Complex Congenital Heart Disease Associated With Disordered Myocardial Architecture in a Midtrimester Human Fetus

Garcia-Canadilla, Patricia; Dejea, Hector; Bonnin, Anne; Balicevic, Vedrana; Lončarić, Sven; Zhang, Chong; Butakoff, Constantine; Aguado-Sierra, Jazmín; Vázquez, Mariano; Jackson, Laurence H.; Stuckey, Daniel J.; Rau, Cristoph; Stampanoni, Marco; Bijnens, Bart; Cook, Andrew C.

doi:10.1161/circimaging.118.007753

Cited by 52 publications

(72 citation statements)

References 27 publications

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“…; Garcia‐Canadilla et al. ). The structure tensor method is an image analysis method which derives a tensor from the distribution of image gradient directions within the neighbourhood of a voxel.…”

Section: Methodsmentioning

confidence: 98%

“…We have recently reported how this gradual change in helical angulation ( HA ) is established early in fetal life (Garcia‐Canadilla et al. ). Cardiomyocytes also show a transmural orientation which is quantified by the transverse ( TA ) or intrusion angle.…”

Section: Methodsmentioning

confidence: 99%

“…3D volumerendered reconstructions were performed in 3DSLICER (Fedorov et al 2012). The orientation of cardiomyocytes was assessed by computation of their helical and intrusion angles by means of an in-house structure tensor method implemented in MATLABâ (The Math-Works Inc., Natick, MA, USA, R2018a) (Bali cevi c et al 2015;Garcia-Canadilla et al 2018). The structure tensor method is an image analysis method which derives a tensor from the distribution of image gradient directions within the neighbourhood of a voxel.…”

Section: Image Processing and Analysis Of Murine Datamentioning

confidence: 99%

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Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

et al. 2019

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Myoarchitectural disarray – the multiscalar disorganisation of myocytes, is a recognised histopathological hallmark of adult human hypertrophic cardiomyopathy (HCM). It occurs before the establishment of left ventricular hypertrophy (LVH) but its early origins and evolution around the time of birth are unknown. Our aim is to investigate whether myoarchitectural abnormalities in HCM are present in the fetal heart. We used wild‐type, heterozygous and homozygous hearts (n = 56) from a Mybpc3‐targeted knock‐out HCM mouse model and imaged the 3D micro‐structure by high‐resolution episcopic microscopy. We developed a novel structure tensor approach to extract, display and quantify myocyte orientation and its local angular uniformity by helical angle, angle of intrusion and myoarchitectural disarray index, respectively, immediately before and after birth. In wild‐type, we demonstrate uniformity of orientation of cardiomyocytes with smooth transitions of helical angle transmurally both before and after birth but with traces of disarray at the septal insertion points of the right ventricle. In comparison, heterozygous mice free of LVH, and homozygous mice showed not only loss of the normal linear helical angulation transmural profiles observed in wild‐type but also fewer circumferentially arranged myocytes at birth. Heterozygous and homozygous showed more disarray with a wider distribution than in wild‐type before birth. In heterozygous mice, disarray was seen in the anterior, septal and inferior walls irrespective of stage, whereas in homozygous mice it extended to the whole LV circumference including the lateral wall. In conclusion, myoarchitectural disarray is detectable in the fetal heart of an HCM mouse model before the development of LVH.

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Section: Methodsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Image Processing and Analysis Of Murine Datamentioning

confidence: 99%

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Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

et al. 2019

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“…This technique, which is destructive, is used as a final step in the pipeline. It is relevant to morphometric analyses, as well as quantification of trabeculation or myofibre orientation (Garcia-Canadilla et al, 2018; Paun et al, 2018). HREM was used here for the heart, but could be extended to other explanted organs, or the whole fetus (Geyer et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Standardised imaging pipeline for phenotyping mouse laterality defects and associated heart malformations, at multiple scales and multiple stages

