RESUMEN
PURPOSE: Finite element simulations are an enticing tool to evaluate heart valve function; however, patient-specific simulations derived from 3D echocardiography are hampered by several technical challenges. The objective of this work is to develop an open-source method to enforce matching between finite element simulations and in vivo image-derived heart valve geometry in the absence of patient-specific material properties, leaflet thickness, and chordae tendineae structures. METHODS: We evaluate FEBio Finite Element Simulations with Shape Enforcement (FINESSE) using three synthetic test cases considering a range of model complexity. FINESSE is then used to estimate the in vivo valve behavior and leaflet strains for three pediatric patients. RESULTS: Our results suggest that FINESSE can be used to enforce finite element simulations to match an image-derived surface and estimate the first principal leaflet strains within ± 0.03 strain. Key considerations include: (i) defining the user-defined penalty, (ii) omitting the leaflet commissures to improve simulation convergence, and (iii) emulating the chordae tendineae behavior via prescribed leaflet free edge motion or a chordae emulating force. In all patient-specific cases, FINESSE matched the target surface with median errors of approximately the smallest voxel dimension. Further analysis revealed valve-specific findings, such as the tricuspid valve leaflet strains of a 2-day old patient with HLHS being larger than those of two 13-year old patients. CONCLUSIONS: FEBio FINESSE can be used to estimate patient-specific in vivo heart valve leaflet strains. The development of this open-source pipeline will enable future studies to begin linking in vivo leaflet mechanics with patient outcomes.
RESUMEN
Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.
