Studies suggested the effect of blood flow forces in pathogenesis and progression of some congenital heart malformations other than the Tetralogy of Fallot (TOF). It is thus of interest to study the fluid mechanic environment of the malformed prenatal heart, especially when little is known in the fetal TOF. In this study, we performed patient-specific ultrasound-based flow simulations of 3 TOF and 7 normal human fetal hearts. TOF right ventricles (RV) had smaller end-diastolic volumes (EDV) but similar stroke volumes (SV), while TOF left ventricles (LV) had similar EDV but slightly increased SV compared to normal ventricles. Simulation showed that TOF ventricles had elevated systolic intra-ventricular pressure gradient (IVPG), and required additional energy for ejection, but IVPG elevations were considered to be mild relative to arterial pressure. TOF RV and LV had similar pressures due to equalization via ventricular septal defect (VSD). Further, relative to normal, TOF RVs had increased diastolic wall shear stresses (WSS), but TOF LVs were not. This was caused by high tricuspid inflow that exceeded RV stroke volume, leading to right-to-left shunting and chaotic flow with enhanced vorticity interaction with the wall to elevate WSS. Two of the three TOF RVs but none of the LVs had increased thickness. As pressure elevations were mild, we hypothesized that pressure and WSS elevation could play a role in the RV thickening, among other causative factors. Finally, the endocardium surrounding the VSD consistently experienced high WSS due to RV-to-LV flow shunt and high flow rate through the over-riding aorta.

Congenital heart disease (CHD) is the most common birth defect among newborns worldwide and contributes to significant infant morbidity and mortality. Owing to major advances in medical and surgical management, as well as improved prenatal diagnosis, the outcomes for these children with CHD have improved tremendously so much so that there are now more adults living with CHD than children. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. For this reason, the complex process of cardiogenesis, which is governed by multiple interlinked and dose-dependent pathways, is a well investigated process. In addition to the sequence of the genome, the contribution of epigenetics to cardiogenesis is increasingly recognized. Significant progress has been made dissecting the epigenome of the heart and identified associations with cardiovascular diseases. The role of epigenetic regulation in cardiac development/cardiogenesis, using tissue and animal models, has been well reviewed. Here, we curate the current literature based on studies in humans, which have revealed associated and/or causative epigenetic factors implicated in CHD. We sought to summarize the current knowledge on the functional role of epigenetics in cardiogenesis as well as in distinct CHDs, with an aim to provide scientists and clinicians an overview of the abnormal cardiogenic pathways affected by epigenetic mechanisms, for a better understanding of their impact on the developing fetal heart, particularly for readers interested in CHD research.

Evidence of diffuse myocardial fibrosis and is already present in children after HTx. It appears to be associated with diastolic dysfunction.