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.

Background: Heart failure causes great suffering and costs for the society each year. Structured care of patients with heart failure can improve treatment, reduce hospitalization and increase quality of life. Patients with heart failure who are compliant can maintain health and well-being to a greater extent but requires patient education. Aim: The aim of the study was to investigate whether patients with heart failure, at an HF outpatient clinic, have high compliance with recommended self-care actions. The study also investigate statistical differences between sex, education level and marital status amongst participants with high compliance. Method: A quantitative approach was used, where patients´ self-care ability was measured using the European Heart Failure Self-Care Behaviour Scale (EHFScBS). Sixtyfour patients were asked for participation and 46 approved (72%). Result: The result showed low compliance with self-care actions in general. The claims regarding medication and limited fluid-intake showed high compliance. Among the participants with high compliance, four statistical differences (p ≤0.05) were identified regarding gender, marital status and education level. The results are in part consistent with previous research, showing that, despite education strategies, it may be difficult for HF-patients to deal with their own self-care. Conclusion: Based on the fact that patients with HF show low compliance with self-care actions, knowledge about different factors affecting the self-care ability in order to provide optimal care for each individual patient is of importance. EHFScBS used in the study can also be used as a measuring instrument for heart failure in the HF-outpatient clinic. / Bakgrund: Hjärtsvikt orsakar stort lidande och kostar samhället stora belopp varje år. Ett strukturerat omhändertagande av patienter med hjärtsvikt kan förbättra behandling, minska antalet sjukhusinläggningar och ge ökad livskvalitet. Patienter med hjärtsvikt som är följsamma till egenvårdsråd kan i högre grad bibehålla hälsa och välbefinnande. För att uppnå detta krävs patientutbildning. Syfte: Syftet med studien var att undersöka om patienter med hjärtsvikt, vilka regelbundet följs upp på hjärtsviktsmottagning, har hög följsamhet till rekommenderade egenvårdsråd. Studien avsåg också att undersöka om det fanns några statistiska skillnader mellan kön, utbildningsnivå och civilstatus vad gäller hög följsamhet till egenvårdsråd. Metod: En kvantitativ ansats tillämpades där patienternas egenvårdförmåga mättes med Europeiska beteendeskalan för egenvård vid hjärtsvikt (EHFScBS). 64 patienter tillfrågades om deltagande och 46 av dessa valde att delta (72%). Resultat: Resultatet av studien visade låg följsamhet till egenvårdsråd överlag. Endast för påståendena med avseende på medicinering och begränsat vätskeintag påvisades hög följsamhet. Bland de deltagare som hade hög följsamhet påvisades fyra statistiska skillnader (p ≤ 0,05) med avseende på kön, civilstatus och utbildningsnivå. Resultaten överensstämmer till viss del med tidigare forskning som påvisat, att det trots utbildningsstrategier kan vara svårt för hjärtsviktspatienter att sköta sin egenvård. Slutsats: Utifrån att patienter med hjärtsvikt har låg följsamhet till egenvårdsråd är det viktigt att som vårdgivare ha kännedom om olika faktorer som påverkar egenvårdsförmågan för att kunna erbjuda varje enskild patient ett så optimalt omhändertagande som möjligt. Egenvårdsskalan (EHFScBS) som använts i studien kan med fördel användas som ett mätinstrument på hjärtsviktsmottagningar.

Ischemic injury in the heart is followed by an increase in SNS activity and the higher this activity, the poorer patient outcomes. An index of SNS activity in models of ischemia can be achieved by measuring NE, β-AR, and perhaps indirectly PDE4 to give an intracellular aspect on SNS signaling. A 20 minute ischemia-reperfusion was induced in a rat model with physiological measurements at 2-5 weeks post IR. At 3 weeks post IR, rats displayed increased PDE4 expression, decreased β 1-AR expression, increased plasma NE, decreased tissue NE storage, increased Doppler E/A ratio and unchanged LV ejection fraction. PET analysis with FDG revealed no infarct at 2 weeks, while analysis with [13N]NH3 displayed no resting flow defect but revealed trends in flow reserve impairment as early as 2.5 weeks with recovery at 5 weeks post-surgery. Applications of this model could be non-invasive imaging of PDE4 with (R)-[11C]Rolipram PET at early time points for development towards prognostic and therapy guidance in humans.

