Introduction: Robust epidemiological data on the incidence of myocardial infarction (MI) are hard to find, but synthesis of data from a number of sources indicates that the average hospital in the UK should admit about two patients with a first MI and one recurrent MI per 1000 population per year. Although age-adjusted incidence may be declining, this may be offset by greater longevity in the general population. The incidence of acute coronary syndromes (ACS) is much higher. The incidence and outcome of both ACS and of MI will depend greatly on how data are collected. The cumulative incidence, persistence and resolution of heart failure (HF) after an MI in the general population are poorly described. Cardiac dysfunction subsequent to MI is a common cause for morbidity and mortality, however, there are few data on what proportion of longterm survivors of MI has important cardiac dysfunction and/or HF. The aim of this thesis is to describe the incidence and outcome of MI in the general population and in different age groups, explain the natural history and prognosis of HF after an MI both during the index admission and long-term (6 year) follow-up in relationship to the presence of HF and also to determine the utility of amino-terminal pro-brain natriuretic peptide (NT-proBNP) alone and in conjunction with other clinical data, as a marker of left ventricular systolic dysfunction (LVSD) and subsequent prognosis in long-term survivors of MI. Subgroup data according to age and anaemia will also be reported. Methods: Patients with a death or discharge diagnosis of MI in 1998 were identified from records of hospitals providing services to a local community of 560,000 people. Records were scrutinized to identify the development of HF, defined as symptoms and signs consistent with that diagnosis and treated with loop diuretics. HF was considered to have resolved if diuretics could be stopped without recurrent symptoms. Analyses were done on the whole population and then sub-groups by age (75 years) and anaemia status. Anaemia was defined according to WHO criteria (men haemoglobin (Hb)1 g below threshold), borderline (within 1g of threshold) and (>1g above threshold). In 2004, surviving patients were invited to attend for clinical assessment, an echocardiogram and measurement of NT-proBNP and were subsequently followed until 31st December 2009 using medical records. Also in 2005, another group of patients admitted with ACS to cardiology or general medical wards were identified prospectively by trained nurses from 1st January to 31st December 2005. Patients with a death or discharge code of MI were also identified by the hospital information department and from Myocardial Infarction National Audit Project (MINAP) records. Results: For the first cohort, 896 patients were identified of whom 54% had died by December 2005. During the index admission, 199 (22%) patients died, many with HF, and a further 182 (20%) patients developed HF that persisted until discharge, of whom 121 died subsequent to discharge. Of 74 patients with transient HF that resolved before discharge, 41 had recurrent HF and 38 died during follow-up. After discharge, 145 (33%) patients developed HF for the first time, of whom 76 died during follow-up. Overall, of 281 deaths occurring after discharge, of which 235(84%) were amongst patients who first developed HF. Of 896 patients, 311 were aged 75 years of whom, respectively, 24%, 57% and 82% had died by December 2005. During the index admission, by age group, 24 (8%), 68 (23%) and 107 (37%) patients died in each group, many with HF, and a further 37 (12%), 63 (21%) and 82 (29%) developed HF that persisted until discharge. After discharge, 53 (24%), 55 (40%) and 37 (47%) patients developed HF for the first time. Overall, of 51, 102 and 128 deaths occurring after discharge, 35 (70%), 93 (91%) and 107 (85%) were among patients who first developed HF. Of 855 patients with an available hemoglobin during index admission, 103 were anaemic, 280 were borderline and 472 were not anaemic based on the first available haemoglobin during the index admission. 