Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect affecting left ventricular development.
• The exact causes of HLHS remain largely unknown, with hemodynamic factors often presumed to be primary drivers.
• Understanding the molecular and cellular basis of HLHS is crucial for developing effective interventions.

Purpose of the Study:

• To investigate the molecular and cellular perturbations underlying ventricular development in HLHS.
• To identify specific gene programs and cellular processes affected in HLHS.

Main Methods:

• Whole-exome sequencing of 87 HLHS parent-offspring trios.
• Nuclear transcriptomics of cardiomyocytes from HLHS patients and controls.
• Single-cell RNA sequencing and 3D modeling using patient-derived induced pluripotent stem cells.

Main Results:

• HLHS is associated with alterations in cell cycle regulation and cardiomyocyte maturation during fetal development.
• Patient-derived stem cells reveal intrinsic defects in the cell cycle, unfolded protein response, and autophagy.
• Premature cell cycle exit in ventricular cardiomyocytes leads to multinucleation, DNA damage, and apoptosis, contributing to left ventricular hypoplasia.

Conclusions:

• Genetic mutations in HLHS converge on critical cellular processes governing cardiac myogenesis.
• Intrinsic cellular defects, including cell cycle dysregulation, play a significant role in HLHS pathogenesis.
• These findings suggest potential novel therapeutic targets for HLHS focused on cellular repair and regeneration.