Tetralogy of Fallot (TOF) is the most common type of cyanotic congenital heart disease. After surgical repair, residual pulmonary regurgitation (PR) is common. Long-term quality of life is limited by the effects of PR, which include an increased risk of heart failure from right ventricular (RV) dilatation. The course of development towards pathological RV dilatation has been poorly characterised. Risk factors are not well defined, myocardial remodelling pathways in RV overload have hardly been studied in patients, and indices predictive of RV dysfunction are lacking. This hampers clinical decision making. In LV disease, neurohormonal and inflammatory markers have contributed to risk stratification in patients. Recently, high density protein arrays have been helpful to identify biomarkers of ventricular remodeling. Hypothesis: In patients who have undergone surgical repair of TOF a.) activation of myocardial extracellular matrix degrading, growth related, and pro-inflammatory pathways contribute to RV remodeling and to deterioration of RV function and clinical state, and b.) activation of pathways associated with adverse RV myocardial remodeling may be assessed in blood using antibody-arrays. Aims of the study: In patients who have undergone surgical repair of TOF, we aim to 1) assess the development of RV dimensions and function in relation to clinical outcome, in a time dependent manner 2) identify, characterize and quantify markers in blood samples, using high density antibody arrays and ELISAs , obtained from Fallot patients at different stages of the development of RV overload and hypertrophy, 3) correlate circulating levels of identified markers with cardiac and systemic parameters, and to identify (a) potential biomarker(s) as a diagnostic and prognostic tool(s). Methods: Data obtained in recent years by contributing centres in TOFpatients on medical history, clinical status, RV volumes, wall mass and ejection fraction (MRI data), ECG, exercise performance and blood markers of ventricular remodeling will provide the baseline measurements for the current study. At these baseline measurements, patients had an age range of 7 - 48 years and a postoperative follow-up duration of 7 - 26 years. In the current project 120 TOF patients will again be studied, obtaining data with similar tests, at a minimum period of 5 years from the baseline measurements. MRI will be used to quantify PR and ventricular volumes, ejection fraction and wall mass. In blood renin, norepinephrine, endothelin-1, (n-)atrial- and (NT-pro-) brain natriuretic peptide, tumor necrosis factor-alpha and interleukin-6 will be assessed. In subgroups of patients, differing in time of follow-up and amount of pulmonary regurgitation, custom made protein-arrays will be used to assess blood markers of ventricular remodeling. The difference between the results from the current study and baseline measurements will allow evaluation of RV size and function over time, and identification of clinical characteristics and specific blood bio-markers that are associated with a decline in RV function over time. Expected results: After this study has been completed, we will have gained insight into 1.) the course of development of RV dilatation and subsequent changes in cardiac function and 2.) the relation between changes in RV dimensions and serum biomarkers. This will contribute to improved early diagnosis of patients at risk for developing RV failure. Objectives In patients who have undergone surgical repair of tetralogy of Fallot, we aim to 1) assess the development of RV dimensions and function in relation to clinical outcome, in a time dependent manner 2) identify, characterize and quantify markers in blood samples, using high density antibody arrays and ELISAs , obtained from Fallot patients at different stages of the development of RV overload and hypertrophy, 3) correlate circulating levels of identified markers with cardiac and systemic parameters, and to identify (a) potential biomarker(s) as a diagnostic and prognostic tool(s). Relevance for cardiovascular diseases Tetralogy of Fallot is the most common type of congenital heart disease (at present 13 % of all patients included in the national CONCOR database have this lesion). Most patients require surgical repair, which can be performed with low operative mortality (< 5 %). Therefore, the population of adults with tetralogy is growing. However, residual lesions, mainly pulmonary regurgitation, are inevitable in the large majority of patients. From the time of correction in (early) childhood, these patients are at increased risks of heart failure, resulting from poor right ventricular function. Clear guidelines for medical and/or surgical therapy, aimed at prevention of heart failure in this group, are lacking. Understanding of underlying meachanisms is limited. The current proposal aims to improve the basis for such guidelines, which may be of benefit to a significant number of patients with cardiovascular disease in the Netherlands.