Novel and Precision Therapies in Neonatal Heart Failure

Neonatal heart failure is a high risk, heterogeneous syndrome that emerges at the intersection of immature myocardial biology, rapid postnatal circulatory transition, and evolving systemic metabolic demand. Rather than a single diagnosis, it represents a shared physiologic endpoint arising from structural congenital heart disease, primary genetic and metabolic cardiomyopathies, and acquired myocardial injury related to inflammation, ischemia reperfusion, hypoxia, or sepsis. In this population, the brain, kidneys, liver, and gastrointestinal tract are uniquely vulnerable to impaired systemic oxygen delivery, making neonatal heart failure fundamentally a systemic disease with downstream multiorgan and neurodevelopmental consequences. This chapter reframes neonatal heart failure through an oximetric physiologic lens centered on the balance between oxygen delivery and oxygen consumption, emphasizing cardiac output and oxygen content over isolated pressure based endpoints. Pharmacologic therapies are organized according to their effects on preload, afterload, contractility, heart rate, energetic efficiency, and venous capacitance, with focused discussion of milrinone, levosimendan, ivabradine, and sacubitril valsartan alongside disease specific metabolic therapies such as carnitine supplementation. Escalation strategies including extracorporeal membrane oxygenation and durable ventricular assist devices are reviewed, as are evolving approaches to neonatal heart transplantation including ABO incompatible transplantation and contemporary size matching strategies. Emerging regenerative and enzymatic therapies for selected metabolic and lysosomal cardiomyopathies further highlight a shift toward disease modifying interventions. Neonatal heart failure is best understood as a disorder of inadequate systemic oxygen delivery with multiorgan consequences. An oximetric, physiology grounded framework that prioritizes cardiac output, oxygen content, and venous physiology enables more precise therapeutic targeting. Integration of advanced therapies with high fidelity physiologic monitoring, imaging, biomarkers, and molecular tools represents a path toward precision driven neonatal care.