Anne-Marie Koop

8 297 with worse functional status and decreased one-year survival rates. 47 Experimental studies showed that upregulation of adrenomedullin inhibited cardiac hypertrophy by the regulation of cardiac growth as an autocrine or a paracrine factor. 48 Infusion of adrenomedullin as therapy in rats with PH lowered vascular resistance in the lung and heart via nitric oxide generation in the vasculature. 49 Based on these finding, one may speculate that MR-proADM in children with RVH is upregulated to counteract hypertrophy on cardiac and pulmonary level. MPO is known to be released into the extracellular fluid during inflammatory activity and oxidative stress and is involved in the pathogenesis of several major chronic diseases including rheumatoid arthritis, liver diseases, diabetes, cancer and also cardiovascular diseases. 50 Elevated plasma levels of MPO have been shown to predict the development of congestive heart failure, the need for heart transplantation or mortality in a variety of pathologic conditions. 51–53 In children with uncorrected TOF, myocardial fibrosis has been described already at a young age (mean (SD) age 0.7±0.2 years). 54 In the current study, the increased plasma MPO plasma levels in the children with RVH are in line with the occurrence of oxidative stress and subsequent fibrosis early in experimental RV pressure overload in rats subjected to pulmonary artery banding. 45,46,55 Galectin-3 has been reported extensively as a biomarker in heart failure to be involved in cell adhesion, inflammation and tissue fibrosis. 56–60 In the current study galectin-3 plasma levels however did not correlate with increased RV pressure overload nor with RV remodelling. GDF-15 also has a role in metabolism, inflammation and fibrosis. In acquired heart disease serum levels of GDF-15 are used in risk stratification and prognostic utility for atrial fibrillation, 61 myocardial infarction, 62 and heart failure. 63,64 In patients with CHD GDF-15 has been positively related to NYHA class, 64,65 and in those with a Fontan circulation, GDF-15 has shown to be an earlymarker of decreased heart function and to predict hospitalization and death. 38 In the current study in children with different abnormal loading conditions of the RV, GDF-15 correlated with the severity of RV pressure overload and RVH a potential role for GDF-15 in the characterization of early RV disease in children with preserved functional status. Whereas other plasma levels of the studied biomarkers increased or remained stable, neprilysin showed decreasing trends in pressure, volume and combined overload, among the different degrees of overload. Neprilysin is known to be activated to counteract in the vasoconstriction and sodium retention cascade activated by the RAAS and the sympathetic nervous system, by the degradation of natriuretic peptides and vasoactive compounds. Recently published data showed that patients with heart failure with preserved ejection fraction (HFpEF) had lower neprilysin levels compared to controls, 66 while increased plasma levels of neprilysin are associated with heart failure in patients with reduced ejection fraction (HFrEF) and with increased mortality. 67 Combing these data with the current findings may suggest that the phenotype of the majority of the included children is comparable to these of patients with HFpEF.