Early clinical outcomes and molecular smooth muscle cell phenotyping using a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome

• Published in: The Journal of thoracic and cardiovascular surgery Vol. 166; no. 5; pp. e332 - e376
• Main Authors: Pedroza, Albert J., Cheng, Paul, Dalal, Alex R., Baeumler, Kathrin, Kino, Aya, Tognozzi, Emily, Shad, Rohan, Yokoyama, Nobu, Nakamura, Ken, Mitchel, Olivia, Hiesinger, William, MacFarlane, Elena Gallo, Fleischmann, Dominik, Woo, Y. Joseph, Quertermous, Thomas, Fischbein, Michael P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2023
• Subjects: aortic aneurysm; aortic arch; aortic root replacement; Loeys-Dietz syndrome; RNA sequencing; smooth muscle cell; RNA sequencing; smooth muscle cell; TGF-ß; MRI; VSARR; SMC; aortic root replacement; modSMC; scRNAseq; ECM; 4D; Loeys-Dietz syndrome; aortic aneurysm; LDS; MFS; aortic arch
• ISSN: 0022-5223; 1097-685X; 1097-685X
• DOI: 10.1016/j.jtcvs.2023.07.023

Patients with Loeys-Dietz syndrome demonstrate a heightened risk of distal thoracic aortic events after valve-sparing aortic root replacement. This study assesses the clinical risks and hemodynamic consequences of a prophylactic aortic arch replacement strategy in Loeys-Dietz syndrome and characterizes smooth muscle cell phenotype in Loeys-Dietz syndrome aneurysmal and normal-sized downstream aorta. Patients with genetically confirmed Loeys-Dietz syndrome (n = 8) underwent prophylactic aortic arch replacement during valve-sparing aortic root replacement. Four-dimensional flow magnetic resonance imaging studies were performed in 4 patients with Loeys-Dietz syndrome (valve-sparing aortic root replacement + arch) and compared with patients with contemporary Marfan syndrome (valve-sparing aortic root replacement only, n = 5) and control patients (without aortopathy, n = 5). Aortic tissues from 4 patients with Loeys-Dietz syndrome and 2 organ donors were processed for anatomically segmented single-cell RNA sequencing and histologic assessment. Patients with Loeys-Dietz syndrome valve-sparing aortic root replacement + arch had no deaths, major morbidity, or aortic events in a median of 2 years follow-up. Four-dimensional magnetic resonance imaging demonstrated altered flow parameters in patients with postoperative aortopathy relative to controls, but no clear deleterious changes due to arch replacement. Integrated analysis of aortic single-cell RNA sequencing data (>49,000 cells) identified a continuum of abnormal smooth muscle cell phenotypic modulation in Loeys-Dietz syndrome defined by reduced contractility and enriched extracellular matrix synthesis, adhesion receptors, and transforming growth factor-beta signaling. These modulated smooth muscle cells populated the Loeys-Dietz syndrome tunica media with gradually reduced density from the overtly aneurysmal root to the nondilated arch. Patients with Loeys-Dietz syndrome demonstrated excellent surgical outcomes without overt downstream flow or shear stress disturbances after concomitant valve-sparing aortic root replacement + arch operations. Abnormal smooth muscle cell–mediated aortic remodeling occurs within the normal diameter, clinically at-risk Loeys-Dietz syndrome arch segment. These initial clinical and pathophysiologic findings support concomitant arch replacement in Loeys-Dietz syndrome.