Genetic and flow anomalies in congenital heart disease

Rugonyi, Sandra

doi:10.3934/genet.2016.3.157

Cited by 12 publications

(7 citation statements)

References 68 publications

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“…Cardiac neural crest cells are required for normal heart development (in the chick and mouse), and ablation of these cells leads to persistent truncus arteriosus (PTA), characterized by lack of separation of the aorta and pulmonary trunk, but also to TOF and DORV. Likewise, diverse genetic anomalies are also associated with conotruncal heart defects ( Srivastava and Olson, 2000 ; Rugonyi, 2016 ). However, the mechanisms by which anomalous genes, neural crest cell ablation, and altered hemodynamics lead to conotruncal defects may differ, and these differences may impact myocardial and myofiber orientation and maturation.…”

Section: Discussionmentioning

confidence: 99%

Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

Rykiel

López

Riesterer

et al. 2020

eLife

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Cardiac pumping depends on the morphological structure of the heart, but also on its sub-cellular (ultrastructural) architecture, which enables cardiac contraction. In cases of congenital heart defects, localized ultrastructural disruptions that increase the risk of heart failure are only starting to be discovered. This is in part due to a lack of technologies that can image the three dimensional (3D) heart structure, to assess malformations; and its ultrastructure, to assess organelle disruptions. We present here a multiscale, correlative imaging procedure that achieves high-resolution images of the whole heart, using 3D micro-computed tomography (micro-CT); and its ultrastructure, using 3D scanning electron microscopy (SEM). In a small animal model (chicken embryo), we achieved uniform fixation and staining of the whole heart, without losing ultrastructural preservation on the same sample, enabling correlative multiscale imaging. Our approach enables multiscale studies in models of congenital heart disease and beyond.

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Section: Discussionmentioning

confidence: 99%

Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

Rykiel

López

Riesterer

et al. 2020

eLife

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“…Studies in animal models have demonstrated that biomechanical aberrations can lead to cardiac maldevelopment and congenital heart malformations. 10 , 43 The success with which minimally-invasive interventions improved structural heart development corroborated this idea, since such interventions are mechanical in nature. It is thus important to understand the biomechanics of fetal cardiac development and congenital heart malformations, such as critical AS, as this may improve our ability to predict gestational and perinatal outcomes.…”

Section: Introductionmentioning

confidence: 89%

Biomechanics of Human Fetal Hearts with Critical Aortic Stenosis

et al. 2020

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Critical aortic stenosis (AS) of the fetal heart causes a drastic change in the cardiac biomechanical environment. Consequently, a substantial proportion of such cases will lead to a single-ventricular birth outcome. However, the biomechanics of the disease is not well understood. To address this, we performed Finite Element (FE) modelling of the healthy fetal left ventricle (LV) based on patient-specific 4D ultrasound imaging, and simulated various disease features observed in clinical fetal AS to understand their biomechanical impact. These features included aortic stenosis, mitral regurgitation (MR) and LV hypertrophy, reduced contractility, and increased myocardial stiffness. AS was found to elevate LV pressures and myocardial stresses, and depending on severity, can drastically decrease stroke volume and myocardial strains. These effects are moderated by MR. AS alone did not lead to MR velocities above 3 m/s unless LV hypertrophy was included, suggesting that hypertrophy may be involved in clinical cases with high MR velocities. LV hypertrophy substantially elevated LV pressure, valve flow velocities and stroke volume, while reducing LV contractility resulted in diminished LV pressure, stroke volume and wall strains. Typical extent of hypertrophy during fetal AS in the clinic, however, led to excessive LV pressure and valve velocity in the FE model, suggesting that reduced contractility is typically associated with hypertrophy. Increased LV passive stiffness, which might represent fibroelastosis, was found to have minimal impact on LV pressures, stroke volume, and wall strain. This suggested that fibroelastosis could be a by-product of the disease progression and does not significantly impede cardiac function. Our study demonstrates that FE modelling is a valuable tool for elucidating the biomechanics of congenital heart disease and can calculate parameters which are difficult to measure, such as intraventricular pressure and myocardial stresses.

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“…Blood flow is intricately linked to any manipulation that alters heart development, including genetic modifications, which frequently result in perturbations to blood flow. Perhaps not surprisingly, perturbed blood flow conditions lead to cardiac malformation phenotypes that independently arise from known gene mutations and teratogen exposures (Rugonyi, 2016; Midgett et al, 2017b). Whether some of these mutations and exposures also lead to altered blood flows that could ultimately underlie the cardiac malformation is not known, but it is certainly an interesting topic of investigation.…”

Section: Altering Hemodynamic Conditions In Animal Models: Lessonsmentioning

confidence: 99%

Influence of blood flow on cardiac development

Courchaine

Rykiel

Rugonyi

2018

Progress in Biophysics and Molecular Biology

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The role of hemodynamics in cardiovascular development is not well understood. Indeed, it would be remarkable if it were, given the dauntingly complex array of intricately synchronized genetic, molecular, mechanical, and environmental factors at play. However, with congenital heart defects affecting around 1 in 100 human births, and numerous studies pointing to hemodynamics as a factor in cardiovascular morphogenesis, this is not an area in which we can afford to remain in the dark. This review seeks to present the case for the importance of research into the biomechanics of the developing cardiovascular system. This is accomplished by i) illustrating the basics of some of the highly complex processes involved in heart development, and discussing the known influence of hemodynamics on those processes; ii) demonstrating how altered hemodynamic environments have the potential to bring about morphological anomalies, citing studies in multiple animal models with a variety of perturbation methods; iii) providing examples of widely used technological innovations which allow for accurate measurement of hemodynamic parameters in embryos; iv) detailing the results of studies in avian embryos which point to exciting correlations between various hemodynamic manipulations in early development and phenotypic defect incidence in mature hearts; and finally, v) stressing the relevance of uncovering specific biomechanical pathways involved in cardiovascular formation and remodeling under adverse conditions, to the potential treatment of human patients. The time is ripe to unravel the contributions of hemodynamics to cardiac development, and to recognize their frequently neglected role in the occurrence of heart malformation phenotypes.

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Genetic and flow anomalies in congenital heart disease

Cited by 12 publications

References 68 publications

Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

Multiscale cardiac imaging spanning the whole heart and its internal cellular architecture in a small animal model

Biomechanics of Human Fetal Hearts with Critical Aortic Stenosis

Influence of blood flow on cardiac development

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