Le ventricule droit (VD) possède une embryogénèse, une géométrie et despropriétés biomécaniques différentes du ventricule gauche (VG). L’infundibulum pulmonaire(RVOT) est une origine fréquente d’arythmies dans le VD sain ou pathologique. La tétralogiede Fallot (TOF) est la cardiopathie congénitale cyanogène la plus fréquente et est associée àune dysfonction du VD. Si la correction chirurgicale a augmenté l’espérance de vie despatients TOF, à l’âge adulte les séquelles chirurgicales du VD et RVOT conduisent souvent àune insuffisance cardiaque, des arythmies voire la mort subite cardiaque. Les objectifs decette thèse sont de : (i) définir les propriétés électrophysiologiques et structurelles du VDsain chez le cochon et (ii) caractériser le remodelage arythmogène des ventricules dans unmodèle porcin de réparation de TOF (rTOF). Nous avons démontré la présence d’unehétérogénéité de repolarisation et de conduction dans le VD sain en lien avec un profild’expression spécifique des canaux ioniques dans le RVOT sub-épicardique. Une approchehistologique a également permis de mettre en évidence une structure tissulaire spécifique auRVOT contribuant au ralentissement de l’activation de cette région. Les coeurs des cochonsrTOF témoignent d’un remodelage électrophysiologique et structurel pro-arythmique du VDcaractérisé par une dispersion de la repolarisation, et un ralentissement de la conductioncorrélé à un remodelage moléculaire et structurel. Nous décrivons également la présenced’un remodelage arythmogène distinct dans le VG rTOF sur le plan électrique et structurelsans modification des propriétés hémodynamiques. En conclusion, ces travaux révèlent laprésence de substrats arythmogènes du VD sain et un profond remodelage pro-arythmiquedans les ventricules rTOF. / The right ventricle (RV) has different embryologic history, geometry andbiomechanics properties compared to the left ventricle (LV). The right ventricular outflow tract(RVOT) is a common arrhythmia origin in the healthy or pathological RV. Tetralogy of Fallot(TOF) is the most frequent cyanotic congenital heart disease and is associated with RVdysfunction. Surgical correction has significantly increased patient’s life expectancy butsurgical lesions often lead to heart failure, arrhythmias even sudden cardiac death inadulthood. The aims of this work are to: (i) define RVOT electrophysiological and structuralproperties in the healthy pig and (ii) characterize a potential arrhythmogenic remodeling inboth ventricles in a porcine model mimicking repaired TOF (rTOF). We showed the presenceof repolarization and conduction heterogeneities in the healthy RV in relation to a specific ionchannel expression profile in the RVOT epicardium. Moreover, an histological approachhighlighted the presence of a specific tissue structure likely to contribute to the slowconduction observed in this region. A pro-arrhythmic electrophysiological and structuralremodeling was found in the RV of rTOF pigs. This remodeling was characterized by anincreased dispersion of repolarization and slower conduction properties which were linked toa molecular and structural remodeling. Interestingly, we also described a distinct electricaland structural arrhythmogenic remodeling in the rTOF LV in the absence of hemodynamicalteration. To conclude, this work revealed the presence of an arrhythmogenic substratewithin the healthy RV and a profound arrhythmogenic remodeling of both ventricles in rTOF.