Background-Pulmonary artery hypertension (PAH) is characterized by progressive vascular changes causing increased pulmonary resistance and eventual right heart failure (HF). It has been suggested that altered myocardial substrate utilization may be associated with right HF, however these changes have not yet been well characterized. The aim of this study was to evaluate in vivo right ventricular (RV) function and RV glucose and fatty acid metabolism in an experimental model of PAH using non-invasive positron emission tomography (PET) imaging and to investigate the effect of a novel endothelin receptor antagonist, Macitentan, on the development of PAH and RV energetics. Methods and Results-Severe PAH was induced in a total of 11 male Sprague-Dawley rats using a single injection of Sugen5416 followed by chronic hypoxia. The rats were then randomized to treatment or no treatment with Macitentan (30 mg/kg daily) Five and eight weeks post injection, substrate utilization was serially assessed with 2-[18F]fluoro-2-deoxyglucose (FDG) and 4-[18F]fluoro-6-thia-heptadecanoate (FTHA) PET scans for glucose and fatty acid metabolism respectively, and reported as a standardized uptake value (SUV). This data was correlated with in vivo functional measurements with echocardiography and multi gated acquisition scans. The Sugen-hypoxia (SuHx) model resulted in an increase in RV FDG uptake over 8 weeks (SUV control: 1.56 ± 0.38, week 5 SuHx: 4.06 ± 1.90, week 8 SuHx: 4.00 ± 1.60, p<0.005 between control and week 5 SuHx). RV FTHA data showed a trend towards increased uptake with onset of PAH at week 5 SuHx (SUV control: 1.50 ± 0.40, week 5 SuHx: 3.06 ± 1.10, p>0.05). Macitentan significantly decreased RV FDG uptake (SUV week 8 SuHx: 4.00 ± 1.60, week 8 SuHx +ERA: 2.54 ± 0.90, p<0.05). This was associated with improved RV ejection fraction (PAH week 8 untreated: 53.15 ± 9.9% vs PAH week 8 treated: 73.22 ± 4.8%, p<0.01) and improved pulmonary artery pressures measured by pulmonary artery acceleration time (PAH week 8 untreated: 17.32 ± 2.30 ms vs. PAH week 8 treated: 24.38 ± 3.90 ms, p<0.001). There was a strong correlation between increased pulmonary artery pressures and increased RV FDG uptake (r=0.87, p=0.001) as well as a significant inverse relationship between improved RV ejection fraction and decreased RV FDG uptake (r=-0.72, p=0.01). Conclusion-PAH is associated with metabolic changes in the RV, characterized by increased glucose uptake and a trend towards increased RV fatty acid uptake with onset of PAH. Macitentan attenuated RV FDG uptake and significantly increased RV function as well as hemodynamics compared to untreated group.

La fonction cardiaque est finement régulée par des hormones de type monoamines qui constituent des régulateurs cruciaux de l’activité cardiaque (chronotropie et inotropie). Ces hormones dérivées d’acides aminés aromatiques comprenant les catécholamines et la sérotonine maintiennent l’activité du myocarde dans un cadre physiologique tout en lui permettant de s’adapter aux contraintes environnementales. Les récepteurs cellulaires des monoamines sont couplés à des voies de signalisation qui impliquent un nucléotide cyclique, l’AMPc, et modulent la contractilité des cardiomyocytes par l’intermédiaire de multiples phosphorylations des protéines régulatrices du cycle du calcium (canal calcique de type L, RyR2 ou phospholamban) par la protéine kinase A AMPc-dépendante. Lorsque les monoamines voient leurs activités dérégulées en contextes pathologiques tels que l’insuffisance cardiaque (IC) ou un lors d'un traitement antidépresseur, elles conduisent à une hyperstimulation de leurs récepteurs spécifiques. Cette dernière altère alors les voies impliquant l’AMPc et les flux calciques engendrant des évènements ectopiques proarythmogéniques nommés post-dépolarisations. Ces dysfonctions de la contractilité cellulaire et de l'homéostasie calcique peuvent être à l’origine d’arythmies tissulaires et de morts subites cardiaques. Les altérations de l’homéostasie calcique subsistent en dépit des approches thérapeutiques actuelles (!