No description available.

No description available.

Gain of function of cardiac voltage-gated sodium channel (Nav1.5) leads to Long QT Syndrome Type 3 (LQT3). LQT3 phenotype can be exacerbated by expanding the perinexus, which is an intercellular nanodomain with high density of Nav1.5 in the intercalated disc. Following this finding, we found that elevating extracellular sodium and widening the perinexus synergistically exacerbated LQT3 phenotype, Importantly, we also found that perinexal expansion increases the susceptibility to cardiac arrest in aged LQT3, which demonstrated that perinexal expansion is an arrhythmogenic risk especially in aged LQT3 patients. Furthermore, we observed that the perinexus narrows with aging and conceals LQT3 phenotype, which suggests that perinexal narrowing may have a cardio-protective role during aging in LQT3. Surprisingly, following the finding of the synergistic effect of extracellular sodium elevation and perinexal widening on LQT3 phenotype in drug-induced LQT3 guinea pig hearts, we found that this synergistic effect was not observed in genetically-modified LQT3 mouse hearts, which is due to high sodium also increasing transient outward potassium current (Ito). In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts which functionally express Ito channels. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose. / Doctor of Philosophy / Long QT Syndrome Type 3 (LQT3) is an inherited heart disease with the phenotype of long QT interval in ECG. It has been found that LQT3 phenotype gets worse when a very tiny space in the heart, termed as the perinexus, is wide due to cardiac edema. Following this finding, we also found that increasing sodium concentration together with wide perinexus can further exacerbate LQT3 phenotype in guinea pig hearts. Furthermore, we found that widening the perinexus in aged LQT3 hearts causes cardiac death but not in adult, which suggests that perinexal widening worsens LQT3 phenotype and even leads to cardiac death in aged hearts. Besides, we found that the perinexus narrows with aging and there is no difference in LQT3 phenotype between adult and aged hearts, which suggests that the narrow perinexus during aging may protect the hearts from cardiac death in LQT3. Surprisingly, we discovered that increasing sodium and widening the perinexus together fails to exacerbate LQT3 phenotype when compared with widening the perinexus alone in LQT3 mouse hearts, which is due to high sodium increasing transient outward potassium current (Ito). Notably, Ito channels are not functionally expressed in guinea pig hearts. In summary, the whole project investigated the role of the perinexus in LQT3 from different conditions including sodium, aging and species. The findings in this project discovered the importance of perinexal expansion in LQT3 and also the involvement of Ito in sodium regulating LQT3 phenotype in hearts. Therefore, a LQT3 animal model which has similar electrophysiology close to human may be a great option for translational purpose.

<p dir="ltr">Torsades de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia associated with QT interval prolongation. Female sex and age > 65 years are risk factors for QT prolongation and TdP, possibly due to the effect of sex hormones. Progesterone shortens QT interval, while estrogen lengthens QT interval in females. Preclinical and clinical evidence indicates that progesterone has protective effects against drug-induced QT interval prolongation. J-Tpeak (JTp) and Tpeak-Tend (Tpe) intervals are biomarkers of early and late repolarization. Population pharmacokinetic/pharmacodynamic (PK/PD) models can be used to describe exposure-response relationships and identify sources of variability. In this study, data