Diabetes Mellitus (DM) is one of the most common metabolic disorders in the world with an estimated prevalence of over 415 million patients. Heart failure (HF) is the most common cardiovascular complication of diabetes. The prevalence of diabetes in patients with HF is reported at approximately 30%. However, the molecular mechanisms that contribute to the development of heart failure in diabetic patients remain uncertain. To study this, a genetic mouse model of diabetes (GENA348) with a point mutation in the glucokinase gene was used. Glucokinase is a glucose sensor that controls insulin release. This mutation in the glucokinase is similar to that found in Maturity Onset Diabetes of the Young Type 2 (MODY2) in humans. Our group has previously shown that GENA348 mice exhibit a diabetic phenotype. At 6 months, the mice developed a diabetic cardiomyopathy analogous to that seen in clinical practice with the development of cardiac hypertrophy and diastolic dysfunction, which progressed to dilatation of the left ventricle and systolic dysfunction at 12 months. The aim of the project was to examine the molecular and pathophysiological mechanisms that contribute to development of this cardiac phenotype in diabetic GENA348 mice in the setting of hypertension and at baseline. To study the mice under hypertensive stress conditions, 6 month old-GENA348 HO and WT mice were infused with angiotensin II (ANG II) via minipump. After ANG II treatment, HO and WT GENA348 mice showed a significantly greater increase in systolic and diastolic blood pressure compared to untreated controls. It was evident that ANG II treatment resulted in cardiac hypertrophy with the same level observed in both HO and WT mice. The diastolic function was generally preserved in the WT and HO mice following the ANG II treatment. Our data indicates that the HO mice have had a blunted hypertrophic response to the hypertension induced by ANG II. At baseline, two hypothesis-generating methods were used. Firstly, gas chromatography-mass spectrometry (GC-MS) and ultra performance liquid chromatography-mass spectrometry (UPLC-MS) were used on 12-month-old GENA348 mice heart and serum samples. Secondly, diabetes PCR array plates were used on 6- and 12-month-old GENA348 mice heart samples. For the GCMS and UPLC-MS, there were 43 differences in metabolites from tissue samples and 93 from serum samples. The main altered metabolites from tissue samples were sugars and fatty acids. However, fatty acids, phospholipids and sphingolipids were the main altered metabolites from serum samples. After the validation of the array plates the most apparent observation was that only two up-regulated genes, Phosphoenolpyruvate carboxykinase 1 (Pck1)and Glucose-6-Phosphatase, Catalytic Subunit (G6pc) showed a comparable pattern as the array results. Pck1 and G6pc are the main enzymes that play a key role in gluconeogenesis regulation. We also looked at the expression level of one of the main transcriptional regulators of gluconeogenesis, Forkhead boxprotein O1 (FoxO1). It was found that the expression was altered at 12 months. In conclusion, it was clear that hyperglycaemia altered gene expression and the metabolites profiles in 12 month old HO mice, with evident alterations detected in genes involved in the metabolic regulation of the heart. In addition, this study may provide preliminary insight into pathophysiological alterations in the cardiac metabolism that may contribute to the development of diabetic cardiomyopathy.

No description available.

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.

No description available.

No description available.

Abstract Cardiac hypertrophy provides an adaptive mechanism to maintain cardiac output in response to increased workload, and although initially beneficial, hypertrophy eventually leads to heart failure, a major cause of morbidity and mortality in Western countries. The hypertrophic response in cardiac myocytes is accompanied by e.g. activation of signal transduction pathways, such as mitogen-activated protein kinases (MAPKs), and complex changes in gene programming. The purpose of this study was to characterize gene expression patterns in experimental models of cardiac load by using high-throughput DNA microarray technologies. In the present study, changes in gene expression were evaluated in response to acute pressure overload and prolonged hypertension as well as during the development of left ventricular hypertrophy (LVH) and the transition to diastolic heart failure in an animal model of genetic hypertension, the spontaneously hypertensive rat (SHR). Increased expression of several immediate early genes was seen in response to acute hemodynamic overload in vivo. The transition from LVH to diastolic hypertensive heart failure was almost exclusively associated with changes in genes encoding extracellular matrix proteins and their regulatory processes showing the importance of progressive extracellular matrix remodeling. The effect of p38 MAPK activation on gene expression patterns in vivo was elucidated. Cardiac-specific overexpression of p38 MAPK resulted in upregulation of genes controlling cell division and inflammation as well as cell signaling and adhesion. Accordingly, the functional role of p38 MAPK was related to myocardial cell proliferation, inflammation and fibrosis. Finally, temporal analysis of mechanical stretch induced gene expression changes in neonatal rat cardiomyocyte cultures in vitro indicated that mechanical stretch induced complex gene expression profiles, demonstrating that both positive and negative regulators are involved in the hypertrophic process. Many novel stretch responsive genes were identified, and a subset of them may be putative downstream targets of p38 MAPK. In conclusion, in the present study a number of well-established gene expression changes of cardiac hypertrophy were observed and novel modulators associated with increased cardiac load, such as thrombospondin-4, were identified. The study provides a better understanding of molecular mechanisms associated with increased cardiac load, and may indicate potential targets for novel therapeutic interventions.