-bloquants, inhibiteurs de l’enzyme de conversion de l’angiotensine) qui vise à freiner le remodelage myocardique post-ischémique et constituent donc une cible active de la recherche cardiovasculaire. Les Rycals, stabilisateurs pharmacologiques du RyR2, représentent une nouvelle approche visant à remédier à ces altérations. Au sein de ces travaux de recherche, nous avons axé nos études sur les deux voies monoaminergiques AMPc cardiaques majeures, les voies adrénergiques et sérotoninergiques. Un premier axe d’étude a consisté en l’évaluation des bénéfices potentiels d’un nouveau Rycal, le S44121, sur la survenue d’arythmies cellulaires et tissulaires en comparaison d’un !-bloquant de référence, le métoprolol, dans un contexte d’IC post-infarctus chez le rat. L’étude n’a cependant pas mise en évidence de bénéfices du S44121 mais a confirmé la cardioprotection exercée par le métoprolol. Un deuxième axe d’étude a évalué l’implication potentielle au niveau cardiaque de la protéine S100A10 dans la modulation de la voie du récepteur à la sérotonine de type 4 (5-HT4R) en conditions physiologiques ou en contexte d’IC. Cette étude originale a mis en avant pour la première fois dans le coeur sain un rôle de la S100A10 dans l’apparition d’une voie 5-HT4R proarythmogène lorsque son expression est induite par une neurotrophine (Brain-derived neurotrophic factor) ou un antidépresseur (imipramine). En revanche, le rôle de la S100A10 dans la modulation de la voie 5-HT4R en contexte d’IC n’a pas été déterminé de façon certaine. / Cardiac function is tightly regulated by hormones such as monoamines which are substantial modulators of cardiac activity (chronotropy and inotropy). These hormones, derived from aromatic amino acids, maintain myocardial activity in a physiological range and allow the cardiac adaptation to environmental conditions. The cellular receptors to monoamines are coupled to signaling pathways involving a cyclic nucleotide, cAMP, and modulate cardiac activity by phosphorylating several key proteins of calcium handling (L-type calcium channel, RyR2 or phospholamban) by the cAMP-dependent protein kinase A. Deregulation of monoamines in pathological conditions such as heart failure (HF) or during antidepressanttreatment leads to a hyperstimulation of their specific receptors. It therefore induces alterations of the cAMP signaling pathway and calcium handling leading to the occurrence of proarrhythmogenic ectopic cellular events known as afterdepolarizations. These dysfunctions in cellular contractility and calcium handling may cause tissue arrhythmias andeven sudden cardiac death. Calcium handling alterations leading to cardiac arrhythmias remain a clinically relevant issue despite the current therapeutical approaches (!-blockers, angiotensin-converting-enzyme inhibitors) which slow the post-ischemic myocardial remodeling and thus represent an active target in the cardiovascular research field. Rycals, RyR2 pharmacological stabilisers, are a new approach to prevent these alterations. In this work, we focused on the two major monoaminergic cAMP-dependent pathways in the heart, the adrenergic and serotoninergic pathways. In the first part of this work, we aimed to evaluate the potential benefits of a new Rycal, S44121, on cellular and tissue arrhythmias occurrence in post-myocardial infarction rat model. These effects were compared to those of the well-known !-blocker, metoprolol. This study failed to show any strong benefit of S44121 but confirmed the cardioprotection associated with the metoprolol use. In a second part of the work presented here, we aimed to evaluate the potential involvement of the S100A10 protein in the modulation of the cardiac serotonin receptor 4 pathway (5-HT4R) in physiological conditions or during HF. This original study unraveled for the first time a new role for S100A10 in the healthy heart by revealing a functional 5-HT4R pathway when S100A10 expression is induced by neurotrophins such as brain-derived neurotrophic factor or by antidepressant drugs such as imipramine. However, we failed to conclude on a direct evidence for a role of S100A10 in the modulation of the 5-HT4R pathway in the failingheart.