were pooled from four clinical trials with similar study design investigating the effect of progesterone on ibutilide-induced ventricular repolarization lengthening in healthy premenopausal women during menses or ovulation phase and healthy postmenopausal women. A nonlinear mixed effect model of ibutilide - QTc interval was first developed with preliminary data from 33 subjects. The model was then updated with new data from a total of 52 subjects, assessing the effect of progesterone on drug-induced QTc interval lengthening and identifying sources of variability through covariate analysis. Finally, two PK/PD models of ibutilide - baseline corrected JTpc (ΔJTpc) interval and Tpe (ΔTpe) interval were developed to assess the effect of progestogen on ibutilide-induced early and late repolarization lengthening. Progesterone showed protective effect against ibutilide-induced QTc interval lengthening, mainly through the shortening of pre-ibutilide baseline QTc interval. Body weight, age, race, hypertension, electrocardiogram (ECG) type and estradiol concentration were not significant covariates. Progesterone attenuates ibutilide-induced lengthening of late ventricular repolarization but did not show significant effect on ibutilide-induced early repolarization lengthening. Higher estradiol concentration was related to higher ibutilide-induced early repolarization lengthening. Black race was related to lower ibutilide-induced late repolarization lengthening.</p>

Le cycle régulier des contractions des oreillettes, suivi par des contractions ventriculaires, pompe le sang de manière efficace à travers le coeur. Par contre, lorsque le fin équilibre qui régule le mécanisme est débalancé, les arythmies peuvent s'installer. Parmi les multiples facteurs qui peuvent affecter l'équilibre électrophysiologique cardiaque, il faut noter une maladie métabolique dont la prévalence ne cesse d'augmenter dans la population mondiale : le diabète de type 2. En effet, cette maladie augmente les risques de souffrir d'arythmie. Nous avons d'abord développé un modèle de cobaye diabétique de type 2 par une alimentation avec une diète spéciale sur une période de 200 jours. Ces animaux nous ont permis d'obtenir nos résultats dans des conditions ex- et in-vivo. Par la suite, nous avons évalué une hypothèse selon laquelle, en présence de diabète, l'ajout d'un bloquant d'IcaL évite la prolongation excessive du QT et la pro-arythmie, lorsque d'autres médicaments prolongeant le QT sont utilisés de manière concomitante. Nous avons quantifié l'effet de l'amlodipine (Norvasc®), un médicament bloquant d'IcaL et du dofétilide (Tikosyn®), un médicament bloquant d'iKr- Les résultats obtenus ont montré que l'amlodipine renverse partiellement l'effet pro-arythmique du dofétilide et protège contre la prolongation excessive de l'intervalle QT et la pro-arythmie médicamenteuse, particulièrement en présence de diabète de type 2. En parallèle, nous avons qualifié et quantifié l'effet pro-arythmique du bupropion (Wellbutrin®, Zyban®), un antidépresseur et adjuvant à la cessation tabagique. Des élargissements du QRS avaient été rapportés lors de surdosages de bupropion. Nous avons voulu vérifier l'hypothèse selon laquelle le bupropion affecte la conduction cardiaque par un bloc des jonctions gap. À l'aide des résultats obtenus, nous avons pu dire que, contrairement aux anti-arythmiques de classe I, le bupropion n'élargit pas le QRS en bloquant IN3, mais plutôt en inhibant les jonctions gap. C'est une propriété pharmacologique exceptionnelle observée chez aucun autre médicament actuellement disponible sur le marché. L'élargissement du QRS et les troubles de conduction cardiaques s'observent à des concentrations de bupropion facilement atteignables en clinique.