300 patients had more than one measurement of haemoglobin, of which 125 (85 unchanged status from first assessment) had definite, 289 (237 unchanged) had borderline and 441 (424 unchanged) had no anaemia on the last available measurement. During the index admission, 77 patients (75%) with definite, 130 (46%) with borderline and 196 (42%) who had no anaemia on the first available haemoglobin developed HF, of whom 41 (53%), 50 (38%) and 60 (31%) died during the admission compared, respectively, to 7 (27%), 14 (9%) and 9 (3%) deaths in patients who did not develop HF. During a six year follow-up, 543 (64%) patients developed HF and 456 (53%) died. Amongst patients with HF during the index admission, the six year mortality rates in those with definite, borderline and no anaemia (last available index admission measurement) were, 90%, 84% and 64% (P=0.0001). In patients without HF on the index admission, 6-year mortality rates were 62%, 42% and 24% (P=0.0001). Anaemia (last available index admission measurement) predicted all-cause mortality independent of the presence of HF (p=0.055). 451 had died by 2004 and only 414 were available for follow-up, of whom 175 patients attended and had NT-proBNP measured. Of these, 51 (29%) patients had LVSD, 66 (38%) had NT-proBNP >50pmol/L (423pg/ml), 86 (49%) had one or the other and 31 (18%) had both. Patients with higher NT-proBNP were more likely to have HF (and be treated with diuretics), LVSD (and therefore treatment with ACE inhibitors), a dilated atrium, substantial mitral regurgitation and atrial fibrillation (and therefore treatment with warfarin and digoxin) (p=0.0001). Thirty six patients died during follow-up; 28 (42%) with an NT-proBNP >50pmol/L (423pg/ml) (77% of all deaths). ROC curves suggested that NT-proBNP 56pmol/L (474pg/ml) had the highest sensitivity (78%) and specificity (77%) for predicting death (AUC 0.78). Echocardiography added little to the prognostic information provided by NT-proBNP alone. In 2005, the prospective survey identified 1,731 admissions (1,439 patients) with ACS, of which 764 (704 patients) were for MI. The hospital information department reported only 552 admissions (544 patients) with MI and only 206 admissions (203 patients) were reported to MINAP. Using all three data-bases, 934 admissions (873 patients) for MI were identified, for which TnT was >1ug/L in 443, 0.04 to 1.0 in 435, 0.03ug/L but did not have ACS ascertained by any survey method. Of 873 patients with MI, 146 died during admission (17% versus 22% in the 1998 cohort) and 218 by one year. Conclusion: The incidence of ACS/MI is highly dependent on the methodology for case-ascertainment and the method used to identify cardiac damage (for instance the sensitivity of the troponin assay used). The development of HF precedes death in most patients who die in the short- or longer-term following an MI. The risk of developing HF and dying after an MI increases progressively with age and anaemia. In patients with a remote history of MI, elevated NT-BNP identifies patients with a high prevalence of LVSD. Regardless of age, most deaths are preceded by the development of HF. Anaemia is associated with a high mortality even in the absence of HF. Prevention of HF, by reducing the extent of myocardial damage and recurrent MI and by subsequent good management could have a substantial impact on prognosis.

Aims: The main objective of this research was to determine if Type D personality predicts distress in Heart failure (HF) patients. The study also sought to examine whether there is a relationship between Type D personality, coping and psychological distress in this cardiac patient group. Method: A cross-sectional, quantitative design was used. 72 (58 %) with HF between September 2005 and March 2006 completed questionnaires in the outpatient clinic of a cardiology department. The DS14 questionnaire was used to measure Type D personality (predictor variable), the Hospital Anxiety and Depression Scale (HADS) measured psychological distress (outcome variable) and the Brief COPE inventory was the measure of coping used (mediator variable) of this HF patient sample. Main analyses: An ANOVA test investigated whether Type D predicted distress. The mediational regression model (National Institute for Clincial Excellence, 1986) was used to analyse the relationships between the three variables. Results: Type D significantly predicted depression (p<O.O 1), even after adjusting for demographical variables however did not predict anxiety. Patients tended to report using a mixture of Engagement and Disengagement Coping Styles. Coping did not act as a mediating variable between Type D personality and depression or anxiety (as measures of psychological distress). However disengagement coping was found to significantly mediate the relationship between the separate subscales of Type D and distress. Conclusion: Early screening of Type D personality may be helpful in identifying HF patients at risk of psychological distress. Increasing awareness of the potential disengaging coping strategies that Type D patients use may determine, not only early intervention, but early screening upon their diagnosis of HF.

