Malignant ventricular arrhythmias are a common cause of sudden cardiac death. Moderate therapeutic hypothermia (MTH) is routinely used in post-resuscitation care for anticipated neuroprotective effects. However, the safety of MTH in terms of the electrical stability of the heart has not been satisfactorily proved yet. Also, the increased sympathetic tone in patients with heart failure contributes to a higher incidence of malignant ventricular arrhythmias. The aim of this work was to verify the safety of MTH as regards the inducibility of ventricular fibrillation (VF) in the pig biomodel, especially in relation to spontaneous changes in the kalemia and QT interval. Furthermore, we assumed that renal denervation (RDN) could reduce the inducibility of VF. In the first part of the thesis, the extracorporeal cooling was introduced in fully anesthetized swine (n = 6) to provide MTH. Inducibility of VF was studied by programmed ventricular stimulation (8 basic stimuli with up to 4 extrastimuli) three times in each biomodel under the following conditions: during normothermia (NT), after reaching the core temperature 32 řC (HT) and after another 60 minutes of stable hypothermia (HT60). VF inducibility, effective ventricular refractory period (ERP), QTc interval, and potassium plasma level were measured. In...

This master´s thesis deals with the analysis of experimental telemetrical ECG records with intention to determine the long-term influence of anticancer drug sunitinib on the electrical activity of heart. A laboratory rat was chosen as a model organism for the experimental study carried out at the Department of Physiology at Faculty of Medicine, Masaryk university. The sunitinib was applied to the rats at an early age and the ECG was measured with a 20-week delay using the Stellar telemetry system. To measure the effect of sunitinib on the electrical activity of the heart chambers, an analysis of the duration of the RR and QT interval and the width of the QRS complex was chosen. These parameters were detected by the wavelet transform method. Statistical analysis was performed using nonparametric tests - the Wilcoxon signed rank test, the MannWhitney test and the Friedman Test. The obtained results suggest that the use of sunitinib has no long-term effect on the observed parameters for the chosen animal model. After extension of the study, the results obtained could contribute to assess the effect of drugs on electrical activity of the human heart several decades after sunitinib treatment termination.

Background: The sensitivity to drug-induced QT prolongation is highly variable in heart failure (HF) patients. QT interval prolongation can lead to a life-threatening ventricular arrhythmia known as torsade de Pointes (TdP), which can result in sudden cardiac death. Although QT prolongation is a surrogate marker for sudden cardiac death, the extent of drug-induced QT prolongation, and thus TdP, is largely unpredictable. Therefore, developing a biomarker to predict patients’ sensitivity to drug-induced QTc prolongation could have a profound clinical impact. MicroRNA (miR) are recognized as important regulators of cardiovascular function as they shape the transcriptome by targeting mRNAs for repression of translation. Our multidisciplinary research group has demonstrated that miR-362-3p regulates a potassium channel (i.e., hERG) that is the most widely implicated in drug-induced QTc prolongation. The primary objects of this analysis focus on characterizing serum miR-362-3p expression in the circulation as a potential biomarker to predict subject’s susceptibility to ibutilide exposure induced QT-interval prolongation.<div><br></div><div>Methods: The dataset utilized to develop the PK-PD models were collected from a previous clinical study carried out by Tisdale et al. (Tisdale,et al. 2020).A total of 22 adult subjects who met the inclusion and exclusion criteria were enrolled and divided into three groups: a group of patients with heart failure with preserved ejection fraction (HFpEF, n=10), a group of patients with heart failure with reduced ejection fraction (HFrEF, n=2), and ten healthy subjects in the control group who were matched to subjects in the HFpEF group for age and sex. Following a baseline day of triplicate 12-lead ECGs, all subjects received ibutilide 0.003mg/kg intravenously infused over 10 minutes. Serial collection of blood samples to determine serum Ibutilide concentrations (HPLC/MS), serum miR-362-3 expression (qPCR), with triplicate ECG readings were obtained pre-and-post ibutilide administration. To describe ibutilide serum concentration exposure and the9relationship with Fridericia-corrected QT (QTF) intervals, a non-linear mixed effect modeling approach was used along with clinical and demographic data, and serum miR-362-3p expression was evaluated as potential covariates on the PK/PD model.