Thesis (PhD)-- Stellenbosch University, 2014. / ENGLISH ABSTRACT: Ventricular arrhythmias are the most important cause of sudden cardiac death (SCD) among adults living in industrialised nations. Genetic factors have substantial effects in determining population-based risk for SCD and may also account for inter-individual variability in susceptibility. Great progress has been made in identifying genes underlying various Mendelian disorders associated with inherited arrhythmia susceptibility. The most well studied familial arrhythmia syndrome is the congenital long QT syndrome (LQTS) caused by mutations in genes encoding subunits of myocardial ion channels. Not all mutation carriers have equal risk for experiencing the clinical manifestations of disease (i.e. syncope, sudden death). This observation has raised the possibility that additional genetic factors may modify the risk of LQTS manifestations. This study establishes the genetic aetiology of LQTS in South Africa and Denmark through the identification and characterisation of LQTS-causative mutations in five previously identified genes, as well as examining possible novel genetic causes of LQTS in a cohort comprising Danish and British probands. We have functionally characterised several of the mutations identified in this study and examined other cardiac phenotypes that may be explained by variants causing repolarisation disorders. / AFRIKAANSE OPSOMMING: Ventrikulêre aritmie bly die enkele belangrikste oorsaak van skielike hart dood (SCD) onder volwassenes wat in geïndustrialiseerde lande woon. Genetiese faktore het aansienlike gevolge in die bepaling van bevolking-gebaseerde risiko vir SCD en kan ook verantwoordelik wees vir die inter-individuele variasie in vatbaarheid. Groot vordering is gemaak in die identifisering van gene onderliggende verskeie Mendeliese siektes wat verband hou met geërf aritmie vatbaarheid. Die mees goed bestudeerde familie aritmie sindroom is die aangebore lang QT-sindroom (LQTS) wat veroorsaak word deur mutasies in gene kode subeenhede van miokardiale ioonkanale. Nie alle mutasie draers het 'n gelyke risiko vir die ervaring van die kliniese manifestasies van die siekte (dws sinkopee, skielike dood). Hierdie waarneming het die moontlikheid genoem dat genetiese faktore anders as die primêre siekte-verwante mutasie kan die risiko van LQTS manifestasies verander. Hierdie studie stel die genetiese oorsake van LQTS in Suid-Afrika en Denemarke deur die identifisering en karakterisering van LQTS-veroorsakende mutasies in vyf voorheen geïdentifiseer gene, asook die behandeling van moontlike nuwe genetiese oorsake van LQTS in 'n groep wat bestaan uit van die Deense en die Britse probands. Ons het funksioneel gekenmerk verskeie van die mutasies wat in hierdie studie ondersoek en ander kardiovaskulêre fenotipes wat deur variante veroorsaak repolarisasie versteurings verduidelik word. / South African National Research Foundation / Harry and Doris Crossley Foundation / Danish Strategic Research Foundation.

<p>Metadon je sintetski agonist opijatnih receptora koji se primenjuje u sklopu supstitucione terapije opijatnih zavisnika metadonom (STM) i u terapiji hroničnog bola. Dugoročna primena STM je praćena blagim, uglavnom prolaznim, neželjenim delovanjima. Međutim, metadon pripada grupi lekova koji mogu da prouzrokuju prolongaciju korigovanog QT intervala (QTc) u elektrokardiogramu (EKG-u) i povećaju rizik za nastanak potencijalno fatalnih aritmija tipa torsades de pointes. Opijatni zavisnici metadon najče&scaron;će koriste u kombinaciji sa benzodiazepinima, i ova kombinacija lekova predstavlja faktor rizika za nastanak smrtnog ishoda. Iako je najveći broj lekara upoznat sa rizikom za razvoj respiratorne depresije prilikom primene opijata u kombinacji sa benzodiazepinima, velika studija otkriva da su ventrikularne aritmije i srčani zastoj najče&scaron;će prijavljivana neželjena delovanja metadona, primenjenog u kombinaciji sa benzodiazepinima. Ciljevi ovoga radu su da se analizom smrtnih slučajeva povezanih sa upotrebom metadona (MRDs) tokom desetogodi&scaron;njeg perioda na teritoriji Vojvodine i sprovođenjem