Desgrange

Lokmer

Marchiol

et al. 2019

Preprint

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20 asymmetry 21 Word count 7005 22 23 24 Desgrange et al. 2 Summary statement 25Laterality defects, which combine anomalies in several visceral organs, are challenging to phenotype. 26We have now developed a standardised approach for multimodality 3D imaging in mice, generating 27 quantifiable phenotypes. 28 29 Abstract 30 31 Laterality defects are developmental disorders resulting from aberrant left/right patterning. In 32 the most severe cases, such as in heterotaxy, they are associated with complex malformations of the 33 heart. Advances in understanding the underlying physiopathological mechanisms have been hindered 34 by the lack of a standardised and exhaustive procedure in mouse models, for phenotyping left/right 35 asymmetries of all visceral organs. Here, we have developed a multimodality imaging pipeline, which 36 combines non-invasive micro-ultrasound imaging, micro-CT and HREM, to acquire 3D images at 37 multiple stages of development and at multiple scales. Based on the position in the uterine horns, we 38 track, in a single individual, the progression of organ asymmetry, the situs of all visceral organs in 39 their thoracic or abdominal environment, together with fine anatomical left/right asymmetries of 40 cardiac segments. We provide reference anatomical images and organ reconstructions in the mouse, 41 and discuss differences with humans. This standardised pipeline, which we validated in a mouse 42 model of heterotaxy, offers a fast and easy-to-implement framework. The extensive 3D phenotyping 43 of organ asymmetry in the mouse uses the clinical nomenclature for direct comparison with patient 44 phenotypes. It is compatible with automated and quantitative image analyses, which is essential to 45 compare mutant phenotypes with incomplete penetrance and gain mechanistic insight into laterality 46 defects. 47 48 Desgrange et al. 3 Introduction 49 50 Laterality defects are developmental disorders, caused by impaired left-right patterning. They 51 affect collectively up to 1/2,000 live births, and comprise a spectrum of malformations ranging from 52 asymptomatic situs inversus or dextrocardia to severe heterotaxy (Desgrange et al., 2018; Lin et al., 53 2014). Heterotaxy corresponds to abnormal symmetry of the viscera (isomerism), and/or situs 54 discordance between visceral organs (Van Praagh, 2006). Many visceral organs (lung, spleen, 55 stomach, intestine, liver and pancreas) may be targeted and functionally impaired, with an abnormal 56 position in the abdominal or thoracic cavity (situs) or an impaired asymmetric shape. Diagnosis is 57 made on the combination of 3 out of 8 criteria, including abdominal situs abnormality, spleen 58 abnormality, isomerism of bronchi and the lungs, biliary atresia, intestinal malrotation, congenital 59 heart defects, isomerism of the atrial appendages, systemic venous anomalies (Lin et al., 2014). The 60 prognosis of heterotaxy mainly depends on the cardiac malformation, which can be complex, with 61 profound functional impacts, such as abnormal oxygen supply or obst...

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“…While the structural (morphological or “geometrical”) characteristics of heart malformations have been extensively studied, it is largely unknown whether cardiac cells from malformed hearts are normal or to what extent they are compromised. Recent studies reveal an abnormal orientation of myocardial cells (the heart muscle cells) within CHD hearts 8–10 . Myocardial cells are elongated, cylindrical-like cells, that contract along their long axis.…”

Section: Introductionmentioning

confidence: 99%

Multiscale cardiac imaging to capture the whole heart and its internal cellular architecture, with applications to congenital heart disease

Rykiel

López

McQuiston

et al. 2020

Preprint

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9Efficient cardiac pumping depends on the morphological structure of the heart, but also on its 10 sub-cellular (ultrastructural) architecture, which enables cardiac contraction. In cases of 11 congenital heart defects, localized sub-cellular disruptions in architecture that increase the risk 12 of heart failure are only starting to be discovered. This is in part due to a lack of technologies 13 that can image the three dimensional (3D) heart structure, assessing malformations; and its 14 ultrastructure, assessing disruptions. We present here a multiscale, correlative imaging 15 procedure that achieves high-resolution images of the whole heart, using 3D micro-computed 16 tomography (micro-CT); and its ultrastructure, using 3D scanning electron microscopy (SEM). 17This combination of technologies has not been possible before in imaging the same cardiac 18 sample due to the heart large size, even when studying small fetal and neonatal animal models 19 (~5x5x5mm 3 ). Here, we achieved uniform fixation and staining of the whole heart, without losing 20 ultrastructural preservation (at the nm resolution range). Our approach enables multiscale 21 studies of cardiac architecture in models of congenital heart disease and beyond. 22 23 51 whole heart morphology and its sub-cellular organization (ultrastructural architecture). Our 52 multiscale procedure uses micro computed tomography (micro-CT) imaging to capture heart 53 morphology at micrometer resolution, and scanning electron microscopy (SEM) to capture 54 cardiac tissue ultrastructure at nanometer resolution. Current SEM technologies allow for three-55 dimensional (3D) imaging of sub-cellular architecture, enabling reconstruction and quantification 56 of ultrastructural features within a tissue volume 14-16 . Among 3D SEM methods, we have 57 selected serial block-face SEM (SBF-SEM) for ultrastructural imaging, as it allows 3D imaging of 58 relatively large volumes (sample size 40x60x40 µm 3 ). The methodology we present herein 59 improves upon previous protocols by achieving uniform staining of a relatively large heart 60 sample (3-4 mm wide, 5-6 mm long), circumventing micro-CT x-ray penetration issues, and 61 allowing sample screening and selection prior to full sample preparation. Our multiscale imaging, 62 further, enables mapping of structural and ultrastructural heart features. 63 129 thickening and enlargement of the RV wall. RV hypertrophy in TOF, however, develops over 130 time as the stenosis of the pulmonary artery increases pressure in the RV after birth 17 and was 131 not present in the heart examined in this study (see Figure 3 for a comparison of the selected 132 normal and TOF hearts). The TOF heart analyzed here featured supravalvular pulmonary 133 stenosis, a ventricular septal defect, and an overriding aorta. The right ventricle was enlarged 134and thin-walled compared to the control heart (Figure 3). Further, the TOF heart was missing 135 the right branch of the pulmonary artery. In humans, this rare condition, called unilateral 136

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Complex Congenital Heart Disease Associated With Disordered Myocardial Architecture in a Midtrimester Human Fetus

Cited by 52 publications

References 27 publications

Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

Myoarchitectural disarray of hypertrophic cardiomyopathy begins pre‐birth

Standardised imaging pipeline for phenotyping mouse laterality defects and associated heart malformations, at multiple scales and multiple stages

Multiscale cardiac imaging to capture the whole heart and its internal cellular architecture, with applications to congenital heart disease

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