Experimental models of hypoplastic left heart syndrome: multidimensional phenotyping for clinical translation

Hypoplastic left heart syndrome (HLHS) and related forms of left heart hypoplasia are among the most severe forms of congenital heart disease, characterized by underdevelopment of left-sided cardiac structures, abnormal fetal circulation, and dependence on complex postnatal management. Compelling evidence indicates that disrupted fetal hemodynamics during critical windows of cardiac morphogenesis contributes substantially to disease development and progression. Because the underlying cellular and molecular mechanisms are difficult to investigate directly in utero , and experimental manipulation of fetal hemodynamics in humans is ethically and practically constrained, animal models are essential for investigating HLHS pathogenesis and linking developmental mechanisms to clinically relevant therapeutic strategies. Although experimental models of HLHS and related left heart hypoplasia have provided important structural, functional, histological, and molecular insights, differences in the selection, depth, and integration of phenotyping endpoints across studies complicate direct comparisons between experimental models. In particular, consistent characterization of right ventricular adaptation and extracardiac consequences remains an important consideration for determining how closely individual models reproduce the integrated phenotype of human HLHS. This review synthesizes current strategies for inducing left heart hypoplasia and critically evaluates the domains used to characterize these models. Based on this analysis, we propose a comprehensive multidimensional phenotyping framework to guide the integrated evaluation of experimental HLHS-like and left heart hypoplasia models. Establishing more standardized phenotyping criteria will strengthen model validation, enhance comparability across studies, and facilitate the translation of experimental findings into clinically relevant strategies spanning fetal intervention, neonatal management, and longer-term therapeutic development in HLHS.