Coping is acknowledged to be an important factor in the process of adjustment to illness, and which has consistently been related to outcomes in chronic health conditions such as heart failure (HF). Despite this, to date coping has been poorly conceptualised which has limited the clarity and usefulness of research findings. A systematic review was conducted to examine the relationship between ways of coping, and dimensions of psychological wellbeing as important health outcomes in the HF population. Electronic databases (CINAHL, Medline, PsychINFO, Scopus and Web of Science) were searched and articles selected based on systematic search, inclusion and exclusion criteria. Sixteen studies were included in the review utilising a variety of designs and measures. Study findings suggested that coping by ignoring, minimising or denying HF is related to poorer outcomes of psychological wellbeing. However, more illness focused ways of coping did not consistently relate to better outcomes. Consistent with research in other populations, the conceptualisation of coping in the reviewed studies was inconsistent. It is argued that coping should be considered within a wider framework of transition and adjustment to more meaningfully examine HF patients‟ experience following diagnosis and inform more appropriate psychological support strategies.

Η γκρελίνη είναι ένα ακυλιωμένο πεπτίδιο που κατά κύριο λόγο παράγεται από το στόμαχο και αποτελεί το φυσικό μόριο-αγωνιστή του μέχρι πρόσφατα ορφανού υποδοχέα GHSR-1a (growth hormone secretagogue receptor type 1a).Η γκρελίνη διαθέτει ισχυρή ικανότητα απελευθέρωσης της αυξητικής ορμόνης καθώς επίσης ασκεί πολλαπλές δράσεις στο ΚΝΣ και σε άλλους ιστούς και όργανα που προκαλούν διέγερση της όρεξης, ρύθμιση του ενεργειακού ισοζυγίου, επίδραση στο γαστρεντερικό σύστημα και στην παγκρεατική λειτουργία.Επιπρόσ- θετα διαμεσολαβεί καρδιαγγειακές δράσεις όπως μείωση των περιφερικών αντιστάσεων, αύξηση της καρδιακής παροχής σε υγιή άτομα και σε ασθενείς με καρδιακή ανεπάρκεια,εξα- σθένηση της καρδιακής καχεξίας, αντιαποπτωτική δράση στην καρδιακή ανεπάρκεια και αντιφλεγμονώδη δράση στο σχηματισμό της αθηρωματικής πλάκας. Η παρούσα εργασία,προσδιορίζοντας τα επίπεδα της γκρελίνης σε ασθενείς με οξεία πρωτοεμφανιζόμενη ή απορρύθμιση χρόνιας συστολικής καρδιακής ανεπάρκειας και μετά την συσχέτισή τους με διάφορες κλινικές,αιμοδυναμικές και υπερηχογραφικές παραμέτρους σε μια περίοδο παρακολούθησης 6 μηνών-1 έτους και την εφαρμογή βέλτιστης εξατομικευμένης φαρμακευτικής αγωγής ,κατέληξε στο συμπέρασμα ότι η παρατηρούμενη διαχρονική αύξηση των επιπέδων της γκρελίνης σε συνδυασμό με την βελτίωση των ανωτέρω παραμέτρων προτείνει στην γκρελίνη ρόλο αιτίου ή αποτελέσματος στην πορεία βελτίωσης της καρδιακής ανεπάρκειας. / Ghrelin is an acylated peptide that mainly is produced from the stomach and constitutes the natural molecule-ligand of until recently orphan receptor GHSR-1a(growth hormone secretagogue receptor type 1a).Ghrelin allocates powerful ability of release of the growth hormone and also practices multiple actions in the CNS and in other tissues and organs that cause excitation of apetite, regulation of energy balance, effect in the gastrointestinal system and in function of pancreas.In addition, ghrelin mediates cardiovascular actions as reductions of systemic resistances, increase of cardiac output in healthy individuals and in patients with heart failure, attenuation of cardiac cachexia, inhibition of the apoptosis of myocardial cells in the heart failure and anti-inflammatory action in the progression of atherosclerosis. The present work, determining the levels of ghrelin in patients with acute de novo or decompensation of chronis systolic heart failure and afterwards their cross-correlation with various clinics, haemodynamic, and other parameters of the cardiac ultrasound in a period of follow-up of 6 months-1 year and the application of most optimal individualized pharmaceutical treatment, led to conclusion that the observed diachronic increase of levels of ghrelin in combination with the improvement of above parameters proposes in ghrelin role of reason or result in the course of improvement of heart failure.