kliničkog ispitivanja kod opijatnih zavisnika na STM proceni kardiolo&scaron;ka bezbednost primene metadona, posebno u kombinaciji sa benzodiazepinima. Sprovedena je retrospektivna studija za određivanje karakteristika MRDs na teritoriji Vojvodine, kao i kliničko ispitivanje u kome su učestvovali opijatni zavisnici koji počinju sa STM. Snimanje EKG-a (za izračunavanje QTc intervala) i uzorkovanje krvi (za određivanje koncentracije metadona i diazepama i vrednosti troponina) je sprovedeno kod svih učesnika istraživanja u 5 vremenskih tačaka (pre početka primene STM, 8. i 15. dana i nakon 1. i 6. meseca primene STM). Koncentracije metadona i diazepama u serumu su određivane metodom tečne hromatografije sa masenom spektrometrijom (LC-MS). U Vojvodini je zapažena rastuća tendencija MRDs, ali ni jedan od umrlih nije bio na STM, i najverovatnije su samoinicijativno koristili metadon i benzodiazepine. Patohistolo&scaron;ki nalaz na srcu može govoriti u prilog kardiotoksičnosti metadona i njegove kombinacije sa benzodiazepinima, pogotovo kod slučajeva sa pronađenim akutnim miokardijalnim o&scaron;tećenjem. &Scaron;to se tiče hroničnih promena na srcu, ne postoji mogućnosti da se potvrdi niti opovrgne uloga psihostimulanasa. Detektovane koncentracije metadona i diazepama kod MRDs su bile u opsegu terapijskih (&lt;1 &mu;g/ml). Poredeći socio-demografske karakteristike opijatnih zavisnika koji su počeli sa STM u ovom istraživanju sa podacima iz sličnih studija sprovedenih &scaron;irom sveta, zapažena je sličnost u pogledu velikog broja karakteristika. Srednje doze metadona 8., 15. dana i nakon 1. i 6. meseca primene STM su bile 40,23&plusmn;17,11 mg, 47,11&plusmn;16,79 mg, 50,00&plusmn;17,55 mg i 78,63&plusmn;18,14 mg, dok su srednje doze diazepama u istim vremenskim tačkama bile 35,92&plusmn;10,47 mg, 33,89&plusmn;9,23 mg, 28,33&plusmn;11,55 mg i 28,12&plusmn;11,67 mg. Srednje koncentracije metadona su u posmatranim tačkama ispitivanja iznosile 153,44&plusmn;111,51 ng/ml, 157,43&plusmn;112,39 ng/ml, 176,77&plusmn;118,56 ng/ml i 342,86&plusmn;181,54 ng/ml, dok su srednje koncentracije diazepama bile 923,00&plusmn;537,89 ng/ml, 923,76&plusmn;739,96 ng/ml, 560,74&plusmn;436,72 ng/ml i 1045,32&plusmn;932,72 ng/ml. Dužina QTc intervala pre primene STM je bila 411,87&plusmn;27,22 ms, tj. 414,64&plusmn;29,38 ms 8. dana STM, 416,97&plusmn;26,39 15. dana, i 425,20&plusmn;17,71 ms nakon 1. meseca tj. 423,50&plusmn;14,72 ms nakon 6. meseca primene STM. Pokazan je statistički značajan porast dužine QTc intervala nakon 1. i nakon 6. meseca primene STM u odnosu na vrednost pre primene STM, kako u grupi svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Pokazano je postojanje statistički značajne korelacije između koncentracije metadona i dužine QTc intervala nakon 15. dana, 1. i 6. meseca primene STM, kako kod svih ispitanika, tako i u podgrupi mu&scaron;kog pola. Ova korelacija ostaje statistički značajna i ukoliko se uključe i drugi faktori &ndash; koncentracija diazepama i dužina perioda upotrebe heroina, kod svih ispitanika i u podgrupi mu&scaron;kog pola nakon 15 dana i mesec dana primene STM, kao i u podgrupi mu&scaron;kog pola nakon 6. meseca STM. Iako nijedan pacijent nije prijavio neko neželjeno delovanje metadona na nivou kardiovaskularnog sistema, najveći broj pacijenata oba pola se nakon prvog meseca primene STM žalio na pojačano znojenje i opstipaciju. Koncentracije metadona i diazepama u uzorcima krvi kod MRDs se nalaze u rasponu koncentracija ovih lekova u krvi ispitanika koji su učestvovali u prospektivnoj studiji. Trećina umrlih je imala samo znake akutnog o&scaron;tećenja srca, dok do porasta troponina i vrednosti QTc intervala preko 500 ms nije do&scaron;lo ni kod jednog ispitanika iz prospektivne studije. Potrebno je sprovesti dalja istraživanja sa ciljem razja&scaron;njenja moguće uloge benzodiazepina u povećanju kardiotoksičnosti metadona kod opijatnih zavisnika na STM.