Predictive modeling of endocardial fibroelastosis recurrence in patients with congenital heart disease

Daniel Diaz-Gil; Natalia Silva-Gomez; Sarah U Morton; Jonathan G Seidman; Christine E Seidman; David Zurakowski; Steven J Staffa; Gerald R Marx; Sitaram M Emani; Pedro J Del Nido; Ingeborg Friehs

doi:10.1016/j.jtcvs.2024.08.036

Predictive modeling of endocardial fibroelastosis recurrence in patients with congenital heart disease

J Thorac Cardiovasc Surg. 2024 Aug 27:S0022-5223(24)00770-0. doi: 10.1016/j.jtcvs.2024.08.036. Online ahead of print.

Authors

Affiliations

¹ Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Pediatrics, Boston University Chobanian & Avedisian School of Medicine, Boston, Mass; Department of Pediatric Heart Medicine and Adults with Congenital Heart Disease, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
² Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass.
³ Department of Pediatrics, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Mass.
⁴ Department of Genetics, Harvard Medical School, Boston, Mass.
⁵ Department of Genetics, Harvard Medical School, Boston, Mass; Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass; Department of Medicine, Harvard Medical School, Boston, Mass; Howard Hughes Medical Institute, Chevy Chase, Md.
⁶ Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Mass; Department of Anesthesia, Harvard Medical School, Boston, Mass.
⁷ Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children's Hospital, Boston, Mass.
⁸ Department of Pediatrics, Harvard Medical School, Boston, Mass; Department of Cardiology, Boston Children's Hospital, Boston, Mass.
⁹ Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Surgery, Harvard Medical School, Boston, Mass.
¹⁰ Department of Cardiac Surgery, Boston Children's Hospital, Boston, Mass; Department of Surgery, Harvard Medical School, Boston, Mass. Electronic address: [email protected].

PMID: 39208926
DOI: 10.1016/j.jtcvs.2024.08.036

Abstract

Background: Endocardial fibroelastosis (EFE) is a major effector in the maldevelopment of the heart in patients with congenital heart disease. Despite successful surgical removal, EFE can redevelop, but the underlying cause of EFE recurrence remains unknown. This study aimed to identify hemodynamic predictors and genetic links to epithelial/endothelial-to-mesenchymal transition (EMT/EndMT) alterations for preoperative risk assessment.

Methods: We assessed the impact of preoperative hemodynamic parameters on EFE recurrence in a cohort of 92 patients with congenital heart disease who underwent left ventricular (LV) EFE resection between January 2010 and March 2021. Additionally, whole-exome sequencing in 18 patients was used to identify rare variants (minor allele frequency <10^-5) in high-expression heart (HHE) genes related to cardiac EMT/EndMT and congenital heart disease.

Results: EFE recurred in 55.4% of patients, within a median of 2.2 years postsurgery. Multivariable analysis revealed specific hemodynamic parameters (mitral valve inflow and area, LV filling pressure, and aortic valve gradient and diameter) as predictors, forming a predictive model with an area under the receiver operating characteristic curve of 0.782. Furthermore, 89% of the patients exhibited damaging variants in HHE genes, with 38% linked to cardiac EMT/EndMT Gene Ontology processes and 22% associated with known congenital heart disease genes. Notably, HHE genes associated with cardiac EMT/EndMT were significantly associated with faster EFE recurrence in a multivariate analysis (hazard ratio, 3.56; 95% confidence interval, 1.24-10.17; P = .018).

Conclusions: These findings established a predictive scoring system using preoperative hemodynamic parameters for EFE recurrence risk assessment. Alterations in HHE genes, particularly those linked to cardiac EMT/EndMT, exacerbate the risk of recurrence.

Keywords: congenital heart defects; endocardial fibroelastosis; endothelial-mesenchymal transition; genetic predisposition to disease; hemodynamics; hypoplastic left heart syndrome.