Background: Exercise-based cardiac rehabilitation (CR) is considered routine practice for patients following an acute cardiac event or surgical intervention. Although there is a seemingly strong evidence base supporting it for patients with chronic heart failure (CHF), provision in the UK remains poor for this patient group. In addition, data for CHF patients reported in key CR reviews and meta-analyses are not a true representation of the UKs CHF population. The transferability of current evidence into actual practice settings in the UK therefore remains incongruous. Rationale and aims: Study outcomes have typically included an increase in VO2 peak/ VO2 max, a decrease in natriuretic peptides, improved left ventricular function and improved health related quality of life (QoL). Access to facilities and equipment, such as cardiopulmonary exercise testing equipment is limited in the UK for the majority of CR services thus an alternative means of assessment and exercise prescription is required. The recommended alternative for testing CHF patients is the six-minute walk test (6MWT); this requires a given space and a full practice test, the latter which adds to valuable clinical and staff time available. Methods: The first set of studies of this thesis therefore investigated two adapted assessment procedures for use with CHF patients: i. the use of a shorter practice walk test of two minutes vs six minutes prior to a 6MWT and ii. the use of the space saving Chester step test with an adapted lower step height protocol to accommodate the anticipated lower fitness in CHF (4-inch vs 6-inch). Having determined a more practical and efficient means of assessing exercise capacity in CHF patients, this thesis then used the 6MWT to evaluate the efficacy of a typically recommended 12-week programme (for the UK) of exercise-based rehabilitation. It was the aim of this PhD to also combine the use of the Chester step test with cardiopulmonary measures as a corresponding physiological outcome in a sub-sample of participants; however due to resource problems, only validation of the low-step protocol was possible. In the main intervention study, the efficacy of a 12-week course of supervised moderate intensity exercise in CHF patients (ejection fraction <44%, NYHA class II to III) was then evaluated. For purposes of evaluating safety and recovery of any acute myocardial stress induced by exercise in CHF, a sub-group study was performed to evaluate the influence of an acute exercise session on two-day post-exercise levels of circulating NT-proBNP. Results: In this current suite of studies, participants were more representative of the UK CHF population than typically reported in the current evidence. Their profile involved a median age of 76 ± 16 years (mean: 67 years and range: 30 to 84 years). 98% of whom were prescribed beta-blockers, 66% were diagnosed with atrial fibrillation and 98% had two or more co-morbidities. Study 1 (Chapter 3a) verified the efficacy of a two-minute practice walk in comparison to the recommended six-minute practice walk prior to performing a baseline 6MWT in patients with CHF. Study 2 (Chapter 3b) demonstrated that a 4-inch Chester step test is a reliable assessment when space is an issue, but the criterion validity of the actual oxygen costs at each stage compared with those estimated in healthy populations were significantly lower than recommended estimations from healthy populations. Study 3 (Chapter 4) revealed individual variability in the acute response of NT-proBNP release to exercise that is worthy of further study. However the NT-proBNP data overall did not suggest a need for ‘rest days’ between exercise training sessions. The main intervention study (Study 4, Chapter 5) demonstrated a significant improvement in 6MWT performance responses, compared with control, where an increased walking distance of 25 m (p < .0001) was coupled with a reduction in heart-rate-walking speed index (T1 16.3 ± 7.3 vs T2 15.3 ± 8.7 beats per 10 walked; p < .0001). Perceptually, patients were walking faster for the same rating of perceived exertion (RPE 12 to 13). This improved aerobic functioning coincided with an improved NYHA class (T1 2.3 ± .5 vs T2 1.8 ± .6; p < .0001); however there was no change in resting NT-proBNP levels after 12 weeks. Patients in the “control group” who then went on to be offered the same 12-week intervention achieved similar outcomes, but delaying their commencement of an exercise programme by 12 weeks negatively impacted on participation uptake. Key findings and conclusions: These results have demonstrated that exercise training in CHF can lead to an improvement in both physical and perceived functioning (NYHA class). In light of some previous studies showing decreases in BNP following an exercise programme and others like this one showing no change, further questions are raised about the effect of different types and doses of activity being offered to CHF patients and the responsiveness to training of different types of patients (disease severity and demographics). The nature of the cross-over design of this study revealed that delayed commencement of exercise negatively affects participation uptake by patients, which supports current UK standards in aiming for early referral to CR.

