Altered haemodynamics causes aberrations in the epicardium

During embryo development, the heart is the first functioning organ. Although quiescent in the adult, the epicardium is essential during development to form a normal four‐chambered heart. Epicardial‐derived cells contribute to the heart as it develops with fibroblasts and vascular smooth muscle cells. Previous studies have shown that a heartbeat is required for epicardium formation, but no study to our knowledge has shown the effects of haemodynamic changes on the epicardium. Since the aetiologies of many congenital heart defects are unknown, we suggest that an alteration in the heart's haemodynamics might provide an explanatory basis for some of them. To change the heart's haemodynamics, outflow tract ( OFT ) banding using a double overhang knot was performed on HH 21 chick embryos, with harvesting at different developmental stages. The epicardium of the heart was phenotypically and functionally characterised using a range of techniques. Upon alteration of haemodynamics, the epicardium exhibited abnormal morphology at HH 29, even though migration of epicardial cells along the surface of the heart was found to be normal between HH 24 and HH 28. The abnormal epicardial phenotype was exacerbated at HH 35 with severe changes in the structure of the extracellular matrix ( ECM ). A number of genes tied to ECM production were also differentially expressed in HH 29 OFT ‐banded hearts, including DDR 2 and collagen XII . At HH 35, the differential expression of these genes was even greater with additional downregulation of collagen I and TCF 21. In this study, the epicardium was found to be severely impacted by altered haemodynamics upon OFT banding. The increased volume of the epicardium at HH 29, upon OFT ‐banding, and the expression changes of ECM markers were the first indicative signs of aberrations in epicardial architecture; by HH 35, the phenotype had progressed. The decrease in epicardial thickness at HH 35 suggests an increase in tension, with a force acting perpendicular to the surface of the epicardium. Although the developing epicardium and the blood flowing through the heart are separated by the endocardium and myocardium, the data presented here demonstrate that altering the blood flow affects the structure and molecular expression of the epicardial layer. Due to the intrinsic role the epicardium in cardiogenesis, defects in epicardial formation could have a role in the formation of a wide range of congenital heart defects.