</p> / <p>Methadone is a synthetic agonist of opioid receptors which is used in methadone maintenance tratment (MMT) of opiate addicts as well as in the treatment of chronic pain. A long-term use of MMT is followed by mild, mostly transient, adverse effects. However, methadone belongs to a group of medicines which can provoke a prolongation of QTc (corrected QT) interval in electrocardiogram (ECG) and thus increase the risk from the development of potentially fatal arrhythmias &ndash; torsades de pointes. Moreover, methadone is widely associated with benzodiazepines use in heroin addicts, and this combination is considered as a risk factor for lethal outcome. Despite the fact that most of health care professionals are aware of possible respiratory depressant effect of methadone and benzodiazepines co-administration, recently published data reveal that ventricular arrhythmia and cardiac arrest are currently the most frequent adverse event attributed to methadone and benzodiazepine co-medication. The aim of this study is to assess cardiac safety of methadone use, especially in combination with benzodiazepines, by analyzing characteristics of methadone-related deaths (MRDs) during 10-year period as well as by conducting a clinical trial among opiate addicts in MMT. A retrospective study to determine the characteristics of MRDs in Vojvodina, as well as a clinical trial in which participated opiate addicts at the start of MMT were performed. ECG (to calculate QTc interval) and blood sampling (to determine methadone and diazepam concentrations and troponin values) were performed in all study participants at five time points (before the introduction of MMT, on 8th, on 15th day, after 1 and 6 months of MMT). Methadone and diazepam concentrations in serum were determined by using liquid chromatography-mass spectrometry (LC-MS). An increasing tendency of MRDs was observed in the region of Vojvodina, but none of the victims were under healthcare professionals&rsquo; control, and, most commonly, they used methadone and benzodiazepines, on their own initiative. Pathohistological findings in the heart in MRDs might support cardiac adverse effects of methadone and its combination with benzodiazepines, especially in cases with acute myocardial damage. As for the chronic heart changes, we can neither confirm nor exclude the role of psychostimulants. Detected concentrations of methadone and diazepam were in therapeutic range (&lt;1 &mu;g/ml). Comparing socio-demographic characteristics of opiate addicts who started with MMT in this study with data from similar studies conducted worldwide, the similarity in terms of large number of features was observed. The mean methadone dose on the 8th, 15th days, and after 1 and 6 months of MMT was 40.23&plusmn;17.11 mg, 47.11&plusmn;16.79 mg, 50.00&plusmn;17.55 mg and 78.63&plusmn;18.14 mg, respectively, while the mean diazepam dose at the same time points was 35.92&plusmn;10.47 mg, 33.89&plusmn;9.23 mg, 28.33&plusmn;11.55 mg and 28.12&plusmn;11.67 mg, respectively. The mean methadone concentration at observed time points was 153.44&plusmn;111.51 ng/ml, 157.43&plusmn;112.39 ng/ml, 176.77&plusmn;118.56 ng/ml and 342.86&plusmn;181.54 ng/ml, respectively, while the mean diazepam concentration was 923.00&plusmn;537.89 ng/ml, 923.76&plusmn;739.96 ng/ml, 560.74&plusmn;436.72 ng/ml and 1045.32&plusmn;932.72 ng/ml, respectively. The length of QTc interval before the introduction of MMT was 411.87&plusmn;27.22 ms, 414.64&plusmn;29.38 ms on the 8th day of MMT, 416.97&plusmn;26.39 on the 15th day of MMT, after 1 month of MMT 425.20&plusmn;17.71 ms and after 6 months of MMT 423.50&plusmn;14.72 ms. There was a statistically significant increase in the length of QTc interval after 1 and 6 months of MMT in comparison to the value before the application of MMT, within the whole group of patients and in the subgroup of men. A statistically significant correlation between the concentration of methadone and QTc interval length after 15 days, 1 and 6 months of MMT, both in the whole group and in the subroup of men was observed. The correlation remained statistically significant if the other factors, such as concentration of diazepam and the length of heroin use, were included, in all patients and in the subgroup of men after 15 days and one month of MMT as well as in the subgroup of men