Flow Disturbances and the Development of Endocardial Fibroelastosis

• Applicant: Dr. Daniel Diaz Gil
• Subject Area: Pediatric and Adolescent Medicine ; Cardiology, Angiology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451778070

• Final Report Year: 2024

Final Report Abstract

Congenital heart defects are common and lead to the majority of birth defect-related deaths. The causes of many of these defects are unknown, limiting treatment options to managing the consequences. Structural changes and alterations in blood flow play a role in their development, with a specific heart tissue called endocardial fibroelastosis (EFE) being involved. Surgical removal of EFE is beneficial, but its exact cellular cause has only recently been discovered. This project aims to improve the treatment of EFE and enhance the quality of life for affected children. It investigates how blood flow within the heart influences EFE development and how EFE can be studied in patients using imaging techniques. By identifying specific triggers and molecular mechanisms, potential pharmacological treatments can be developed. The results of the project show that healthy and EFE-affected cells respond differently to flow. Atorvastatin, an approved drug for atherosclerosis, shows potential in reducing EFE formation in our cell model as well as in our animal model. Based on whole exome sequencing we identified that genetic variants associated with the underlying mechanism of endothelial-to-mesenchymal transition also play a role in EFE disease progression. Single-nuclei RNA sequencing was used to gain insights into cell function in EFE patients. Further, this project explores the relationship between EFE and blood flow in patients using 3D echocardiography and 4D MRI. The findings can improve the treatment of EFE patients. This project has provided important insights into the development and treatment of EFE. It contributes to the development of personalized therapeutic approaches and improves the quality of life for patients.

Publications

• Abstract 13352: Differential Response of Healthy Endocardial Cells versus Endocardial Fibroelastosis-Derived Cells to Flow Alterations and Statins. Circulation, 146(Suppl_1).
  Silva-Gomez, Natalia; Diaz-Gil, Daniel; Winkler, Aimee; Emani, Sitaram; Piekarski, Breanna L.; Del Nido Pedro, J. & Friehs, Ingeborg
  
• Case report: Active clinical manifestation of endocardial fibroelastosis in adolescence in a patient with mitral and aortic obstruction–histologic presence of endothelial-to-mesenchymal transformation. Frontiers in Cardiovascular Medicine, 9.
  Diaz-Gil, Daniel; Carreon, Chrystalle Katte; Silva-Gomez, Natalia; Benheim, Alan E.; Emani, Sitaram M.; del Nido Pedro, J.; Marx, Gerald R. & Friehs, Ingeborg
  
• Effects of Hemodynamic Triggers and Genetic Predisposition on Endocardial Fibroelastosis Recurrence. Circulation. 2022;146:A12290.
  Diaz-Gil D., Silva-Gomez N., Morton S.U., Seidman J.G., Zurakowski D., Staffa S., Piekarski B.L., Marx G.R., Emani S., Del Nido P.J. & Friehs I.
  
• Endocardial Fibroelastosis Recurrence: Comparing Single Ventricle Palliation versus Biventricular Repair. The Thoracic and Cardiovascular Surgeon. Georg Thieme Verlag KG.
  Diaz-Gil, D.; Piekarski, B. L.; Marx, G. R.; Del Nido, P. J.; Emani, S. & Friehs, I.
  
• Response of Endocardial Fibroelastosis-Derived Cells to Flow Alterations and Statins: Hypoplastic Left Ventricle versus Normal Size Left Ventricle. The Thoracic and Cardiovascular Surgeon. Georg Thieme Verlag KG.
  Silva-Gomez, N.; Diaz-Gil, D.; Winkler, A.; Emani, S.; Piekarski, B. L.; Wolf, C. M.; Del Nido, P. J. & Friehs, I.