<div><br></div><div>Results: A three-compartment model best described the time course of ibutilide concentrations profile with a proportional residual error. The individual ibutilide concentrations time profile was then used in an indirect response model where ibutilide concentrations are indirectly driving the QT interval prolongation through inhibition of the output (Kout) parameters linked to an indirect response model with zero‐order input parameter best described the ibutilide concentrations QT interval lengthening relationship. The Individual PK/PD parameters using the base model for the Imax and IC50 were 11.4% (9.9%RES) and 0.36(8.4% RES)ng/mL, respectively. Following stepwise forwarding inclusion steps, the final covariate analyses identified circulating miR-362-3p expression associated with a history of myocardial infarction covariate influencing both the Imax and IC50( p<0.05). <div><br></div><div>Conclusions: An indirect response model has been developed to describe the effects of ibutilide concentrations on QT-intervals. Although the semi-mechanistic model could not be developed; serummiR-362-3p expression was identified as a significant predictor for ibutilide-induced QT-interval prolongation. Moreover, the upregulation of serum miR-362-3p expression enhanced IC50 seen after ibutilide administration. The potential use of miR-362-3p as a biomarker warrants further investigation to identify patients at the greatest risk of TdP </div></div></div>

No description available.

Objectives: The inverse relationship between QT interval variability (QTV) and T wave amplitude potentially confounds QT variability assessment. We quantified the influence of the T wave amplitude on QTV in a comprehensive dataset and devised a correction formula. Methods: Three ECG datasets of healthy subjects were analyzed to model the relationship between T wave amplitude and QTV. To derive a generally valid correction formula, linear regression analysis was used. The proposed correction formula was applied to patients enrolled in the Evaluation of Defibrillator in Non-Ischemic Cardiomyopathy Treatment Evaluation trial (DEFINITE) to assess the prognostic significance of QTV for all-cause mortality in patients with non-ischemic dilated cardiomyopathy. Results: A strong inverse relationship between T wave amplitude and QTV was demonstrated, both in healthy subjects (R2 = 0.68, p < 0.001) and DEFINITE patients (R2 = 0.20, p < 0.001). Applying the T wave amplitude correction to QTV achieved 2.5-times better group discrimination between patients enrolled in the DEFINITE study and healthy subjects. Kaplan-Meier estimator analysis showed that T wave amplitude corrected QTVi is inversely related to survival (p < 0.01) and a significant predictor of all-cause mortality. Conclusion: We have proposed a simple correction formula for improved QTV assessment. Using this correction, predictive value of QTV for all-cause mortality in patients with non-ischemic cardiomyopathy has been demonstrated.

<p dir="ltr"><b>Background</b></p><p dir="ltr">Heart failure (HF) is a chronic clinical syndrome characterized by symptoms including breathlessness, fatigue, swelling of the ankles, and signs such as edema pulmonary crackles etc. During HF, pathogenic mechanisms including hemodynamic overload, ventricular remodeling, aberrant calcium handling, excessive neurohormonal stimulation contribute to the worsening and progression of the condition. Ventricular arrhythmias are the common cause of sudden cardiac death (SCD) in HF patients.</p><p dir="ltr">Hyperactivation of the sympathetic nervous system (SNS), a characteristic of HF, causes an increase in circulating catecholamines which becomes detrimental to-adrenergic receptors (-AR) leading to signaling dysfunction, and decrease in contractility and the ionotropic reserve. Expression of calcium/calmodulin-dependent protein kinase II (CaMKII), a downstream effector of-AR and a key regulator of calcium homeostasis, has been shown to be enhanced in HF. CaMKII-mediated mechanisms have been demonstrated to contribute to cardiac remodeling, arrhythmias by pathological regulation of ion channels, and contractile dysfunction.