Background-Heart failure is common in patients with chronic kidney disease. We studied risk factors for incident heart failure among 3557 participants in the CRIC (Chronic Renal Insufficiency Cohort) Study. Methods and Results-Kidney function was assessed by estimated glomerular filtration rate (eGFR) using serum creatinine, cystatin C, or both, and 24-hour urine albumin excretion. During an average of 6.3 years of follow-up, 452 participants developed incident heart failure. After adjustment for age, sex, race, and clinical site, hazard ratio (95% CI) for heart failure associated with 1 SD lower creatinine-based eGFR was 1.67 (1.49, 1.89), 1 SD lower cystatin C-based-eGFR was 2.43 (2.10, 2.80), and 1 SD higher log-albuminuria was 1.65 (1.53, 1.78), all P< 0.001. When all 3 kidney function measures were simultaneously included in the model, lower cystatin C-based eGFR and higher log-albuminuria remained significantly and directly associated with incidence of heart failure. After adjusting for eGFR, albuminuria, and other traditional cardiovascular risk factors, anemia (1.37, 95% CI 1.09, 1.72, P= 0.006), insulin resistance (1.16, 95% CI 1.04, 1.28, P= 0.006), hemoglobin A1c (1.27, 95% CI 1.14, 1.41, P< 0.001), interleukin-6 (1.15, 95% CI 1.05, 1.25, P= 0.002), and tumor necrosis factor-a (1.10, 95% CI 1.00, 1.21, P= 0.05) were all significantly and directly associated with incidence of heart failure. Conclusions-Our study indicates that cystatin C-based eGFR and albuminuria are better predictors for risk of heart failure compared to creatinine-based eGFR. Furthermore, anemia, insulin resistance, inflammation, and poor glycemic control are independent risk factors for the development of heart failure among patients with chronic kidney disease.

Bakgrund: Kronisk hjärtsvikt är idag en folkhälsosjukdom vilket vanligtvis drabbar den äldre generationen som i sin tur påverkar både patienter, anhöriga men även samhället med stora sjukvårdskostnader. Fysisk aktivitet har visat sig ge positiva effekter hos personer med hjärtsvikt gällande morbiditet, livskvalité samt fysisk kapacitet. Syfte: Syftet med litteraturstudien var att undersöka om en förbättrad livskvalité kunde uppnås med egenvård inriktad mot fysisk aktivitet. Metod: Litteraturstudie, 11 randomiserade kontrollerade studier från databaserna PubMed och Cinahl. Resultat: Resultatet presenterades utifrån litteraturstudiens två frågeställningar som berörde olika träningsprogram med fokus på fysisk aktivitet samt egenvårdshantering och livskvalité hos patienter med kronisk hjärtsvikt. Resultatet visade att strukturerade träningsprogram gav en ökad fysisk prestationsförmåga i interventionsgrupperna efter programmens slut. Det fanns även ett samband mellan den förbättrade prestationsförmågan och undervisningen vilket innebar stöttning och utbildning hur patienterna kunde uppnå ett bättre resultat under träningsperioden. Genom utbildning, information och rådgivning kunde patienterna förbättra sin egenvårdshantering genom att få insikt om sin sjukdom och kunde därmed identifiera tidiga tecken på försämring av symtomen vilket i sin tur resulterade i en bättre livskvalité efter interventionens slut. Genom ett gruppbaserat egenvårdsprogram vilket baserades på att deltagarna skulle utbyta erfarenheter och få ökad kunskap om sin sjukdom från varandra uppnåddes en bättre egenvård, dock inte en ökad livskvalité. Slutsats: Det framgår att olika former av strukturerade träningsprogram kan öka den fysiska prestationsförmågan hos patienter med kronisk hjärtsvikt. Genom att patienten utövar någon form av fysisk aktivitet som en egenvårdsåtgärd kan det resultera till en förbättrad fysisk prestationsförmåga samt en ökad livskvalité. Gällande vilken typ av fysisk aktivitet som är den mest effektivaste metoden kan dock inte fastslås och det behövs mer omfattande forskning inom området. / Background: Chronic heart failure is today a public health disorder that usually affects the older generation and it´s relatives, but also the community with high medical costs. Physical activity has been shown to have positive effects in people with heart failure regarding morbidity, quality of life and physical capacity. Objective: The aim of the literature study was to investigate whether an improved quality of life could be achieved with self care focused on physical activity. Method: This was a literature study with 11 randomized controlled trials from the databases PubMed and Cinahl. Results: The result was presented on the basis of the two questions of the literature study, which concerned different training programs focusing on physical activity, self-care and quality of life in patients with chronic heart failure. The results showed that structured exercise programs gave increased physical performance in the intervention groups after the end of the programs. There was also a relationship between the improved physical performance and teaching, which meant support and education how patients could achieve better results during the training period. Through education, information and counseling, patients could improve their self-care management by gaining insight into their illness and thus identify early signs of impairment of the symptoms, which in turn resulted in a better quality of life after the end of the intervention. Through a group-based self-care program, which was based on the participants exchanging experiences and gaining knowledge about their illness from each other, better self-care was achieved, but not an increased quality of life. Conclusion: It appears that different types of structured exercise programs can increase the physical performance of patients with chronic heart failure. As the patient perform some kind of physical activity as a self-care method, it can result in improved physical performance and increased quality of life. However, which kind of physical activity is the most effective method couldn´t be determined and more extensive research is needed in the field.