Die Fallot-Tetralogie ist ein angeborener Herzfehler, der sich aus der Kombination von vier verschiedenen anatomischen Fehlbildungen zusammensetzt. In der Diagnostik kommen bevorzugt die Echokardiografie und die Magnetresonztomografie (MRT) zum Einsatz. Die MRT stellt dabei bei der Erfassung volumetrischer Parameter, insbesondere beim echokardiographisch nicht immer vollständig einsehbaren rechten Ventrikel, den Goldstandard dar. Zudem bietet die MRT die Möglichkeit der Gewebecharakterisierung, inklusive der Darstellung von myokardialer Fibrose. In dieser Studie wurden 67 Patienten nach korrigierter Fallot-Tetralogie mittels MRT untersucht. Dabei lag der Schwerpunkt auf der Visualisierung und Quantifizierung der myokardialen Fibrose mittels Delayed Enhancement-Technik in beiden Ventrikeln. Ziel war es, die Prädilektionsstellen von Delayed Enhancement nach Korrektur einer Fallot-Tetralogie zu beschreiben und seine Beziehung zum Auftreten von ventrikulären Arrhythmien und weiteren kardialen und anamnestischen Parametern zu ermitteln. Es stellte sich heraus, dass Delayed Enhancement bevorzugt im rechten Ventrikel zu finden ist. Es konnte kein Zusammenhang mit dem Auftreten ventrikulärer Arrhythmien, zum Patientenalter während der Korrektur-Operation sowie zu volumetrischen- und Ergometriedaten hergestellt werden. Das Auftreten ventrikulärer Arrhythmien war jedoch signifikant abhängig sowohl vom Patientenalter zum Zeitpunkt der Korrektur-Operation als auch vom Patientenalter zum Zeitpunkt der MRT-Untersuchung.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

An abnormal chronotropic response to exercise is a common finding following surgical repair of tetralogy of Fallot (TOF) which has generally been attributed to a putative sympathetic dysfunction. There exists little information on sympathetic function in patients operated for a congenital heart defect to support such a claim. This study used spectral analysis of heart rate (HRV) and blood pressure (BPV) variability to examine sympathovagal influences on the sinus node in 9 adolescents operated for TOF 13.0 +/- 1.12 years previously and in 8 healthy age and sex-matched control (CTRL) subjects. Continuous ECG and BP recordings were obtained under supine or seated resting positions, with or without controlled respiration at 0.20 Hz (CR); after passive 85° head-up tilt (HUT); during cycling at steady-state heart rates of 100 and 120 bpm (Ex 100, Ex 120), and after 10 and 20 minutes of passive seated recovery. (Abstract shortened by UMI.)

