Animal models of hypoplastic left heart syndrome: genetic and anatomical approaches

Hypoplastic Left Heart Syndrome (HLHS) is a life-threatening congenital heart disease characterized by underdevelopment of the left heart and aorta. Animal models of HLHS are used to study mechanisms of disease onset and progression and generally fall into two in vivo categories: genetic and mechanical. Genetic models primarily employ zebrafish and mice, whereas mechanically induced models are developed in chick embryos, fetal lambs, and rodents. Together, genetic and mechanical models provide insight into developmental and hemodynamic mechanisms of HLHS but differ in their ability to reproduce key anatomical and physiological features. Genetic models have identified genes and pathways involved in structural abnormalities and disrupted cell lineage. Mechanical models commonly restrict left-heart inflow using surgical or catheter-based techniques to induce hypoplasia of the left ventricle, valves, and aorta. Findings across chick embryos, fetal lambs, and mouse models support the "no flow, no grow" theory. This review synthesizes current HLHS animal models, evaluates their advantages and limitations, and considers their translational relevance from genetic and hemodynamic perspectives, while emphasizing species-specific limitations. IMPACT: Systematically evaluate genetically and mechanically induced HLHS models across zebrafish, mice, rats, chick embryos, and fetal lambs. Discuss how these models elucidate developmental and hemodynamic mechanisms of HLHS, highlight innovations such as CRISPR-based gene editing and staged in utero flow restriction, and assess their translational relevance, particularly for fetal intervention research. Provide practical criteria for model selection and interpretation, weighing strengths, limitations, and fidelity to human HLHS for mechanistic and translational aims.