Integrated multi-omic characterization of congenital heart disease

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.