Determinants of extracellular matrix remodelling are differentially expressed in paediatric and adult dilated cardiomyopathy

Abstract

Aims: The left ventricular phenotype of idiopathic dilated cardiomyopathy (DCM) can appear similar in paediatric and adult patients. However, the aetiology of paediatric DCM is usually idiopathic, and often leads an aggressive clinical course. A structural underpinning of DCM is extracellular matrix changes, which are determined by a balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). This study tested the hypothesis that different MMP/TIMP profiles occur in paediatric and adult DCM patients.

Methods and results: Left ventricular samples from paediatric (age 9 ± 5 years; n = 10) and adult (age 62 ± 3 years; n = 20) DCM (at time of transplant) were subjected to an MMP/TIMP multiplex array and immunoassay in order to measure the MMP subclasses; collagenases (MMP-8, -13), gelatinases (MMP-2, -9), stromelysin/matrilysin (MMP-3, -7), membrane type (MT1-MMP), as well as for the four known TIMPs. MMP-8 and -9 levels increased by over 150% (P < 0.05), whereas MMP-3 and -7 levels decreased by over 30% (P < 0.05) in paediatric DCM when compared with adult DCM. TIMP-1 and -2 levels increased two-fold (P < 0.05), but TIMP-3 fell by 41% (P < 0.05) in paediatric DCM. Myocardial levels of specific interleukins (IL-1beta, IL-2, IL-8) were increased by approximately 50% in paediatric DCM.

Conclusions: These unique findings demonstrated that a specific MMP/TIMP profile occurs in paediatric DCM when compared with adult DCM, and that local cytokine induction may contribute to this process. These distinct differences in the determinants of myocardial matrix structure and function may contribute to the natural history of DCM in children.

Figure 1

Immunoblotting of myocardial MMP-13, -7, and MT1-MMP was performed from left ventricular myocardial samples from adult and paediatric idiopathic dilated cardiomyopathy. MMP-7 abundance was lower in the paediatric group, and the quantitative results are summarized in Table 1.

Figure 2

Left ventricular myocardial levels of the interleukins, IL-1b, IL-2, IL-6, and IL-8 were quantified by high sensitivity multiplex suspension array in both adult and paediatric dilated cardiomyopathy (DCM) samples. Detectable levels were obtained in both sample sets, but IL-1b, IL-2, and IL-8 were significantly increased in paediatric DCM. The distribution of absolute values, in femtograms/mg wet weight of myocardium (fg/mg) is shown along with the mean and standard error of the mean (SEM). *P < 0.05 vs. adult DCM.