</p><p dir="ltr">The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the voltage-gated potassium channel that conduct the rapid component of the delayed rectifier potassium current, <i>I</i>_Kr. The gating kinetics of <i>I</i>_Krmakes it a crucial determinant of the duration of the plateau phase of atrial and ventricular action potential (AP). Reduced <i>I</i>_Kr density due to loss-of-function mutations or pharmacological blockage of hERG channels precipitate arrhythmias. Downregulation of <i>I</i>_Kr density and protein have been reported in HF. Recent studies suggest that microRNAs (miRNAs) are involved in pathological downregulation of hERG.</p><p dir="ltr">miRNA are small non-coding RNAs of approximately 22 nucleotides in length that function as gene expression regulatory elements by repression translation. Aberrant miRNA expression has associated with cancer, cardiovascular, autoimmune, and inflammatory disorders.</p><p dir="ltr"><b>Objective</b></p><p dir="ltr">The overarching objective of this study is to investigate the mechanisms of CaMKII-mediated regulation of hERG function, including assessment of an interplay with miR-362-3p during sustained β-AR stimulation. In Specific Aim 1, the effect of CaMKII activation through sustained β-AR stimulation on hERG function and miR-362-3p expression will be assessed. The mechanism of miR-362-3p upregulation will be evaluated in Specific Aim 2, and in Specific Aim 3, the interactome of miR-362-3p and binding sites will be characterized and predicted, respectively.</p><p dir="ltr"><b>Methods</b></p><p dir="ltr">Whole-cell, voltage clamp electrophysiology experiments were performed in HEK 293 cells stably expressing hERG (hERG-HEK) and both hERG and wild-type CaMKIIδ<br>(hERG/CaMKII-HEK) following treatment with isoproterenol for 48 hours, and after transfection with miR-362-3p. The effect of CaMKII activation on miR-362-3p was assessed using real-time quantitative polymerase chain reaction (RT-qPCR). Total RNA was isolated 48 hours after isoproterenol treatment and the TaqMan assay was used to reverse transcribe and analyze miR-362-3p expression. Cells were transfected with cJun siRNA and precursor miR-362-3p to assess the role of cJun miR-362-3p upregulation during sustained β-AR stimulation with isoproterenol. The interactome of miR-362-3p was assessed in both cell lines using enhanced crosslinking immunoprecipitation (eCLIP) assay. miR-362-3p binding sites were predicted using RNAStructure Duplexfold after identification of miR-362-3p chimeric molecules from eCLIP experiment. Interaction analysis was performed using GeneMania in Cytoscape to identify genes that were potentially downregulated by miR-362-3p and been reported to interact with hERG.</p><p dir="ltr"><b>Results</b></p><p dir="ltr">In Specific Aim 1, the effect of sustained β-AR stimulation on hERG currents and endogenous miR-362-3p was assessed in hERG-HEK and hERG/CaMKII-HEK cells. Using whole-cell voltage clamp electrophysiology, we demonstrated that 48 hours treatment with 100 nM isoproterenol reduced hERG currents in hERG/CaMKII-HEK cells (p = 0.032) but had no effect on the voltage dependence of activation (p = 0.61) relative to control vehicle. Isoproterenol treatment for 48 hours, however, had no effect on hERG currents (p = 0.58) and the voltage dependence of activation (p = 0.99) in hERG-HEK cells. The effect of sustained isoproterenol treatment on miR-362-3p was also assessed using RT-qPCR. In hERG/CaMKII cells, 48 hours isoproterenol treatment increased miR-362-3p expression (2.3 folds; p = 0.038) relative to control vehicle. hERG/CaMKII-HEK cells were also treated with 500 nM KN-93 or its inactive analogue, KN-92, in an attempt to reverse CaMKII effect on miR-362-3p expression. Treatment with KN-93 decreased miR-362-3p expression (0.5-fold; p = 0.002) relative KN-92 treatment. Isoproterenol treatment had no effect on miR-362-3p expression in hERG-HEK cells (p = 0.38).