Les médicaments sont des substances chimiques exerçant un ou plusieurs effets pharmacodynamiques par l'intermédiaire de leurs interactions sur des systèmes biologiques plus ou moins complexe. Pour chaque individu, cette réponse, qu’elle soit souhaitée ou indésirable, est variable car modulée par de nombreux facteurs dépendant notamment des propriétés pharmacocinétiques du médicament et de facteurs génétiques, physiopathologiques ou environnementaux. Dans cette thèse, des travaux de pharmacologie de précision ont été menés afin d’identifier les sources de variabilité de la réponse individuelle à certains médicaments cardiovasculaires.Dans la première partie, il est montré que les paramètres actuellement utilisés en échocardiographie (notamment E/e’) pour estimer les pressions de remplissage ventriculaire gauche de manière non invasive afin de guider les thérapeutiques de déplétion ou de remplissage des patients insuffisants cardiaques systoliques décompensés ne sont pas fiables en cas d’utilisation concomitante d’inotropes.Une seconde partie détaille les sources de variabilité de l’effet de l’amiodarone sur le contrôle de la fréquence cardiaque dans le traitement des arythmies cardiaques supra-ventriculaires en réanimation. La co-administration de magnésium et le remplissage permettent d’améliorer l’efficacité de l’amiodarone tandis que l’utilisation de dobutamine a un effet inverse.La dernière partie rapporte les résultats d’une étude d’association pangénomique chez 1000 personnes dont le but était d’identifier des sources génétiques de variabilité des modifications de la repolarisation ventriculaire de type inhibition du canal IKr induites par le Sotalol chez des sujets sains. / Drugs are chemical substances leading to pharmacodynamic responses through interactions with biological systems of variable complexity. For each individual, this response, whether desired or not, is variable and modulated by many parameters including the pharmacokinetic properties of the drug and pathophysiological, genetic and environmental factors. In this thesis, personalized medicine work were conducted to identify sources of variability in individual response to several cardiovascular drugs.In the first part, it is shown that parameters currently used in echocardiography (including E/e') to estimate non-invasively left ventricular filling pressures in patients with decompensated systolic heart failure, in order to guide depletion or filling therapeutics, are not reliable in case of concomitant use of inotropes.The second part details the pharmacodynamics modeling work that identified sources of variability altering the effect of amiodarone on heart rate control in the treatment of supra-ventricular arrhythmias in unstable patients admitted in Intensive Care. Co-administration of magnesium and fluid repletion improved the effectiveness of amiodarone to slow heart rate while the use of dobutamine had an opposite effect.The last part reported the results of a study where 1000 individuals were challenged by a same dose of sotalol in order to perform a genome-wide association study aiming at identifying genetic sources of variability of sotalol induced IKr block ventricular repolarization abnormalities in healthy subjects. Another study evaluating the impact of sex hormones on ventricular repolarization is also detailed.