Fibrosis and Fibrotic Gene Expression in Pediatric and Adult Patients With Idiopathic Dilated Cardiomyopathy

Abstract

Background While fibrosis seems to be prognostic for adverse outcomes in adults with idiopathic dilated cardiomyopathy (IDC), little is known about the prevalence and development of fibrosis in pediatric IDC hearts. We hypothesize there is less activation of fibrosis at a molecular level in pediatric IDC hearts than in the failing adult heart. Methods and Results Pediatric hearts were analyzed histologically to determine the prevalence of fibrosis. Left ventricular tissue from adult and pediatric IDC hearts and adult and pediatric non-failing (NF) hearts were subjected to qRT-PCR to study the expression of important mRNAs that affect fibrosis. We found age-specific differences between IDC and NF hearts in regulation of non-coding galectin 3, Corin, MMP-2, MMP-9, TIMP-2, and TIMP-3. We also found markers that were similarly altered in both adult and pediatric IDC (ST2L, TIMP-1, and TIMP-4). Finally, microRNAs 29a-c were significantly decreased in the pediatric IDC patients. Conclusion Pediatric IDC patients demonstrate age-specific differences in the molecular pathways implicated in fibrosis in the adult heart. At the ultrastructural level the unique gene expression pattern appears to limit fibrosis in the failing pediatric heart.

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).…”

Fibrosis-Related Gene Expression in Single Ventricle Heart Disease

“…Interestingly, the down-regulation of TIMPs 1, 3 and 4 in Stage III is similar to what has previously been described in ischemic cardiomyopathy 33 as well as adult idiopathic dilated cardiomyopathy 26 although increases in TIMPs 1–4 have also been described in adult dilated cardiomyopathy 29 . TIMPs are potent reversible inhibitors of activated MMPs and may have additional MMP-independent pro-fibrotic activity 34 .…”

“…Given the significant inverse correlation between Col1α and Col3 expression and age in this cohort (Figure 2), higher Col1α and Col3 gene expression in the SV-NF group may be a physiological process that contributes to a developmental accumulation of functional collagen similar to what has been previously described in animal models 17, 18 . Lastly, an attenuated fibrotic response has been demonstrated specifically in young rats 25 and in pediatric patients with dilated cardiomyopathy 26 , suggesting that age and duration of disease also influence fibrosis development. Although we cannot determine whether collagen downregulation is pathologic in SV based on our current associative data, our results do support the conclusion that RV failure can occur independently from histologic fibrosis and pro-fibrotic gene expression, the latter of which also varies with age in young SV patients.…”

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

“…Basing pediatric HF treatment guidelines on data from adults with HF does not take into consideration the possibility of age-related intrinsic differences in biologic factors driving the disease process. We have previously shown that myocellular characteristics of pediatric DCM patients are different than their adult counterparts, including pediatric-specific downregulation of the β 2 -adrenergic receptor (4), an age-specific miRNA expression profile (5), lack of interstitial fibrosis (8), and a unique molecular response to phosphodiesterase 3 inhibitor therapy (6). These results suggest an age-or development-dependent molecular profile in pediatric DCM patients, warranting an investigation of changes in gene expression specific to the pediatric DCM population.…”

“…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.…”