after 6 months of MMT. Although none of the patients reported any cardiac adverse effect of methadone, the majority of them complained of sweating and constipation after the first month of MMT. Concentrations of methadone and diazepam in blood samples in MRDs were within the range of concentrations of these drugs in blood of patients who participated in the prospective study. In one third of MRDs only signs of acute myocardial damage were detected, while an increase in troponin values and the length of QTc interval over 500 ms did not occur in any patient in the prospective study. Further studies could clarify the possible role of benzodiazepines in the increasing cardiotoxicity of methadone in opiate addicts in MMT.</p>

La prolongation de l’intervalle électrocardiographique QT est un facteur de risque d’arythmie ventriculaire et de mort subite. Cette anomalie, retrouvée chez certains patients atteints de lupus érythémateux disséminé, pourrait contribuer à la mortalité cardiovasculaire élevée dans cette population. L’anti-Ro/SSA, un auto-anticorps retrouvé chez environ 30% des patients atteints de lupus, est associé à la présence de blocs cardiaques chez le nouveau-né et pourrait aussi augmenter le risque de prolongation pathologique de l’intervalle QT chez l’adulte. Le présent mémoire est constitué de cinq chapitres traitant de l’association potentielle entre l’anticorps anti-Ro/SSA et la prolongation de l’intervalle QT. Le premier chapitre constitue une introduction permettant de mettre en contexte les éléments essentiels à la compréhension du projet d’étude. Le deuxième chapitre constitue une revue de l’état des connaissances actuelles sur le lien potentiel entre anti-Ro/SSA et intervalle QT. Le troisième chapitre présente le projet d’étude par l’intermédiaire d’un article publié dans Arthritis Care and Research. Dans cette étude, les patients de la cohorte de lupiques du Centre Universitaire de santé McGill ont subi des électrocardiogrammes dans l’objectif d’estimer l’association entre l’anti-Ro/SSA et les anomalies électrocardiographiques, en tenant compte d’autres facteurs démographiques et cliniques. L’association entre la prolongation de l’intervalle QT et la présence de l’anti-Ro/SSA a été démontrée (rapports de cotes ajustés de 5.1 à 12.6) et les patients porteurs de l’anti-Ro/SSA pourraient donc bénéficier de dépistage électrocardiographique systématique. Les points faibles et forts de cet article sont discutés dans le quatrième chapitre et des perspectives de recherches futures sont finalement abordées. / QT interval prolongation on the electrocardiogram is a risk factor for ventricular arrhythmias and sudden cardiac death. This abnormality is found in patients with systemic lupus erythematosus and could contribute to the high cardiovascular mortality rate in this population. Anti-Ro/SSA is an auto-antibody presents in about 30% of lupus patients and is associated with congenital cardiac block. This auto-antibody could also increase the risk of pathologic prolongation of the QT interval in adults. This master’s thesis is comprised of five chapters discussing the potential association between anti-Ro/SSA antibody and QT interval prolongation. The first chapter is an introduction to the essential elements for the understanding of the study project. The second chapter is a literature review of the potential link between anti-Ro/SSA and QT interval prolongation. The third chapter presents the study project through an article published in Arthritis Care and Research. In this study, patients from the McGill lupus cohort were invited to undergo electrocardiograms in order to estimate the association between anti-Ro/SSA antibody and electrocardiographic abnormalities, while taking into account the other potentially associated demographic and clinical factors. This study shows an association between anti-Ro/SSA and prolonged QT interval (Odds ratios: 5.1 to 12.6) and patients positive for anti-Ro/SSA may thus benefit from electrocardiographic testing. Strengths and weaknesses of this article are discussed in the fourth chapter and future research areas are finally explored.