</p><p dir="ltr">The regulatory mechanism of miR-362-3p expression was evaluated in Specific Aim 2. The role of an activator protein-1 (AP-1)-like sequence located at 98 base pairs upstream of miR-362-3p transcription start site was probed using siRNA inhibition of cJun, a central protein of the AP-1 complex, and deletion of the site sequence. The effect of exogenous miR-362-3p on hERG currents were first assessed. Precursor miR-362-3p decreased hERG currents (p = 0.003) compared to control plasmid. The effect of CaMKII overexpression was also assessed on exogenous miR-363-3p expression. Isoproterenol treatment in hERG/CaMKII-HEK cells transfected with precursor miR-362-3p increased mature miR-362-3p expression (0.029) compared to control vehicle treatment. Inhibition of cJun inhibition with cJun-specific siRNA decreased mature miR-362-3p expression (0.5-fold; p = 0.027) compared to scramble siRNA in hERG-HEK cells. In hERG-HEK cells transfected with mutated precursor miR-362-3p (AP-1-like site deleted), cJun inhibition with siRNA had no effect on miR-362-3p expression (p = 0.40).</p><p dir="ltr">The focus of Specific Aim 3 was to characterize the interactome of miR-362-3p as well as predict the miRNA response element (MRE) of its target mRNAs using enhanced crosslinking immunoprecipitation. A network analysis was also performed to identify miR-362-3p targets that have been reported to interact with hERG. Approximately 23% of miR-362-3p mRNA targets from the eCLIP assay have also been catalogued in miRNA database, TargetScanHuman, as miR-362-3p targets. miR-362-3p chimeric molecules with 853 unique targets, of which 75 were identified to interact with hERG through the network analysis. Four unique chimeric molecules between miR-362-3p and hERG mRNA were identified, but the interactions were non-canonical (located in the coding sequence of hERG and outside the seed region of miR-362-3p). Thirty five of the 75 miR-362-3p targets that were identified to interact had a chimeric read ≥ 3, a cutoff number indicating non-random chimeric formation. Using RNAStructure DuplexFold, miR-362-3p was predicted to form canonical binding with 12 of 35 mRNA targets. HSPA4, a heat shock protein involved in the maturation and trafficking of hERG, was identified in a canonical interaction (8-mer) with miR-362-3p.</p><p dir="ltr"><b>Conclusion</b>:</p><p dir="ltr">Sustained β-AR stimulation increases miR-362-3p expression and decreases hERG currents in CaMKII overexpressing cells. cJun mediates miR-362-3p upregulation by interacting with an AP-1-like sequence upstream of miR-362-3p transcription start site. Pathological regulation of <i>I</i>_Kr by CaMKII mediated by miR-362-3p during sustained-AR may contribute to increased risk of arrhythmias in states of increase catecholaminergic activity, such as HF.</p>

<p>  </p> <p><strong>Background: </strong></p> <p>Torsades de pointes (TdP) is a polymorphic ventricular tachycardia (VT) associated with heart rate-corrected QT interval (QTc) prolongation on the electrocardiogram (ECG). TdP can cause sudden cardiac arrest (SCA), a catastrophic outcome. The antiarrhythmic drugs dofetilide and sotalol can cause QTc prolongation and arrhythmias, as can more than 200 other medications available on global markets. Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced TdP, and HFrEF heightens sensitivity to drug-induced QTc lengthening. However, ~55% of patients with HF have preserved, rather than reduced, ejection fraction. It remains unknown whether patients with HF with preserved ejection fraction (HFpEF) are at increased risk for drug-induced VT/SCA. Assessment of the risk of drug-induced VT/SCA in HFpEF patients is important, so that recommendations can be made regarding the safety of QTc-prolonging drugs and need for enhanced ECG monitoring in this population. </p> <p><strong>Objective:</strong></p> <p>In aim 1, we sought to determine the risk of VT and SCA associated with dofetilide and sotalol in patients with HFpEF. In aim 2, we were able to use QTc interval to determine the odds of dofetilide/sotalol-associated QT interval prolongation in patients with HFpEF. In Aim 3, we investigated the influence of HFpEF on VT and SCA associated with a broader group of drugs known to cause TdP (“known “TdP drugs”), as designated by the QT drugs list at www.crediblemeds.org. </p> <p><strong>Methods:</strong></p> <p>In aim 1, we used Medicare claims (2014-2016) and ICD-9/10 codes to identify patients taking the QT interval-prolonging drugs dofetilide or sotalol, which are used commonly in patients with HF and atrial fibrillation, as well as non-dofetilide or sotalol users among 3 groups: HFpEF, HFrEF, and no HF. Multinomial propensity score-matching was performed. Cochran–Mantel–Haenszel statistics and standardized differences were used to compare baseline characteristics. A generalized Cox proportional hazards model was used to estimate hazard ratios (HRs) and test the association of VT and SCA among dofetilide/sotalol users, HFpEF, HFrEF, and no HF.