Pediatric dilated cardiomyopathy and the progression to heart failure: mechanisms and interventions focusing on the “gene-inflammation-metabolism” axis
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy in children and a leading indication for heart transplantation. Despite considerable progress in understanding its genetic architecture, translating these insights into improved outcomes for children remains challenging. The pathophysiology of pediatric dilated cardiomyopathy is highly complex, extending beyond a simple monogenic model to encompass intricate interactions between genetic predisposition, inflammatory triggers, and metabolic dysregulation. This review systematically synthesizes current evidence on the mechanisms driving heart failure progression in pediatric dilated cardiomyopathy, focusing on the integrated framework of the “gene-inflammation-metabolism” axis. We begin by outlining the genetic landscape of pediatric dilated cardiomyopathy, highlighting key pathogenic genes and their associated phenotypes, with particular emphasis on features distinct from adult disease. We then explore how environmental “second hits” (such as viral infection and autoimmune responses) trigger excessive inflammatory reactions, and discuss the significance of special clinical phenomena such as “hot phase” myocarditis in genetically susceptible children. Concurrently, we systematically examine the metabolic reprogramming of the failing heart, including mitochondrial dysfunction, substrate utilization shifts, insulin resistance, and iron metabolism disturbances, analyzing how these processes further compromise energy-starved cardiomyocytes. By integrating these three interconnected domains, this review presents a pediatric-specific triaxial framework that unifies known DCM pathways into a single actionable model for precision risk stratification and targeted therapy. This framework supports the development of novel biomarkers, multi-dimensional risk stratification strategies, and targeted interventions—ranging from anti-inflammatory agents and metabolic modulators to gene therapy, psychological support, and AI-assisted risk prediction. This review aims to provide a novel theoretical framework and practical roadmap for the clinical management and future research of pediatric dilated cardiomyopathy.