Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation.

RATIONALE: Fibrosis is mediated partly by extracellular matrix-depositing fibroblasts in the heart. Although these mesenchymal cells are reported to have multiple embryonic origins, the functional consequence of this heterogeneity is unknown. OBJECTIVE: We sought to validate a panel of surface markers to prospectively identify cardiac fibroblasts. We elucidated the developmental origins of cardiac fibroblasts and characterized their corresponding phenotypes. We also determined proliferation rates of each developmental subset of fibroblasts after pressure overload injury. METHODS AND RESULTS: We showed that Thy1(+)CD45(-)CD31(-)CD11b(-)Ter119(-) cells constitute the majority of cardiac fibroblasts. We characterized these cells using flow cytometry, epifluorescence and confocal microscopy, and transcriptional profiling (using reverse transcription polymerase chain reaction and RNA-seq). We used lineage tracing, transplantation studies, and parabiosis to show that most adult cardiac fibroblasts derive from the epicardium, a minority arises from endothelial cells, and a small fraction from Pax3-expressing cells. We did not detect generation of cardiac fibroblasts by bone marrow or circulating cells. Interestingly, proliferation rates of fibroblast subsets on injury were identical, and the relative abundance of each lineage remained the same after injury. The anatomic distribution of fibroblast lineages also remained unchanged after pressure overload. Furthermore, RNA-seq analysis demonstrated that Tie2-derived and Tbx18-derived fibroblasts within each operation group exhibit similar gene expression profiles. CONCLUSIONS: The cellular expansion of cardiac fibroblasts after transaortic constriction surgery was not restricted to any single developmental subset. The parallel proliferation and activation of a heterogeneous population of fibroblasts on pressure overload could suggest that common signaling mechanisms stimulate their pathological response.

The Utility of Simulation in the Management of Patients With Congenital Heart Disease: Past, Present, and Future.

Significant advancements have been made in the diagnosis and management of congenital heart disease (CHD). As a result, a higher percentage of these patients are surviving to adulthood. Despite this improvement in management, these patients remain at higher risk of morbidity and mortality, particularly in the perioperative setting. One new area of interest in these patients is the implementation of simulation-based medical education. Simulation has demonstrated various benefits across high-acuity scenarios encountered in the hospital. In CHD, simulation has been used in the training of pediatrics residents, assessment of intraoperative complications, echocardiography, and anatomic modeling with 3-dimensional printing. Here, we describe the current state of simulation in CHD, its role in training care providers for the management of this population, and future directions of CHD simulation.