Heart failure (HP) is a common, disabling and deadly condition that causes high rates of morbidity and mortality worldwide. It is widely recognised that the failing heart is energy-starved, and that restoring energy homeostasis is a promising approach towards improving cardiac output. This thesis aims to address the role of energetics in the failing heart, by focussing on modulation of the creatine transporter (CrT). Creatine (Cr), together with the phosphocreatine shuttle, plays a vital role in maintaining energy supplies via ATP in times of high energy demand. Key to the regulation of intracellular [Cr] is the CrT, a Na+ and Cl - dependent membrane transporter. Previous CrT genetic mouse models include a knockout model, found to still express cardiac CrT, and a cardiac-specific CrT overexpressing (OE) model with large variations in myocardial [Cr] between animals and Cr levels high enough to cause spontaneous hypertrophy. To overcome the shortfalls of this CrT-OE model, a novel in vivo model of temporal inducible expression of CrT is described, using a cardiac-specific tetracycline inducible (Tet-On) system . ..,. .A' Ten transgenic lines (RCT) were created with a construct containing . zhe CrT-HA (CrT cDNA with an haemagglutinin epitope tag), following successful doxycyline-inducibility in vitro. Eight lines showed germline transmission, with LV CrT OE achieved in an individual mouse that displayed double LV [Cr] compared to WT. Issues with the inducer line (rtTA) were ruled out by its use in the creation of a luciferase overexpressing mouse line; all mice tested demonstrated LV luciferase expression in response to doxycycline feeding. The failure to overexpress CrT could be attributed to position or copy number dependent suppression, or to position effect variegation in the case of the single OE mouse obtained. Subsequent work focus sed on regulatory pathways in vitro in a cell line of mouse fibroblasts stably overexpressing CrT·HA. Post-translational modifications (PTMs) had been previously suggested to regulate CrT activity. Two N-linked glycosylation sites exist, in addition to the putative phosphorylation sites. Inhibition of glycosylation by tunicamycin led to decreased CrT activity, reflected by decreased Cr uptake capacity. Strategies to confirm the presence of phosphorylation were employed, including isolation of CrT -HA by immunoprecipitation and subsequent LC-MS / MS analysis to identify PTMs. Although the presence of CrT was confirmed in 5 different sized species- one previously unreported- inadequate sequence coverage prevented identification of any PTM sites. Tyrosine phosphorylation was not detected using a phosphospecific antibody on immunopurified CrT -HA. Candidate signalling pathways in vitro were then investigated to elucidate CrT regulation, namely the IGF-IR signalling pathway. This study included a cardiomyocyte-like mouse cell line (HL-l) in addition to 3T3-CrT -HA. Exposure of cells to extracellular insulin, growth hormone and IGF-1 led to increased Cr uptake of 125% - 300% of normal. Pharmacological inhibition of the downstream kinases PKA and PKC reduced the effect of insulin and GH, while PMA, sapintoxin (STX) and Go 6976 induced CrT activity. The mammalian target of rapamycin (mTOR) is also a candidate regulator of CrT, as incubation with rapamycin decreased Cr uptake in 3T3-CrT -HA. Finally, a targeted approach on transcription factors in the 5'UTR region of mouse CrT identified HEYl as a highly conserved site. In siRNA experiments, HEYl was found to exert a mild effect on CrT activity, suggesting that regulation at the transcriptional level merits further investigation. Together, this work has provided novel insights into the modulation of CrT in vitro, identifying molecular and pharmacological targets in a known therapeutic signalling pathway. Further work could potentially develop these findings by identifying candidate compounds that would increase CrT activity, potentially in a tissue-specific manner. 3

