was 17% (7%-36%) and 28% (14%-51%), respectively. For SMAD3 patients, estimated survival was 94% (99%-63%) at both 5 and 10 years, and estimated incidence of aortic events at both 5- and 10-year follow-ups was 0%. Single-cell RNA sequencing analysis (n = 3 TGFBR1/2, n = 5 SMAD3) demonstrated altered smooth muscle cell phenotype modulation patterns, with greater retention of contractile gene expression, enriched collagen, and integrin receptor expression in TGFBR1/2 smooth muscle cells, whereas SMAD3 patients showed activation of osteochondrogenic matrix components (TNFRSF11B, CYTL1) and inflammatory pathways.

Loeys-Dietz syndrome subtypes may demonstrate variable clinical outcomes after aortic root replacement. Distinct gene dysregulation patterns suggest varying smooth muscle cell-extracellular matrix interactions may participate in clinical variation.