Related Experiment Video
Updated: Sep 7, 2025
A Pipeline to Characterize Structural Heart Defects in the Fetal Mouse
Published on: December 16, 2022
Integrated multi-omic characterization of congenital heart disease
Matthew C Hill1,2,3, Zachary A Kadow1, Hali Long4
1Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
Insights
Congenital heart disease (CHD) involves unique cellular changes in heart cells and immune cells. This study reveals novel insights into CHD progression, paving the way for personalized treatments.
Area of Science:
- Cardiovascular Biology
- Developmental Biology
- Immunology
Background:
- Congenital heart disease (CHD) arises from complex embryonic heart development defects.
- While survival rates for CHD have improved, many adults face premature death from heart failure and other causes.
- Understanding the cellular and molecular underpinnings of CHD is crucial for improving long-term patient outcomes.
Purpose of the Study:
- To investigate the cellular and molecular alterations in congenital heart disease (CHD) using advanced sequencing techniques.
- To identify specific cell states and molecular pathways involved in CHD progression, including hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot.
- To explore the immune microenvironment and peripheral immunity in patients with CHD.
Main Methods:
- Single-nucleus RNA sequencing of 157,273 nuclei from control and CHD patient hearts (including HLHS, tetralogy of Fallot, cardiomyopathies).
- Imaging mass cytometry to analyze the spatial microenvironment.
- Peripheral immune cell profiling.
Main Results:
- Identified CHD-specific cardiomyocyte states exhibiting insulin resistance and altered FOXO signaling and CRIM1 expression.
- Observed activated cardiac fibroblasts in HLHS characterized by a low-Hippo/high-YAP state.
- Uncovered a spatially resolved perivascular immunodeficient microenvironment in CHD.
- Detected deficient monocytic immunity in peripheral blood of CHD patients, correlating with increased infection and cancer risk.
Conclusions:
- Comprehensive single-cell and spatial phenotyping reveals distinct cellular and immune alterations in CHD.
- Findings provide a detailed molecular and cellular roadmap for understanding CHD pathogenesis.
- This research lays the groundwork for developing personalized therapeutic strategies for congenital heart disease.
Abstract:
The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes1. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer2. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.
More Related Videos
Related Concept Videos
01:25Cardiomyopathy I: Introduction and Classification
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:27Development of the Heart
As the embryo undergoes lateral folding, these paired tubes approach each other, merging into a single primitive heart...