L'allongement de l'espérance de vie a fait de l'insuffisance cardiaque (IC) l'un des problèmes majeurs de santé publique. Le syndrome métabolique (SMet) et l'hypertension sont deux facteurs conduisant à l'IC. Les modifications qui interviennent au niveau structural et cellulaire de la paroi artérielle dans le SMet, l'hypertension et l'IC pourraient entraîner des anomalies de l'hémostase qui aggravent ces tableaux cliniques. Nous avons montré au cour de ce travail les modifications du phénotype de l'hémostase dans différents modèles animaux de pathologies impliquées dans la mise en place de l'IC. L'altération de l'hémostase précède les modifications de la paroi et pourrait favoriser le développement de l'IC chez le rat Zucker. Le modèle de rat spontanément hypertendu SHR présente une hypercoagulablité de la paroi via les cellules musculaires lisses. Ces résultats ne permettent pas d'impliquer uniquement l'hypertension artérielle dans l'hypercoagulabilité plasmatique trouvée chez le rat Zucker. L'activation du récepteur à l'aldsotérone au niveau endothélial chez la souris induit un phénotype antithrombotique provoqué par une augmentation de la réactivité du système anticoagulant de la protéine C, via son récepteur, l'EPCR. L'étude d'une cohorte de patients insuffisants cardiaques a permis de distinguer des paramètres de fonction cardiaque et de rigidité artérielle. Cette caractérisation est indispensable pour comprendre les mécanismes des événements thrombotiques associés à l'IC. La conclusion de ce travail est que les pathologies pouvant conduire à la mise en place d'une IC modifient l'hémostase vers un état d'hypercoagulabilité qui fait intervenir la paroi artérielle / Increasing life span has made heart failure (HF) a major issue for public health. The metabolic syndrome (MetS) and hypertension are two important factors which can lead to HF. Structural and cellular modification occurring in the arterial wall in the MetS, hypertension and HF may provoke hemostasis alterations that can worsen the clinical situation. We have shown in this work, hemostasis modifications in animal models of pathologies implicated in HF development. Hemostasis alterations were shown to precede functional modifications of the arterial wall and could favor HF development in Zucker rats. Spontaneously hypertensive rats showed an arterial wall hypercoagulability via smooth muscle cells. These results don't permit the implication of hypertension in the hypercoagulable state found in the Zucker rat. A mouse model with aldosterone receptor activation in the endothelium lead to a hypocoagulable state by increasing the protein C anticoagulant system via his receptor, the EPCR. Studying a human HF patient cohort permitted the measurement of cardiac function and of arterial stiffness parameters. This characterization is important to understand thrombosis events associated with HF in humans. The general conclusion of this work is that, in pathologies leading to HF, modification of hemostasis to a procoagulable state, implicates the arterial wall

Ο ρόλος της εξωκυττάριας ουσίας στην καρδιακή ανεπάρκεια. / The functional role of extracellular matrix in heart failure.

