Tetralogy of Fallot (TOF) is a congenital heart defect which presents soon after birth and is the most common cause of ‘blue baby syndrome’. It is characterised by by subpulmonic stenosis, overriding aorta, a ventricular septal defect and right ventricle (RV) hypertrophy. Early TOF repair now provides affected infants with near-certain post-operative survival and relatively normal development into early adulthood. However, TOF patients approaching adulthood develop pulmonary valve regurgitation, leading to RV volume overload and subsequent complications such as RV dilatation and possible RV failure. For treatment, pulmonary valve replacement (PVR) is required. With infants undergoing TOF repair, gene expression arrays have shown a failure of cardiac development pathways, suppressed expression of genes involved in cardiac contraction, and upregulation of apoptotic regulators[1, 2]. To date there has been no study of the gene expression profile of TOF adults undergoing PVR. Our aim was to utilise a transcriptomic approach to compare RV tissue samples from TOF patients undergoing PVR (n=7) compared with healthy RV from unused donor hearts (n=6), with the goal of understanding potential mechanisms underpinning pathologic changes in the dilated RV myocardium of TOF adults at the time of PVR. All patients gave informed consent for inclusion to the study prior to undergoing PVR and parental consent was gained in the cases where the subject was under 18 years of age. Tissue was obtained during surgery of PVR patients or from the explanted donor hearts and was flash-frozen. mRNA was extracted from the frozen samples and used to perform affymetrix genechip arrays (HTA 2.0 array). Principle component analysis was performed with p-value threshold of <0.004 and false discovery rate (q) of 0.47, which showed segregation of TOF from RV donor clusters, suggesting distinct gene expression profiles. Differential expression of genes revealed ECM remodelling, angiogenesis, cell cycle regulation, apoptosis and development as dominant functional themes. Upregulation of the genes for ECM modifiers lumican (2.16 fold change, p<0.001) and osteoglycin (1.99 fold change, p<0.004), both members of the class II small leucine-rich proteoglycans (SLRPs), suggested a strong ECM component to RV myocardial dysfunction. To investigate the role of the ECM further, Collagen I and III mRNA levels were measured by qPCR and showed no difference between cohorts. Additionally, histological assessment showed no obvious myocardial disorganisation, whilst image quantitation of picrosirius red staining showed no difference in the collagen deposition of PVR myocardium compared to RV donor. We conclude that gene expression changes in patients undergoing PVR indicate a program of tissue repair characterised by subtle ECM modifications. We speculate that qualitative rather than quantitative changes to ECM composition contribute to pathophysiology of RV myocardium in TOF patients undergoing PVR.