Decreased left heart flow in fetal lambs causes left heart hypoplasia and pro-fibrotic tissue remodeling.
Miriam S ReuterDustin J SokolowskiJ Javier Diaz-MejiaJohannes KeunenBarbra de VrijerCadia ChanLiangxi WangGreg RyanDavid A ChiassonTroy KetelaStephen W SchererMichael D WilsonEdgar JaeggiRajiv R ChaturvediPublished in: Communications biology (2023)
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.
Keyphrases
- rna seq
- heart failure
- aortic valve
- extracellular matrix
- gene expression
- single cell
- atrial fibrillation
- cell proliferation
- blood flow
- left ventricular
- stem cells
- systemic sclerosis
- preterm infants
- public health
- transcatheter aortic valve implantation
- pulmonary artery
- idiopathic pulmonary fibrosis
- computed tomography
- bone marrow
- multiple sclerosis
- pulmonary hypertension
- magnetic resonance
- aortic valve replacement
- endothelial cells
- coronary artery
- angiotensin ii
- case report
- anti inflammatory
- left atrial
- genome wide identification
- left atrial appendage