Each year in the United Kingdom, approximately 250 babies are born with tetralogy of Fallot (TO F); a serious form of cyanotic congenital heart disease that is usually fatal if left untreated. Fortunately, as the result of pioneering work in the 1940s and 50s, the vast majority of infants born with this condition today survive corrective surgery and reach adulthood with a near normal quality of life. However, surgical repair of TOF is not a cure. A patient's residual anatomical, physiological and electrical abnormalities progress with time, causing vulnerability to late complications such as exercise intolerance, arrhythmia, heart failure and sudden cardiac death. The importance of a slowly evolving postoperative pathophysiology in patients with TOF was only recognised in the 1980s and 90s, as the patients who underwent the earliest repairs reached mid-adulthood. Since that time surgical strategies and techniques have changed and it remains unclear whether children who underwent TOF repair in the past two decades will have similar late outcomes to the adults repaired decades earlier. This thesis details an investigation of children during the early years after TOF repair. Two separate, but interlinked prospective studies were conducted, seeking early evidence of post-surgical pathophysiology that is now well recognised in adult patients. The first study looked for early indicators of biventricular compromise and the other for mechanistic connections that might lie behind between pathophysiological associations well documented in adults with repaired TOF. Children with TOF and age and sex- matched healthy controls were carefully studied by echocardiogram at rest and during exercise. Children with TOF were also studied by MRI and underwent cardiopulmonary exercise studies. The results of these investigations show that even while they remain asymptomatic, children with repaired TOF exhibit clear signs of biventricular compromise, electrical disturbance and mechanical dyssynchrony and that exercise both provokes and augments these abnormalities. The work described in this thesis suggests a new hypothesis to explain the intimate connection between mechanical and electrical disturbance after TOF repair. In addition, the early hallmarks of ventricular compromise identified by these investigations may make useful a contribution to the long-term follow- up and clinical management of these patients.

Εισαγωγή: Οι υπερκοιλιακές ταχυκαρδίες (ΥΤ) αποτελούν σημαντική αιτία νοσηρότητας στα παιδιά. Λόγω της χρονιότητας των συμπτωμάτων, η αντιαρρυθμική φαρμακευτική αγωγή δεν είναι ιδεώδης λύση. Η κατάλυση με ρεύμα ραδιοσυχνότητας (ΡΡ) μπορεί να προσφέρει ριζική θεραπεία. Στόχος: Η μελέτη αυτή είχε ως στόχο την ανάλυση των αποτελεσμάτων κατάλυσης υπερκοιλιακής ταχυκαρδίας (ΥΤ) στα παιδιά με ρεύμα ραδιοσυχνότητας (ΡΡ). Μεθοδολογία: Εξετάσαμε αναδρομικά τα στοιχεία 140 παιδιών ηλικίας 4-18 (12,8±3,5) ετών με ΥΤ που υπεβλήθησαν σε πλήρη ηλεκτροφυσιολογικό έλεγχο και κατάλυση με ΡΡ, είτε υπό γενική αναισθησία (84), είτε υπό καταστολή (56). Αποτελέσματα: Η τελική επιτυχία της κατάλυσης με ΡΡ μετά από τυχόν υποτροπές, ήταν 90/94 (95,7%) για ασθενείς (Α) με παραπληρωματικά δεμάτια (ΠΔ), 36/37 (97,3%) για Α με κομβική ταχυκαρδία επανεισόδου (ΚΤΕ), 10/10 για Α με έκτοπη κολπική ταχυκαρδία (ΕΚΤ), 3/3 για Α με κολπική ταχυκαρδία επανεισόδου και 1/1 για Α έκτοπη κομβική ταχυκαρδία. Σε Α με πρόσθια/διάμεσα διαφραγματικά ΠΔ παρατηρήθηκε υψηλότερος χρόνος ακτινοσκόπησης (p=0,05) και χαμηλότερη τελική επιτυχία (p=0,02). Οι υπόλοιπες κατηγορίες είχαν παρόμοια μεταξύ τους αποτελέσματα. Τα δεξιά πλάγια ΠΔ είχαν υψηλότερο ποσοστό συγγενών καρδιοπαθειών (p<0,001). Οι υποτροπές ήταν συχνότερες σε Α με πολλαπλά ΠΔ (p=0,007). Το ποσοστό μόνιμων σοβαρών επιπλοκών ήταν 1,4% (1 Α με ανεπάρκεια αορτής μετά από κατάλυση αριστερού ΠΔ με διαορτική τεχνική και 1 Α με πλήρη κολποκοιλιακό αποκλεισμό μετά από κατάλυση ΚΤΕ). Η τελική επιτυχία της επέμβασης, και τα ποσοστά υποτροπών και επιπλοκών ήταν ανεξάρτητα της ηλικίας. Συμπεράσματα: Η κατάλυση με ΡΡ μπορεί να αποτελέσει ριζική θεραπεία των ΥΤ στα παιδιά, χωρίς διαφορές στα αποτελέσματα σε ηλικίες >4 ετών. / Background: Supraventricular tachycardia (SVT) represents a significant cause of morbidity in children. Because of the chronic course, long-term treatment with antiarrythmic drugs is not an ideal solution. Radiofrequency ablation (RFA) may offer curative treatment. Purpose: The purpose of this study was to