The role of Midkine in Children with Dilated Cardiomyopathy

Abstract

Introduction: While current medical therapies benefit adult heart failure (HF) patients, these therapies do not confer the same improvement in survival in children with HF. This difference suggests that the underlying cellular mechanisms in failing myocytes are uniquely regulated. We have found that serum circulating factors are important in cardiomyocyte remodelling in pediatric patients with Dilated Cardiomyopathy (DCM). In our preliminary results, we identified a specific heparin-binding growth factor, midkine (MDK), which is highly upregulated in the serum of pediatric DCM patients. The objective of this study is to investigate the relation between serum MDK levels and clinical outcome, and to define the effect of MDK in modulating pathologic responses. Methods and results: Our current serum bank contains 5 non-failing (NF) and 44 DCM samples from individual patients. The level of serum (circulating) MDK was determined in the banked serum from pediatric DCM patients by ELISA, and correlated with the patient’s clinical outcome. Our results show that MDK levels in serum was elevated in pediatric DCM patients who died or were transplanted in comparison with pediatric DCM patients who are clinically stable. The contribution of serum MDK to primary cardiomyocytes was investigated by treating neonatal rat ventricular myocytes (NRVMs) with human recombinant MDK for 72 hours. Our results show an increase in the expression of genes associated with pathologic remodelling in MDK-treated NRVMs. In addition, there is an increase in cell area and ANF expression in MDK-treated NRVMs compared to NF serum-treated cells. In our unique mouse model of pediatric cardiac pathologic growth (isoproterenol infusion –30mg/kg/day), MDK treatment (3mg/kg/week) resulted in increased heart/body weight. Conclusions: Our results suggest that MDK is detrimental to cardiac function. This finding combined with increased circulating MDK in end-stage pediatric DCM patients, suggests an important regulatory role for MDK in pediatric HF.