Evidence-based treatment strategies for hypoplastic left heart syndrome: The role of EFNA1/EphA.

Cardiovascular health among the US general population remains largely suboptimal. Major contributing factors include diet, physical activity, and sleep, and these influences begin early in life, despite broad access to health information regarding healthy choices and access to medical care. Advances in perinatal care allow earlier detection of both maternal and congenital conditions, enabling interventions and planning that can improve outcomes. Research exploring the foundations of hypoplastic left heart syndrome (HLHS) has significantly expanded in the last 25 years. HLHS represents a prototypical complex congenital heart defect arising from multifactorial perturbations in left-sided cardiac development, with converging contributions from genetic susceptibility, dysregulated signaling pathways, and environmental modifiers. Early diagnosis, now largely achieved through fetal and postnatal echocardiography, enables timely identification of ductal-dependent systemic circulation and facilitates coordinated perinatal management strategies. Contemporary management remains rooted in staged single-ventricle palliation or cardiac transplantation, supported by intensive perioperative care aimed at maintaining systemic perfusion and improving survival, albeit with significant long-term morbidity. Increasingly, advances in genomics and molecular cardiology are redefining the field, with patient-specific cellular models and pathway-targeted approaches offering the potential to uncover disease mechanisms and develop novel, mechanism-based therapies that move beyond surgical palliation. This review summarizes current knowledge on the etiology of HLHS, current treatments, and emerging therapeutic strategies, with emphasis on the potential for modulation of EFNA/EphA signaling to influence multiple aspects of disease progression.