An official website of the United States government
Congenital heart disease (CHD) affects about 1 in 100 newborns and its causes are multifactorial. In the embryo, blood flow within the heart and vasculature is essential for proper heart development, with abnormal blood flow leading to CHD. Here, we discuss how blood flow (hemodynamics) affects heart development from embryonic to fetal stages, and how abnormal blood flow solely can lead to CHD. We emphasize studies performed using avian models of heart development, because those models allow for hemodynamic interventions, in vivo imaging, and follow up, while they closely recapitulate heart defects observed in humans. We conclude with recommendations on investigations that must be performed to bridge the gaps in understanding how blood flow alone, or together with other factors, contributes to CHD.
more »
« less
An anatomically informed computational fluid dynamics modeling approach for quantifying hemodynamics in the developing heart
Congenital heart defects occur in approximately 1% of newborns in the US annually. Currently, less than a third of congenital heart defects can be traced to a known genetic or environmental cause, suggesting that a large proportion of disease-causing mechanisms have yet to be fully characterized. Hemodynamic forces such as wall shear stress are critical for heart development and are known to induce changes in embryonic cardiac patterning leading to malformations. However, measuring these hemodynamic factorsin vivois infeasible due to physical limitations, such as the small size and constant motion of the embryonic heart. This serves as a significant barrier towards developing a mechanics-based understanding of the origins of congenital heart defects. An alternative approach is to recapitulate the hemodynamic environment by simulating blood flow and calculating the resulting hemodynamic forces through computational fluid dynamics modeling. Thus, we have developed a robust computational fluid dynamics modeling pipeline to quantify hemodynamics within cell-accurate anatomies of embryonic chick hearts. Here we describe the implementation of single plane illumination light sheet fluorescent microscopy to generate full three-dimensional reconstructions of the embryonic heartin silico, quantitative geometric morphometric methods for identifying anatomic variability across samples, and computational fluid dynamic approaches for calculating flow, pressure, and wall shear stress within complex tissue architectures. Together, these methods produce a fast, robust, and accessible system of analysis for generating high-resolution, quantitative descriptions of anatomical variability and hemodynamic forces in the embryonic heart.
more »
« less
- PAR ID:
- 10673669
- Editor(s):
- Sequeira, Adélia
- Publisher / Repository:
- PLOS
- Date Published:
- Journal Name:
- PLOS One
- Volume:
- 20
- Issue:
- 5
- ISSN:
- 1932-6203
- Page Range / eLocation ID:
- e0322233
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
Hypertrophic cardiomyopathy (HCM) is a congenital heart disease characterized by thickening of the heart’s left ventricle (LV) wall that can lead to cardiac dysfunction and heart failure. Ventricular wall thickening affects the motion of cardiac walls and blood flow within the heart. Because abnormal cardiac blood flow in turn could lead to detrimental remodeling of heart walls, aberrant ventricular flow patterns could exacerbate HCM progression. How blood flow patterns are affected by hypertrophy and inter-patient variability is not known. To address this gap in knowledge, we present here strategies to generate personalized computational fluid dynamics (CFD) models of the heart LV from patient cardiac magnetic resonance (cMR) images. We performed simulations of CFD LV models from three cases (one normal, two HCM). CFD computations solved for blood flow velocities, from which flow patterns and the energetics of flow within the LV were quantified. We found that, compared to a normal heart, HCM hearts exhibit anomalous flow patterns and a mismatch in the timing of energy transfer from the LV wall to blood flow, as well as changes in kinetic energy flow patterns. While our results are preliminary, our presented methodology holds promise for in-depth analysis of HCM patient hemodynamics in clinical practice.more » « less
-
BackgroundThe prediction of rupture in intracranial aneurysms is challenging. Aneurysm growth has been identified as a strong risk factor for rupture and aneurysm wall motion is a potential biomarker for growth, but visualizing aneurysm wall motion using conventional imaging techniques is difficult. Computational fluid dynamic simulations have been used to identify hemodynamic risk factors of intracranial aneurysm instability, but often lack observable and quantifiable biomechanical correlates that can be directly measured in vivo. MethodsIn this retrospective case–control study of matched patients, cohorts with growing (n=6) and stable (n=6) unruptured intracranial aneurysms were selected from our institutional database of 4D Flow MRI scans. The amplified Flow algorithm was used to extract maps of wall motion for each aneurysm. Hemodynamics within the aneurysm dome were calculated using established computational fluid dynamic methods, and hemodynamic variables were evaluated against wall motion for stable and growing aneurysms. ResultsSeveral hemodynamic variables were found to be both significant predictors of aneurysm growth and highly correlated with aneurysm wall motion. The hemodynamic variable most correlated with both the maximum value of aneurysm wall motion and spatial variance of aneurysm wall motion, the time coefficient of variance of the directional wall shear stress gradient (representing changing directions of wall shear stress), was also the best hemodynamic predictor of aneurysm growth. ConclusionsSpatial variance of wall motion and hemodynamic variables are increased in growing aneurysms, and the fluctuations in the directional wall shear stress correlate directly with wall motion, indicating that heterogeneous wall motion and hemodynamics are interrelated and play a critical role in aneurysm instability.more » « less
-
null (Ed.)Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.more » « less
-
Clinically serious congenital heart valve defects arise from improper growth and remodeling of endocardial cushions into leaflets. Genetic mutations have been extensively studied but explain less than 20% of cases. Mechanical forces generated by beating hearts drive valve development, but how these forces collectively determine valve growth and remodeling remains incompletely understood. Here, we decouple the influence of those forces on valve size and shape, and study the role of YAP pathway in determining the size and shape. The low oscillatory shear stress promotes YAP nuclear translocation in valvular endothelial cells (VEC), while the high unidirectional shear stress restricts YAP in cytoplasm. The hydrostatic compressive stress activated YAP in valvular interstitial cells (VIC), whereas the tensile stress deactivated YAP. YAP activation by small molecules promoted VIC proliferation and increased valve size. Whereas YAP inhibition enhanced the expression of cell-cell adhesions in VEC and affected valve shape. Finally, left atrial ligation was performed in chick embryonic hearts to manipulate the shear and hydrostatic stress in vivo. The restricted flow in the left ventricle induced a globular and hypoplastic left atrioventricular (AV) valves with an inhibited YAP expression. By contrast, the right AV valves with sustained YAP expression grew and elongated normally. This study establishes a simple yet elegant mechanobiological system by which transduction of local stresses regulates valve growth and remodeling. This system guides leaflets to grow into proper sizes and shapes with the ventricular development, without the need of a genetically prescribed timing mechanism.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript
- Journal Article:
- https://doi.org/10.1371/journal.pone.0322233