</p> <p>In Aim 2, the data source was electronic health records from the Indiana Network for Patient Care (February 2010 to May 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, absence of QT interval records, and no validated record of using dofetilide or sotalol, we identified patients taking dofetilide or sotalol among three groups: HFrEF, HFpEF, and no HF. Cochran–Mantel–Haenszel statistics were used to compare baseline characteristics. QT interval prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) of QT interval prolongation were determined by univariate analysis, and adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates.</p> <p>In aim 3, we used Medicare enrollment in fee-for-service medical and pharmacy benefits (2014 to 2016) and ICD-9/10 codes, we identified patients taking drugs known to cause torsades de pointes (TdP drugs; www.crediblemeds.org) and non-TdP drug users among three groups: HFrEF, HFpEF, and no HF. Multinomial propensity score-matching was performed to minimize baseline differences in covariates (patient demographics, comorbidities, health care utilization and drug history). Cochran–Mantel–Haenszel statistics and standardized differences were used to compare baseline characteristics. A generalized Cox proportional hazards model was used to estimate HRs and test the association of VT and SCA among TdP drug users with HFpEF, HFrEF, and no HF.</p> <p><strong>Results:</strong></p> <p>In Aim 1, VT and SCA occurred in 166 (10.68%) and 16 (1.03%), respectively, of 1,554 dofetilide/sotalol users with HFpEF, 543 (38.76%) and 40 (2.86%) of 1,401 dofetilide/sotalol users with HFrEF, and 245 (5.06%) and 13 (0.27%) of 4,839 dofetilide/sotalol users with no HF. The adjusted HR for VT in patients with HFrEF was 7.00 (95% CI 6.12-8.02) and in patients with HFpEF was 1.99 (1.71-2.32). The risk of VT associated with dofetilide/sotalol was increased across the overall study population (HR: 2.47 [1.89-3.23]). Use of dofetilide/sotalol increased the risk of VT in patients with HFrEF (HR: 1.53 [1.07-2.20]) and in those with HFpEF (HR: 2.34 [1.11-4.95]). However, while the overall risk of SCA was increased in patients with HFrEF (HR: 5.19 [4.10-6.57]) and HFpEF (HR: 2.53 [1.98-3.23]) compared to patients with no HF, dofetilide/sotalol use was not significantly associated with an increased risk of SCA.</p> <p>In Aim 2, QTc prolongation associated with dofetilide/sotalol occurred in 51.2% of patients with HFpEF, 70.1% of patients with HFrEF, and 29.4% of patients with no HF. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of having QTc interval larger than 500ms during the hospital stay were 5.23 [3.15-8.67] for HFrEF and 1.98 [1.17-3.33] for HFpEF with no HF as the reference group. </p> <p>In Aim 3, of 23,910 known TdP drug users with HFrEF, VT and SCA occurred in 4,263 (17.8%) and 493 (2.1%) patients, respectively. In comparison, among 31,359 known TdP drug users with HFpEF, VT and SCA occurred in 1,570 (5.0%) and 340 (1.1%) patients. VT and SCA occurred in 3,154 (0.8%) and 528 (0.1%) of 384,824 known TdP drug users without HF. The overall HR of both VT and SCA was increased in patients with HFrEF (HR: 7.18 [6.13-8.40])  and in those with HFpEF (HR: 2.09 [1.80-2.42]). The risk of VT associated with known TdP drugs was increased across the overall population (HR: 1.34 [1.20-1.51]). Use of known TdP drugs significantly increased the risk of VT and SCA in patients with HFrEF (HR: 1.34 [1.07-1.67]), but not in patients with HFpEF.</p> <p><strong>Conclusion:</strong></p> <p>HFpEF may exhibit an enhanced response to drug-associated VT, and is associated with a higher risk of drug-associated QTc interval prolongation. Further study is needed to identify methods to minimize this risk for patients with HFpEF requiring therapy with dofetilide, sotalol, or drugs known to cause TdP. </p>

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.

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.