analyze the outcome of radiofrequency ablation (RFA) of supraventricular tachycardia (SVT) in children. Methodology: We reviewed retrospectively the charts of 140 patients (pts) 4-18 (12,8±3,5) years of age, who underwent complete electrophysiologic study and RFA., either under general anesthesia (84), or conscious sedation (56). Results: The final success of RFA, after possible recurrences, was 90/94 (95,7%) for pts with accessory pathways (AP), 36/37 (97,3%) for pts with AV nodal reentry tachycardia (AVNRT), 10/10 for pts with ectopic atrial tachycardia, 3/3 for pts with atrial reentry tachycardia, and 1/1 for a pt with junctional ectopic tachycardia. Longer fluoroscopy time (p=0,05) and lower final success (p=0,02) was observed in pts with anterior/mid-septal AP. The remaining categories had comparable results. Patients with right lateral AP had a higher prevalence of congenital heart disease (p<0,001). Recurrences were more frequent in pts with multiple AP (p=0,007). The incidence of severe permanent complications was 1,4% (1 pt with aortic insufficiency after retrograde RFA of left lateral AP, and 1 pt with complete AV block after RFA of AVNRT). The final success, recurrence rates and complication rates were independent of age. Conclusions: Treatment of SVT in children with RFA may offer permanent cure, without differences in outcomes in pts older than 4 years of age.

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Cardiovascular disease is one of the largest killers in the UK representing 30% of all global deaths. The underlying processes of the disease are thought to begin in childhood. Whilst traditional risk factors of CV disease (e.g. hypertension, hyperlipidemia, obesity, smoking, stress and sedentary lifestyles) are becoming increasingly prevalent within the younger generation there remains the need for the establishment of earlier or "pre-clinical" markers of future CV disease risk or current atherosclerotic load such as left ventricular (LV) mass, diastolic function and carotid intima-media thickness( cIMT). Further, assessing the association of these markers to other risk factors and then determining the impact of physical activity (PA) interventions is warranted. Initially we assessed the impact of body composition, PA and cardiorespiratory (CR) fitness upon left ventricular LV mass, carotid-intima media thickness (cIMT) and LV diastolic function in 218 9-11 year old primary schoolchildren. Pubertal status was assessed through a maturity offset calculation. LV mass, cIMT, and LV diastolic function were assessed via ultrasound. Body mass index was assessed via anthropometry whilst fat mass [FM] and lean mass [LM] were determined via dual X-ray absorptiometry. Average 3-day PA was recorded via a uni-axial accelerometer and CR (VO₂peak) was determined from a graded treadmill test. Relationships were analysed using bivariate correlations and forced entry multiple regression. All children were classified as being below their peak height velocity. Together LM, FM, sex and moderate to vigorous (MV)PA accounted for 59% of the variance in LV mass with LM being the most important predictor (P<0.005). Sex, LM, FM and VO₂peak explained only 19% variance in cIMT and just 9% of the variance in LV diastolic function was accounted for by LM, FM blood pressure and sex. Data for MVPA had no significant relationship to any cardiovascular (CV) variables although was negatively correlated with FM. The strong association between LV mass and body composition likely represents normal growth. The limited shared variance between predictor variables and cIMT and LV diastolic function suggests that those pre-peak height velocity children in the current cohort who were overweight, inactive and unfit were not yet at an increased CV disease risk. Thus there is a window of opportunity for intervention programmes to be implemented that reduce CV disease risk before adolescence and adulthood. Following this, an exploratory trial was conducted to introduce the use of PA interventions in pre-pubertal children. Sixty-one 10-11 year old Liverpool primary school children volunteered and were randomly assigned by school to a STEX programme (2 x 60 min sessions per week at a heart rate of ~145 beats min⁻¹), a PASS programme (weekly physical activity tasks and pedometer challenges) and a control (CON; no intervention). Pre-clinical CV measures and body composition were measured before and after the 9-week intervention period. The primary