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

Congenital heart defects are the most common birth defects occurring in 8:1000 live births and are the leading cause of birth defect-related deaths. The underlying commonality of most congenital heart defects are structural alterations and hemodynamic changes which affect normal growth and development of one or both ventricles during the fetal and postnatal period. Blood flow has a major influence on the structural development of the fetal heart and postnatally. With mechanical interventions for repairing of valves and restoring blood flow, several structural defects can be addressed, but there is additional potential to treat other pathologies such as the presence of a thick layer of cellular fibro-elastic tissue, termed endocardial fibroelastosis (EFE). The presence of EFE has been reported in several cardiac diseases such as cardiomyopathies, infectious diseases, immunologic diseases and most severely in hypoplastic left heart syndrome (HLHS). In severe cases, the entire left ventricle is lined with this white layer of thick fibrotic tissue. In up to 70% of all HLHS patients, EFE restricts the left ventricular outflow tract (LVOT) and surgical removal of EFE tissue has been found to be beneficial, allowing for curative repairs, however, recurrence is common.Based on the current understanding and approach towards EFE, a novel approach in the treatment of EFE is warranted to improve the quality of life for children affected by this condition. Biomechanical forces generated by flowing blood can influence the structure and function of endocardial cells and induce alterations leading to EFE formation. For the first time, a recently published report associates mechanical forces such as flow disturbances with EFE development and identifies endothelial-to-mesenchymal transition (EndMT) as underlying mechanism. With a target amenable to pharmacological intervention identified, the goal of this proposal is now to establish the hemodynamic forces that trigger EndMT-mediated EFE formation and progression, and to identify compounds of transcriptional regulation that orchestrate the pattern of expression of pathophysiologically relevant genes, in order to target EndMT. AIM I: To establish the causative relationship of altered hemodynamic forces and EFE progression. AIM II: To correlate localized EFE formation with hemodynamic alterations in patients with EFE through 4D-MRI.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Ingeborg Friehs