Regional changes in cellular and molecular pathology in children with end-stage dilated cardiomyopathy: Correlation with regional and global cardiac performance

Background Paediatric dilated cardiomyopathy (DCM) carries a poor prognosis. We previously identified regional heterogeneity and patterns of left ventricular (LV) dysfunction that correlated with outcomes. In this project, we aimed to describe associations of regional myocardial performance with fibrosis and molecular signalling. Methods We prospectively studied children undergoing heart transplantation for DCM. Pre-transplant clinical and echocardiographic features were correlated with regional histological and molecular findings from explanted hearts. Ten LV and one right ventricular (RV) regions were assessed for fibrosis, myocyte area, and protein expression related to hypertrophy and fibrosis signalling (p38, ERK, phospho-JNK, phospho-GSK3β, SMA, cadherin, ILK), contractile function (myosin heavy chain), and calcium handling (SERCA2a, phospho-CamKII, phospholamban [PLN], and phospho-PLN). Results Eight children were included [median age 2.0years (0.3–15.1years)], of whom six required mechanical circulatory support. There was no difference in fibrosis burden or myocyte area between LV segments, and between ventricles. LV dimensions, ejection fraction and diastolic parameters were not related to fibrosis, myocyte area or molecular signalling. Tricuspid annular systolic plane excursion was related to myocyte volume (r=0.89, p<0.01). There was an inverse relationship between fibrosis and segmental longitudinal strain for LV basal and mid-posterior segments (basal posterior, r=0.96, p<0.01; mid-posterior, r=0.74, p=0.05). Global longitudinal strain was related to expression of ILK (r=0.78, p=0.02) and SERCA2a (r=0.71, p=0.04). Conclusion In paediatric end-stage DCM, regional cardiac function is associated with interstitial fibrosis and expression of calcium-cycling and contractile proteins. Phenotypic and molecular expression is variable. The RV shows similar injury and protein expression to the LV despite better myocardial function. These findings suggest that even with severely reduced LV function, paediatric DCM is a highly heterogeneous disease involving both ventricles.