Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling
Abstract Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by impla...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05132-2 |
| _version_ | 1797774030561869824 |
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| author | Miriam S. Reuter Dustin J. Sokolowski J. Javier Diaz-Mejia Johannes Keunen Barbra de Vrijer Cadia Chan Liangxi Wang Greg Ryan David A. Chiasson Troy Ketela Stephen W. Scherer Michael D. Wilson Edgar Jaeggi Rajiv R. Chaturvedi |
| author_facet | Miriam S. Reuter Dustin J. Sokolowski J. Javier Diaz-Mejia Johannes Keunen Barbra de Vrijer Cadia Chan Liangxi Wang Greg Ryan David A. Chiasson Troy Ketela Stephen W. Scherer Michael D. Wilson Edgar Jaeggi Rajiv R. Chaturvedi |
| author_sort | Miriam S. Reuter |
| collection | DOAJ |
| description | Abstract Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs. |
| first_indexed | 2024-03-12T22:15:02Z |
| format | Article |
| id | doaj.art-8284083b8cd142eb97e9e9c59d7a03d6 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-12T22:15:02Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-8284083b8cd142eb97e9e9c59d7a03d62023-07-23T11:22:41ZengNature PortfolioCommunications Biology2399-36422023-07-016111410.1038/s42003-023-05132-2Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodelingMiriam S. Reuter0Dustin J. Sokolowski1J. Javier Diaz-Mejia2Johannes Keunen3Barbra de Vrijer4Cadia Chan5Liangxi Wang6Greg Ryan7David A. Chiasson8Troy Ketela9Stephen W. Scherer10Michael D. Wilson11Edgar Jaeggi12Rajiv R. Chaturvedi13CGEn, The Hospital for Sick ChildrenGenetics and Genome Biology, SickKids Research InstitutePrincess Margaret Cancer Centre, University Health NetworkOntario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai HospitalDepartment of Obstetrics & Gynaecology, Western UniversityGenetics and Genome Biology, SickKids Research InstituteGenetics and Genome Biology, SickKids Research InstituteOntario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai HospitalDepartment of Paediatric Laboratory Medicine, The Hospital for Sick ChildrenPrincess Margaret Cancer Centre, University Health NetworkThe Centre for Applied Genomics, The Hospital for Sick ChildrenGenetics and Genome Biology, SickKids Research InstituteOntario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai HospitalOntario Fetal Centre, Department of Obstetrics & Gynaecology, Mount Sinai HospitalAbstract Low blood flow through the fetal left heart is often conjectured as an etiology for hypoplastic left heart syndrome (HLHS). To investigate if a decrease in left heart flow results in growth failure, we generate left ventricular inflow obstruction (LVIO) in mid-gestation fetal lambs by implanting coils in their left atrium using an ultrasound-guided percutaneous technique. Significant LVIO recapitulates important clinical features of HLHS: decreased antegrade aortic valve flow, compensatory retrograde perfusion of the brain and ascending aorta (AAo) from the arterial duct, severe left heart hypoplasia, a non-apex forming LV, and a thickened endocardial layer. The hypoplastic AAo have miRNA-gene pairs annotating to cell proliferation that are inversely differentially expressed by bulk RNA-seq. Single-nucleus RNA-seq of the hypoplastic LV myocardium shows an increase in fibroblasts with a reciprocal decrease in cardiomyocyte nuclei proportions. Fibroblasts, cardiomyocytes and endothelial cells from hypoplastic myocardium have increased expression of extracellular matrix component or fibrosis genes with dysregulated fibroblast growth factor signaling. Hence, a severe sustained ( ~ 1/3 gestation) reduction in fetal left heart flow is sufficient to cause left heart hypoplasia. This is accompanied by changes in cellular composition and gene expression consistent with a pro-fibrotic environment and aberrant induction of mesenchymal programs.https://doi.org/10.1038/s42003-023-05132-2 |
| spellingShingle | Miriam S. Reuter Dustin J. Sokolowski J. Javier Diaz-Mejia Johannes Keunen Barbra de Vrijer Cadia Chan Liangxi Wang Greg Ryan David A. Chiasson Troy Ketela Stephen W. Scherer Michael D. Wilson Edgar Jaeggi Rajiv R. Chaturvedi Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling Communications Biology |
| title | Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling |
| title_full | Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling |
| title_fullStr | Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling |
| title_full_unstemmed | Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling |
| title_short | Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling |
| title_sort | decreased left heart flow in fetal lambs causes left heart hypoplasia and pro fibrotic tissue remodeling |
| url | https://doi.org/10.1038/s42003-023-05132-2 |
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