Beta-adrenergic adaptation in paediatric idiopathic dilated cardiomyopathy

Abstract

There is a different adaptation of β-AR and adrenergic signalling pathways in children with HF compared with adults. Our results begin to address the disparities in cardiovascular research specific to children and suggest that age-related differences in adaptation could influence the response to therapy. These findings could lead to a paradigm shift in the contemporary management of children with HF.

Pediatric and adult dilated cardiomyopathy represent distinct pathological entities

“…Our data provides a mechanistic rationale for why children do not respond to adult heart failure therapeutics and strongly suggest that prognostic and therapeutics strategies routinely used in adults may have limited clinical utility in the pediatric population. These results are consistent with prior studies showing that hallmarks of adverse remodeling, including β-adrenergic receptor downregulation, fetal gene expression, and fibrosis, occur to a lesser extent in pediatric DCM (10,38). In addition, the lack of myocardial fibrosis in pediatric patients with DCM may provide an explanation as to why sudden death is more prevalent in adult compared with pediatric DCM patients (39).…”

“…Pathways upregulated in adult DCM included those associated with oxidative reduction, fatty acid metabolism, response to endogenous stimuli and organic substances, and inflammatory/wounding responses. While differences in substrate utilization and β-adrenergic signaling have been previously described in pediatric and adult heart failure (10,33,34), distinctions in inflammation have yet to be explored. Among the genes associated with inflammation, numerous proinflammatory chemokines, cytokines, danger signals, key signal transduction components, and transcription factors were selectively upregulated in adult DCM ( Figure 6E and Supplemental Table 1).…”

“…hypothesis, some hallmarks of adverse remodeling including β-adrenergic receptor downregulation, and upregulation of fetal gene expression appears to occur to a lesser extent in pediatric compared with adult heart failure specimens (10). Intriguingly, no studies have rigorously determined whether adverse remodeling occurs in children or deciphered at what age adverse remodeling occurs in adults.…”

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

“…Therefore, there is a clear need for new approaches to better understand this disease process. Our work has shown differences in the molecular characteristics of pediatric and adult DCM hearts (4)(5)(6)(7)(8). These differences suggest that there are underlying myocardial cellular mechanisms uniquely regulated in children with HF.…”

“…When expression of genes related to pluripotency and proliferation was analyzed in adult DCM patients, WNT9A, DDX17, and JAK2 were the only genes dysregulated in the adult population ( Figure 5). Atrial natriuretic factor (ANF) was included as a control, since it has been previously shown to be upregulated in pediatric and adult DCM patients (4).…”