outcome variable was cIMT, with LV mass, LV diastolic function, and body composition defined as secondary outcomes. Delta (Δ) scores were analysed by ANCOVA, with baseline scores as the covariate. For the primary outcome, the probability that the population effect of the intervention is at least as great as the pre-specified minimum clinically importance difference (MCID) was estimated, to evaluate clinical relevance. All participants met 75% compliance criteria for STEX and PASS. The effect of the STEX intervention (compared with CON) was a mean benefit of -0.018mm for average maximum cIMT (90% CI, -0.039 to 0.002mm), and -0.016mm for average mean cIMT (90 % CI, -0.040 to 0.008mm). The probability (% chances) that the true population effect of the STEX intervention would be clinically beneficial was 79% for average maximum and 71% for average mean cIMT. The PASS intervention did not result in clinically important effects, and no other substantial changes were observed for the secondary outcome variables. The relatively high probability of clinically beneficial effects of the STEX intervention suggests that a larger, "definitive" randomised trial with longer follow-up is warranted to define the effectiveness of the intervention more precisely. As a consequence the longer PA intervention study observed 152 children aged 9 to 10 years over 12 months. All of the echocardiographic, body composition, CR fitness and PA variables mentioned were assessed as previously discussed. Children were randomly assigned by school to an intervention group. Control (no intervention), PASS (as before except delivered during school hours to enhance compliance), high intensity physical activity (the same as STEX but renamed due to the addition of another structured exercise group) or fundamental movement skill ([FMS] 2x 60 min sessions per week of skill based activities). These interventions took place over a year period with participants being assessed at baseline, approximately mid-way through and post-test (52 weeks). Initial factorial ANOVA analysis comparing all 3 intervention groups and a control group before, during and after the 12 month intervention period, found limited statistically significant evidence for a positive impact of PA interventions compared to controls in pre-pubertal children. However, after adjusting for confounding variables in an ANCOVA analysis some sporadic benefits of PA interventions on CV variables were uncovered. An increase in LV mass over 12 months, after adjustment, was lower in the HIPA group compared to CON group (11.5 g; 90% CI, 2.0 to 21.0 g). This change was also lower in the FMS group compared to CON group (13.8 g; 90% CI, 4.6 to 23.1 g). The ANCOVA adjusted change scores for both mean and max cIMT were less in the intervention groups compared to CON group but only in the PASS group were these differences significant (P<0.05). PASS increased its mean cIMT (-0.014mm less than control (90% CI, -0.002 to -0.030)). Somewhat surprisingly the intervention programmes had no positive effect on CR fitness (indeed this decreased), PA measures and/or body composition over and above changes observed due to growth. This thesis has provided a unique insight into the 'pre-clinical' CV disease risk factors in pre-pubertal children and the impact of differing PA activity interventions with this group. Interestingly the research has shown that within this population overweight/obese, inactive low CR fit individuals are generally not at a higher CV disease risk than their aged matched 'healthier' counterparts. When PA interventions are introduced in the short term positive changes in cIMT were seen, however, this is not reciprocated in longer PA interventions possibly due to a larger maturation effect over 12 months. Interestingly year long interventions provide some attenuation of growth-related changes in CV disease risk factors but these changes are generally small and sporadic. It is suggested that further research over a longer period of time with more 'at risk' populations is needed. The PA interventions adopted achieved high attendance and compliance records and thus may be transferable out of the research process. It is interesting to also speculate that future research may not need to administer high impact activity, as previously thought, as some positive data was obtained in more general lifestyle interventions involving more knowledge transfer.

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