Pediatric viral myocarditis remains an enigmatic and critical challenge within the field of cardiology, demanding a deeper mechanistic understanding and the refinement of experimental models to better replicate the disease as it occurs in infants and children. Recent investigations emphasize the crucial need to distinguish the clinical and biological nuances of myocarditis in pediatric populations, which diverge significantly from adult presentations. Emerging evidence increasingly underscores that existing adult mouse models, while invaluable, provide an incomplete picture of the pediatric condition due to developmental, immunological, and virological distinctions.
At the core of current research are murine models infected with well-established viruses such as Coxsackievirus B3 (CVB3), Encephalomyocarditis virus (EMCV), and Mouse adenovirus type 1 (MAV-1). These models have been instrumental in dissecting viral tropism, immune responses, and the subsequent myocardial damage resulting from infection. CVB3, for instance, has a predilection for cardiomyocytes and readily induces myocarditis with a strong inflammatory profile, while EMCV triggers acute myocarditis with rapid fatality depending on the strain and dosage. MAV-1 adds another dimension by modeling adenoviral infections, although its pathology differs in timing and immune cell involvement. However, while informative, these models bear intrinsic limitations when extrapolated to pediatric myocarditis primarily due to species- and age-specific immunological landscapes.
One pivotal limitation is the developmental disparity in immune system maturation between adult mice and human neonates or children. Pediatric myocarditis frequently involves a unique immune milieu characterized by immature antigen presentation, reduced memory cell populations, and a propensity for persistent viral infection. Contrastingly, adult mouse models lack this developmental window, resulting in immune responses and pathophysiological trajectories that may not adequately replicate the pediatric scenario. This developmental immunodeficiency influences infection control, tissue damage, and repair processes, which in turn affect disease severity and long-term cardiac outcomes.
Moreover, human pediatric myocarditis is often caused by a broader spectrum of viruses beyond those traditionally modeled in laboratory mice. Enteroviruses, specific adenovirus serotypes, and certain human herpesviruses dominate the virological landscape in children and exhibit differential interactions with the host myocardium compared to the viruses generally employed in experimental models. These pathogens engage distinct cellular receptors, induce varied cytokine profiles, and trigger unique patterns of immune cell infiltration, necessitating the development of refined models to capture these viral-host dynamics authentically.
The anatomical and physiological differences in cardiac tissue between mice and humans add another layer of complexity. Murine hearts differ in size, cellular composition, regenerative capacity, and electrophysiological properties. These disparities influence viral replication kinetics, myocardial damage, and the remodeling response. Specifically, pups’ hearts undergo significant structural maturation postnatally, which affects susceptibility to viral insult and subsequent fibrosis or functional decline. Consequently, translating findings from adult or even neonatal mouse hearts to pediatric human myocardium demands cautious interpretation and model validation.
Genetic background is also a determinant of myocarditis susceptibility and progression. Mouse strains display variable disease severity and immune profiles following viral infection. This genetic heterogeneity parallels human population diversity but complicates the application of murine data. Understanding polygenic contributions and epigenetic regulation in both mice and humans is essential to elucidate the multifaceted pathogenesis of pediatric viral myocarditis and uncover targeted therapeutic opportunities.
Apart from pathogen-host considerations, the immune landscape in pediatric myocarditis includes the interplay of innate and adaptive immunity under developmental constraints. Neonates rely predominantly on innate defenses, with limited adaptive memory and altered cytokine secretion patterns. These deviations impact viral clearance, immune-mediated myocardial injury, and shifts in inflammatory versus reparative signaling pathways. Adult mouse models typically do not reflect this immunological configuration, potentially obscuring critical therapeutic targets.
Longitudinal outcomes from pediatric myocarditis also diverge from adult cases due to differences in immune regulation, cardiac plasticity, and growth-related stress. While adult myocarditis may resolve or progress to heart failure with relatively stable pathology, pediatric cases often experience distinct chronic sequelae, including dilated cardiomyopathy and arrhythmias that evolve with cardiac development. This underscores a pressing need for long-term pediatric models to study the evolving pathophysiology and identify windows for intervention.
Current mechanistic studies harnessing adult murine models have illuminated pathways involving viral entry mechanisms, pro-inflammatory cytokines such as TNF-alpha and IL-6, and immune cell subsets including macrophages and T cells. However, extrapolating these insights to pediatric myocarditis requires validating these pathways in age-appropriate models that recapitulate neonatal immune ontogeny and developmental cardiac physiology. Failure to do so risks overlooking pediatric-specific mechanisms that could underpin distinct therapeutic vulnerabilities.
Confronting these research gaps involves innovating experimental paradigms that integrate pediatric-relevant viral strains, genetically engineered mice expressing human viral receptors, and immune system-modulated pups that mimic neonatal immunity more closely. Such approaches hold promise for generating reproducible and translatable results that bridge the current disconnect between murine models and pediatric myocarditis in clinical practice.
Precision in modeling pediatric myocarditis will also benefit from advances in omics technologies, allowing detailed profiling of viral-host interactions across developmental stages. Integrating transcriptomic, proteomic, and metabolomic datasets will shed light on unique pathogenic signatures and molecular drivers specific to early life viral myocarditis. This systems biology perspective is indispensable for unraveling the complexity of this syndrome and tailoring interventions accordingly.
Likewise, the development of in vitro human pediatric cardiac tissue systems, including organoids and stem cell-derived cardiomyocytes, provides complementary platforms to investigate viral tropism, cytopathicity, and immune response under controlled conditions. Combining these human-specific tools with improved animal models creates a synergistic framework to dissect the multifactorial mechanisms driving pediatric viral myocarditis.
Ultimately, enhancing model fidelity to reflect pediatric disease intricacies will accelerate vaccine and antiviral drug development targeted to the viruses most implicated in childhood myocarditis. Furthermore, it enables exploration of immunomodulatory strategies that consider the immature immune milieu, aiming to mitigate myocardial inflammation without impairing essential viral clearance in young patients.
The imperative to resolve these challenges is underscored by the clinical burden of pediatric myocarditis. This condition can culminate in acute heart failure, the need for mechanical circulatory support, or even cardiac transplantation in severe cases. Early and accurate modeling not only informs pathophysiological insights but could revolutionize diagnostic markers and therapeutic approaches, substantially improving prognosis and quality of life for affected children.
In conclusion, while foundational experimental mouse models have propelled understanding of viral myocarditis, their limitations in replicating pediatric disease are increasingly evident. The confluence of age-specific viral pathogens, developmental immunology, and cardiac physiology demands bespoke pediatric models. Addressing this crucial gap represents a pivotal frontier in cardiovascular research, promising to unlock targeted, effective treatments for the youngest myocarditis patients and fundamentally alter their clinical trajectory.
Subject of Research: Pediatric viral myocarditis, experimental models, mechanisms, and translational research challenges
Article Title: Pediatric viral myocarditis: mechanisms, experimental models, and research gaps
Article References:
Ling, I., Aponte Alburquerque, R.A. & Steed, A.L. Pediatric viral myocarditis: mechanisms, experimental models, and research gaps. Pediatr Res (2026). https://doi.org/10.1038/s41390-026-04845-4
Image Credits: AI Generated
DOI: 10.1038/s41390-026-04845-4
Keywords: Pediatric myocarditis, viral myocarditis, Coxsackievirus B3, mouse models, pediatric immunology, cardiac development, virus-host interactions, immune responses, experimental models, translational research