Bien que le changement dans le choix des substrats énergétiques des acides gras (AGs) vers les glucides soit considéré comme bénéfique pour le cœur insuffisant, il n’est pas clair à savoir pourquoi les patients atteints de désordres de la β-oxydation (β-OX) des AGs à chaîne longue (AGCLs) développent des troubles du rythme et des cardiomyopathies. De plus, le traitement actuel ne permet pas de prévenir l’apparition du phénotype clinique chez tous les patients, spécifiquement en condition de jeûne ou de stress. Ainsi, plusieurs modèles de souris déficientes pour des enzymes impliquées dans l’oxydation des acides gras ont été développés de manière à améliorer les connaissances de la maladie ainsi que les traitements offerts aux patients. À cet égard, cette étude vise à évaluer le phénotype métabolique et fonctionnel des cœurs de souris déficientes pour le récepteur activé de la prolifération des peroxysomes-α (PPARα), un facteur de transcription des gènes impliqués notamment dans la β-OX des AGs, et pour la déshydrogénase des acyl-CoA à très longue chaîne (very-long chain acyl-CoA dehydrogenase, VLCAD), le déficit de l’oxydation des AGCLs le plus commun chez l’humain. L’approche expérimentale utilisée comprend plusieurs techniques dont (i) la perfusion ex vivo de cœur de souris au travail combinée à l’utilisation de substrats marqués au carbone 13 (13C) et à l’analyse par chromatographie gazeuse-spectrométrie de masse (GCMS), (ii) l’analyse de l’expression génique par qPCR et (iii) l’analyse de l’activité électrique du cœur in vivo par télémétrie. De manière inattendue, les résultats de cette étude menée chez la souris ont permis de mettre en évidence que des déficits pour des protéines impliquées dans l’oxydation des AGCLs sont associés à des altérations du métabolisme (i) des glucides, (ii) des AGs polyinsaturés (AGPIs), et (iii) mitochondrial, incluant l’anaplérose, en plus d’être liés à des désordres de la fonction électrique du cœur, à savoir une prolongation du segment QTc. Pris dans leur ensemble, les résultats de cette thèse pourraient servir à l’élaboration de nouvelles interventions métaboliques destinées à améliorer les traitements possibles et donc, la qualité de vie des patients atteints de désordres héréditaires de la β-OX des AGCLs. / While a shift from fatty acids to carbohydrate is considered beneficial for the failing heart, it is unclear why patients with fatty acid oxidation disorders present clinical manifestations such as cardiomyopathy, arrhythmia and conduction defects. Unfortunately, the current nutritional treatment for these patients is limited in its ability to prevent these symptoms, especially under fasting and stress conditions. Many mouse models of fatty acid oxidation deficiency have been developed to improve the knowledge of the disease and the treatment of these patients. In this regard, this study aims to characterize the metabolic and functional phenotype of hearts from mice that are deficient for the peroxisome proliferator-activated receptor α, a transcription factor for gene involved in fatty acid oxidation, and very long chain acyl-CoA dehydrogenase, the most common inherited long chain fatty acid oxidation disorder in human, under various conditions. In this study, numerous approaches have been used, which includes validated experimental paradigms, namely, (i) ex vivo heart perfusion in the working mode with concomitant evaluation of myocardial contractility and metabolic fluxes, employing 13C-labeled substrates combined with mass isotopomer analysis by gas chromatography coupled to mass spectrometry, (ii) gene expression analysis by qPCR and (iii) electrocardiogram monitoring in vivo by telemetry. Unexpectedly, results from the present thesis demonstrate that fatty acid oxidation disorders cause alterations in metabolism of (i) carbohydrates (ii) polyunsaturated fatty acids of the omega-3 type, specifically docosahaexanoic acid, and (iii) mitochondria including anaplerosis, in addition to lead to functional abnormalities, namely a prolongation of the QT interval. Altogether, results from this thesis could contribute to new metabolic therapy development to improve the quality of life of the patients with inherited long chain fatty acid oxidation disorder.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.