Cardiovascular disease is a leading cause of death worldwide and becomes increasingly prevalent in the elderly population. Independent of etiopathogenesis, heart failure (HF) is the final common stage of numerous heart diseases. Cardiac stem cell (CSC) therapy has emerged as a promising cell-based strategy for treatment of HF. However, cell replacement is not able to fully restore a structurally damaged myocardium in advanced and end-stage HF. The objective of this project was to test the following hypotheses: that a bioengineered heart extracellular matrix (ECM) with preserved intact geometric structure could be generated using decellularization by coronary perfusion; and that autologous CSCs, to repopulate this ECM, could be isolated and expanded from the adult heart, with the caveat that autologous CSCs are depleted and impaired by both aging and chronic dilated cardiomyopathy. This will help to develop a possible therapeutic approach for advanced HF, using a combination of CSCs and engineering technique. Resident CSCs were isolated from explant-derived cells (EDCs) and expanded into cardiosphere-derived cells (CDCs) via cardiosphere formation. The CDCs expressed CSC markers (c-kit and Sca-1), pluripotent markers (Oct3/4 and Sox2), and the cardiac lineage-committed marker (Nkx2.5), and showed clonal expansion, self-renewal, and cardiomyogenic potential in vitro. In tissue engineering experiments, CDCs survived and proliferated within biomaterial alginate scaffolds for up to 7 weeks. An engineered bioartificial ECM scaffold was successfully produced from a whole rat heart using retrograde coronary perfusion and possessed an intact 3D architecture with functionally perfusable vascular network. Compared with ventricles, cultures derived from atria produced significantly higher number of c-kit+ and Sca-1+ CSCs (c-kit: 13% vs. 3.4%; Sca-1: 82% vs. 53%, respectively) and exhibited greater clonogenic and proliferative capacity. CDCs could be grown from young and aged mice, but the yield of CSCs significantly declined with age, as did cell migration and differentiation potential. In comparison to wild-type mice, atrial-CDCs from dystrophic mice showed no significant differences in CSC subpopulations and characteristics, despite confirmation of cardiac dysfunction using MRI. In conclusion, CDCs could be considered to be a viable cell candidate for cardiac therapy and may be used to treat HF at various stages, in combination with myocardial tissue engineering.

L’utilisation d’antagonistes du récepteur aux minéralocorticoïdes (ARM) a prouvé son efficacité dans le traitement de l’insuffisance cardiaque (IC). Un des facteurs de risque majeur de l’IC, le syndrome métabolique (SMet), est également associé à une production augmentée d’aldostérone et une activation excessive de son récepteur. Dans ce contexte, nous avons émis l’hypothèse que l’utilisation des ARM pouvait être appliquée pour cibler les facteurs de risques du SMet et prévenir la progression subséquente vers l’IC. Dans ce projet, des rats Spontanément Hypertendus et développant une IC (rats SHHF) portant ou non une mutation du récepteur de la leptine (« cp ») conduisant à un SMet (respectivement SHHFcp/cp et SHHF+/+) ont été utilisés comme modèle expérimental. Les animaux ont reçu soit un placebo soit le traitement ARM (Eplérénone, Eplé) dès l’âge de 1.5 à 12.5 mois et leurs paramètres métaboliques et cardiovasculaires ont été régulièrement évalués. Les fonctions moléculaires altérées dans le coeur et le tissu adipeux lors du développement du SMet et la progression de l’IC, ainsi que celles modulées par l’action de l’Eplé ont été caractérisées par l’analyse du transcriptome et miRNome des animaux. Nos résultats montrent que les rats SHHFcp/cp développent à 12.5 mois une hypertrophie cardiaque excentrique associée à une dilatation du ventricule gauche (VG) et une fraction d’éjection diminuée comparés aux SHHF+/+. Alors que l’Eplé ne modifie pas les paramètres métaboliques et cardiovasculaires des SHHF+/+, Les rats Eple-SHHFcp/cp présentent une moindre prise de masse corporelle ainsi qu’une moindre dyslipidémie. Sans effet sur la pression artérielle (PA), ni le transcriptome et miRNome adipeux, les animaux SHHFcp/cp traités présentent en outre une moindre dilatation et hypertrophie de leur VG, une fraction d’éjection, un temps de relaxation isovolumique