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect and infants with TOF incur significant right ventricular(RV) dysfunction due to perioperative injury. Insulin has been shown to reduce perioperative myocardial injury and significantly improve postoperative cardiac function. However, studies are limited to the adult population and the effects in a pediatric heart with a CHD are unknown. To the best of our knowledge, this is the first randomized, double blind, placebo-controlled clinical study designed to investigate insulin’s potential cardioprotective effects postoperatively and mechanisms of action during pediatric cardiac surgery. Thirty infants with TOF were equally randomly allocated to receive either standard cardioplegia (SC) or 10UI insulin-enhanced (IC). Expression profiles of surgery were generated from biopsies extracted from the right ventricular outflow tract (end ischemia and five minutes of reperfusion) and hybridized to Affymetrix HG-U133A GeneChips. Gene expression profiles were generated using two softwares, ArrayAssist V2.6 (paired t-test) and affylmGUI (ANOVA). Survival rate was 100%. Compared to patients in the SC group, patients in the IC group demonstrated a trend toward a 1.8 fold decrease (p = .06) in reperfusion duration (61.93 ± 61.12 vs. 35.20 ± 23.16 hrs., respectively), a significant 2-fold decrease in the length of ICU stay (p = .04) (4.2 ± 3.9 vs. 2.3 ± 1.1 days, respectively) and a trend toward a 2.5 fold decrease in intubation duration (p= .06) (2.5± 12.2 vs. 55.0 ± 67 hrs., respectively). Patients in the IC group also demonstrated significantly lower inotropic scores, calculated at 12-hour intervals across a 48-hour ICU period, (ANOVA p = .01) and significantly greater urine volume, by 71%, (p = .02). IC evoked a cardioprotective gene expression profile aimed at mitigating perioperative myocardial injury, specifically; apoptosis, inflammation, cardiac hypertrophy, arrythmias and fibrosis. The improved postoperative outcome and cardioprotective gene expression signature with IC suggests that, administration of insulin during cardiac surgery in infants with TOF may prevent cardiac dysfunction as a result of mitigating perioperative myocardial injury. Overall, this exploratory study demonstrated insulin-enhanced cardioplegia to be a potential cardioprotective agent during pediatric heart surgery.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart defect and infants with TOF incur significant right ventricular(RV) dysfunction due to perioperative injury. Insulin has been shown to reduce perioperative myocardial injury and significantly improve postoperative cardiac function. However, studies are limited to the adult population and the effects in a pediatric heart with a CHD are unknown. To the best of our knowledge, this is the first randomized, double blind, placebo-controlled clinical study designed to investigate insulin’s potential cardioprotective effects postoperatively and mechanisms of action during pediatric cardiac surgery. Thirty infants with TOF were equally randomly allocated to receive either standard cardioplegia (SC) or 10UI insulin-enhanced (IC). Expression profiles of surgery were generated from biopsies extracted from the right ventricular outflow tract (end ischemia and five minutes of reperfusion) and hybridized to Affymetrix HG-U133A GeneChips. Gene expression profiles were generated using two softwares, ArrayAssist V2.6 (paired t-test) and affylmGUI (ANOVA). Survival rate was 100%. Compared to patients in the SC group, patients in the IC group demonstrated a trend toward a 1.8 fold decrease (p = .06) in reperfusion duration (61.93 ± 61.12 vs. 35.20 ± 23.16 hrs., respectively), a significant 2-fold decrease in the length of ICU stay (p = .04) (4.2 ± 3.9 vs. 2.3 ± 1.1 days, respectively) and a trend toward a 2.5 fold decrease in intubation duration (p= .06) (2.5± 12.2 vs. 55.0 ± 67 hrs., respectively). Patients in the IC group also demonstrated significantly lower inotropic scores, calculated at 12-hour intervals across a 48-hour ICU period, (ANOVA p = .01) and significantly greater urine volume, by 71%, (p = .02). IC evoked a cardioprotective gene expression profile aimed at mitigating perioperative myocardial injury, specifically; apoptosis, inflammation, cardiac hypertrophy, arrythmias and fibrosis. The improved postoperative outcome and cardioprotective gene expression signature with IC suggests that, administration of insulin during cardiac surgery in infants with TOF may prevent cardiac dysfunction as a result of mitigating perioperative myocardial injury. Overall, this exploratory study demonstrated insulin-enhanced cardioplegia to be a potential cardioprotective agent during pediatric heart surgery.

No description available.

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

Proefschrift Universiteit van Amsterdam. / Met samenvatting in het Nederlands.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital cardiac defect with a global annual incidence of 40,000 cases. Advances in surgery and perioperative care led to improvements in perioperative mortality and, thus, a growing number of survivors. TOF survivors often suffer from complications related to a failing right ventricle. Follow-up studies evaluating TOF repair strategies suggest an association between the type of surgical repair strategy and late right ventricular health. However, surgical practices remain unchanged and led by institution-level biases. The body of evidence addressing outcomes based on TOF surgical repair strategy is weak and controversies persists on the management of these patients.  This thesis comprises 6 chapters that form the foundation of a multi-centre research program on outcomes after TOF surgical repair. The program uses various methodologies to generate evidence with a vision to change surgical practices.  Chapter 1 is an introduction providing background on TOF and contemporary areas of controversy.  Chapter 2 presents the results of a retrospective analysis evaluating the use of early echocardiogram parameters in predicting late cardiac magnetic resonance imaging evaluation of the right ventricle.  Chapter 3 presents the results of a retrospective cohort exploring the association between TOF repair strategy and development of right bundle branch block.  Chapter 4 presents the results of a multinational survey aiming to explore contemporary biases in TOF surgical repair strategy selection.  Chapter 5 presents the background, rationale, design and baseline cohort characteristics of the Tetralogy of Fallot for Life (TOF LIFE) study. The study is a multi-centre inception cohort study with a follow-up period of 2 years.  Finally, Chapter 6 discusses the conclusion, limitations, and future implications of this research program. / Thesis / Doctor of Science (PhD)