Developmental Anatomy of Congenital Heart Defects: Insights into Fetal Cardiac Morphogenesis

Abstract

Congenital heart defects (CHDs) are among the most prevalent birth anomalies worldwide, contributing significantly to neonatal morbidity and mortality. Despite advances in developmental biology, the precise molecular and biomechanical mechanisms driving CHD pathogenesis remain incompletely understood. This study employs an integrative, multidisciplinary approach to investigate the genetic, molecular, and biomechanical factors involved in fetal cardiac morphogenesis and their disruption in CHDs. Through whole-exome and transcriptomic analyses of human fetal cardiac tissue, combined with CRISPR-Cas9-modified zebrafish and murine models, we identified pathogenic mutations in key cardiac transcription factors—Nkx2.5, Tbx5, and Gata4—which led to aberrant gene expression and structural malformations. Gene expression profiling revealed significant downregulation of cardiac developmental pathways, including Wnt, Notch, and BMP signaling. Biomechanical simulations using finite element analysis demonstrated that altered stress distribution in mutant hearts exacerbates structural defects, highlighting the critical role of mechanical forces in morphogenesis. Complementary imaging using 3D fetal echocardiography and high-resolution MRI enabled early detection of septal and conotruncal anomalies as early as 12 weeks of gestation, reinforcing the potential for prenatal diagnostic application. Our findings underscore the need for a systems-level approach that integrates genetic and biomechanical data to understand the complex etiology of CHDs. This study contributes to the foundational knowledge required to improve risk stratification, enhance prenatal diagnostic accuracy, and guide future therapeutic interventions for congenital heart disease.