et un ratio E/A plus élevés. Les analyses du transcriptome et miRNome cardiaques révèlent que l’Eplé induit une diminution significative de l’expression de gènes impliqués dans le remodelage et l’inflammation myocardiques ainsi qu’une augmentation de l’expression de gènes relatifs à l’oxydation des acides gras dans le coeur. L’intégration et l’exploration bioinformatique des profils d’expression du transcriptome et du miRNome ont permis d’établir des réseaux de régulation de l’expression génique potentiellement impliqués dans les mécanismes physiopathologiques à l’oeuvre chez les rats SHHF obèses et dans ceux impactés par le traitement. Dans leur ensemble, nos données montrent que l’initiation d’un traitement ARM lors du développement du SMet permet d’atténuer l’obésité et la dyslipidémie et d’améliorer les paramètres de structure et fonction cardiaque. De façon intéressante, ces effets cardioprotecteurs sont obtenus via des mécanismes indépendants de la diminution de la PA, les analyses du transcriptome/miRNome cardiaque indiquent un mécanisme basé sur une diminution des processus de remodelage et d’inflammation ainsi qu’ une restauration de la fonction de métabolisme énergétique des acides gras au niveau myocardique / Mineralocorticoid Receptor Antagonists (MRA) are clinically beneficial in individuals with chronic heart failure (HF). One of the major risk factors for HF, the metabolic syndrome (MetS), has been also reported to be associated with increased aldosterone production and excessive MR activation. In this context, we hypothesized that the use of MRA could be applied to target the MetS features and prevent the subsequent progression towards HF. In this project, Spontaneously Hypertensive Heart failure rats (SHHF) carrying or not a mutation in the leptin receptor (« cp ») leading to MetS development (SHHFcp/cp and SHHF+/+respectively) were used as experimental model. Animals from both genotypes were given either the selective MRA (Eplerenone, Eple) or placebo from 1.5 to 12.5 months of age and their metabolic and cardiovascular parameters were regularly monitored. The molecular functions altered in the heart and visceral adipose tissues as MetS develops and progresses towards HF as well as those modulated by Eple action were characterized by the analysis of animal’s transcriptome and miRNome. Our data showed that SHHFcp/cp exbiting MetS developed at 12.5 months of age eccentric cardiac hypertrophy associated with left ventricular (LV) dilatation and reduced ejection fraction (EF) as compared to SHHF+/+. While Eple did not induced differences in metabolic and cardiovascular phenotypes in SHHF+/+ rats, Eple-SHHFcp/cp had lower body weight gain and less dyslipidemia. Without effects on blood pressure (BP) and adipose transcriptome and miRNome, Eple-SHHFcp/cp rats had lower LV dilatation and hypertrophy, higher ejection fraction, isovolumic relaxation time and E/A ratio. Transcriptome and miRNome analysis of cardiac tissues revealed that Eple markedly reduced the expression of several genes involved in cardiac remodeling and inflammatory processes and increased the expression of genes related to cardiac fatty acid oxidation and metabolism. The integration and the bioinformatic exploration of transcriptome and miRNome expression profiles allowed the construction of gene regulatory networks potentially involved in the physiopathological mechanisms occuring in the SHHFcp/cp rats and those impacted by the treatment. Altogether, our data demonstrated that treatment with Eple during MetS development attenuated SHHFcp/cp weight gain and dyslipidemia contributing to the amelioration of their cardiac structural and functional parameters. Interestingly, those beneficial cardioprotective effects were obtained via mechanisms independent of BP lowering, the analysis of cardiac transcriptome/miRnome revealed that Eple may have acted by depressing cardiac remodeling and inflammatory processes and restoring the function of fatty acid metabolism in the myocardium

L’insuffisance cardiaque (IC) est une cause majeure de mortalité dans les pays industrialisés. Ce syndrome est le résultat de nombreuses maladies cardiaques qui induisent dans un premier temps un remodelage adaptatif du myocarde : l’hypertrophie du ventricule gauche (HVG). Dans le cœur, le calcium libéré à partir du réticulum sarcoplasmique (RS) est à l’origine de la contractilité. Ce mécanisme est contrôlé par un macro-complexe moléculaire, composé du récepteur de la ryanodine (RyR2), et de protéines stabilisatrices associées dont la junctine (JCN), la calséquestrine (CSQ2), et la triadine (Trd). Ces dernières années, des dysfonctionnements de ce complexe, par des relâchements aberrants de Ca2+ du RS (vu comme des fuites de Ca2+ hors du RS) ont été remarqué au cours de l’IC, conduisant à une HVG associée à une dysfonction contractile et à la survenue d’arythmies cardiaques létales. De très nombreuses études se sont intéressées aux protéines principales du RS, telles que RyR2 et CSQ2, mais peu de données sont disponibles sur le rôle de Trd, protéine considérée comme mineure en physiopathologie cardiaque. Afin d’étudier son rôle dans le cœur, notre travail s’est articulé autour de trois modèles de pathologie cardiaque : 1-une surcharge de pression par une sténose de l’aorte transverse (TAC), 2-une diffusion de catécholamines (isoprotérénol, Iso) par mini-pompe osmotique et 3-une IC chronique par un infarctus du myocarde (IM), chez des souris dont le gène de la triadine a été invalidé (KO Trd). En réponse à une TAC ou à l’ISO, les animaux développent une HVG plus importante que les souris WT. Suite à une TAC, cette HVG est supérieure et excentrique et s’accompagne d’une dysfonction cardiaque comparativement aux animaux sauvages. Suite à un IM, les souris KO Trd présentent une mortalité accrue post-chirurgie. L’accroissement de cette mortalité accrue résiderait dans l’augmentation significative d’arythmies ventriculaires sévères (tachycardies ventriculaires, TV) chez ces souris suite à une stimulation catécholaminergique, pouvant être la conséquence d’une augmentation des fuites de Ca2+ hors du RS. Nous avons également observé qu’en réponse à la TAC la réexpression du gène TRDN avec un adénovirus AAV9 dans notre modèle KO Trd permet le maintien de la fonction cardiaque et de prévenir le développement de l’HVG. Au final, ces travaux montrent que l’absence de la triadine accélère la transition vers l’IC en modulant à la fois l’HVG et la dysfonction contractile associée mais également la survenue d’arythmies ventriculaires létales. / Heart failure (HF) is a serious public health issue with a growing prevalence in industrialized countries. This syndrome results from several cardiac diseases which begin with an adaptative myocardial remodeling: left ventricular hypertrophy (LVH). In heart, contractility depends on calcium release from sarcoplasmic reticulum (SR). This release is controlled by a macro-molecular complex, composed by ryanodine receptor (RyR2) and its associated regulatory protein junctin (JCN), calsequestrin (CSQ2) and triadin (Trd). During the past years, alterations of this complex by disturbed calcium release outside SR (as « sparks ») was often observed during the development of HF, being associated with LVH, dysfunction and fatal ventricular arrhythmias. Most studies were focused on RyR2 and CSQ2 function but few data are available regarding the role of Trd, considered until now having minor role in cardiac physiopathology. To elucidate its role, we realized 3 cardiac pathological experimental models on mice with triadin gene invalidation (KO Trd): 1- a pressure overload with transversal aorta constriction (TAC) 2-a chronic infusion of catecholamines (Isoproterenol, Iso) with osmotic minipumps and 3- a chronic HF with myocardial infarction (MI). In response to TAC or Iso, KO mice developed a greater LVH compared to wild-type mice. Also, with TAC, KO mice show an eccentric LVH associated with a severe cardiac dysfunction, as compared to wild-type mice. After MI, we observed a greater mortality post-surgery in KO Trd mice. This prevalence may be due to increasing of severe ventricular arrhythmias (ventricular tachycardia, VT) after catecholaminergic stimulation. This observation could be a consequence of increasing number of « sparks », and thus an increased calcium release during diastole. More interestingly, delivery of TRDN gene using AAV9 in KO mice, prevent adverse remodeling and the associated cardiac dysfunction following 28 days TAC surgery. To conclude, this work shows that the lack of triadin accelerate the transition towards heart failure, acting on LVH , contractile dysfunction, and the occurrence of lethal ventricular arrhythmias.