L'insuffisance cardiaque (IC) est une maladie dont la prévalence est élevée, cette prévalence augmente avec l'âge. La découverte de la maladie se fait le plus souvent lors d'un épisode de décompensation (ou insuffisance) cardiaque aiguë (ICA). L'ICA est très fréquente chez les sujets âgés et est caractérisée par des difficultés diagnostiques quand le patient est admis avec une dyspnée aiguë. L'apport de biomarqueurs plasmatiques tels que le BNP ou le NT-proBNP a été majeur pour le diagnostic de l'ICA. La décompensation cardiaque aiguë est suivie d'un taux de réhospitalisations et d'une mortalité très élevés. Les objectifs de la thèse était 1- de préciser l'épidémiologie de l'ICA en France lors d'un observatoire d'une journée des hospitalisations pour ICA dans 170 hôpitaux français (OFICA), 2- d'identifier la puissance diagnostiques et pronostiques des peptides natriurétiques lors de l'ICA, 3-de définir l'importance des modifications post-transcriptionnelles de ces PNs lors de l'ICA, 4- de rechercher de nouveaux biomarqueurs.La comparaison des propriétés diagnostiques et pronostiques des peptides natriurétiques révèle que les 4 peptides natriurétiques commercialement accessibles (BNP, NT-proBNP, proBNP et MR-proANP) ont des qualités diagnostiques et pronostiques globalement très similaires. Néanmoins, proBNP et BNP semblent meilleurs pour le diagnostic tandis que MR-proANP apparaît meilleur pour son association avec la mortalité à 5 ans.Parmi les modifications post-transcriptionnelles du BNP, nous avons étudié l'impact de la glycosylation du pro-BNP. La O glycosylation en 71 inactive proBNP, qui est libéré hors de la cellule sans action préalable des enzymes de « cleavage » la corine ou la furine. En revanche, le proBNP non-glycosylé est scindé en BNP et NT-proBNP par la corine ou la furine. Nous avons pu montrer que la non-glycosylation du proBNP et l'activation de la furine étaient deux mécanismes très importants d'accélération de la production de peptides natriurétiques lors de l'ICA. On a pu également montrer que la production du NT-proBNP était beaucoup plus liée au niveau glycosylation du proBNP que ne l'est la production de BNP. Ainsi, nos résultats suggèrent fortement d'utiliser le NT-proBNP pour toute étude future souhaitant explorer le concept de « biomarker-guided therapy » dans l'ICA.Pour la recherche de nouveaux biomarqueurs, nous avons exploré 1-la concentration plasmatique de 5 microRNAs (miR-l/-21/-23/-126/-423-5p), chez des patients avec dyspnée aiguë. Aucun de ces miR n'a de valeur diagnostique, en revanche, le miR-423-5p apparaît être un marqueur pronostique de réhospitalisation à un an ; 2-les conséquences de la congestion cardiaque sur le foie. Les marqueurs hépatiques étudiés étaient la phosphatase alcaline et les transaminases : les marqueurs de la cholestase étaient associés à une congestion hépatique tandis que ceux de la nécrose cellulaires (transaminases) étaient liés à l'hypotension artérielle et au bas débit cardiaque. L'augmentation des transaminases a été associée à divers critères dont une surmortalité à court terme / Heart failure (HF) is highly prevalent disease, and prevalence increases with age. HF is generally discovered on presentation of an acute episode of decompensation (or insufficiency). Acute decompensated heart failure (ADHF) is very frequent in elderly subjects and is difficult to diagnose when the patient is admitted with acute dyspnoea. The advent of plasma biomarkers, such as BNP or NT-proBNP represents a major advancement in the diagnostic of ADHF. ADHF leads to high rates of re-admission and mortality. The objectives of this doctoral thesis were: (1) to describe the epidemiology of ADHF in France in a one-day observational study of admissions for ADHF in 170 French hospitals; (2) to evaluate the prognostic and diagnostic value of natriuretic peptides (NPs) in ADHF; (3) to describe the extent of post-transcriptional modifications in these NPs in ADHF; and (4) to search for new biomarkers.The comparison of the prognostic and diagnostic properties of NPs showed that the 4 commercially available NPs (namely BNP, NT-proBNP, proBNP and MR-proANP) overall have very similar prognostic and diagnostic abilities. However, proBNP and BNP seem to be more useful for diagnosis, while MR-proANP appears to be better for the association with 5-year mortality.Amongthe post-transcriptional modifications of BNP, we studied the impact of glycosylation of pro¬BNP. Threonin 71 0-glycosylation prevents cleavage of proBNP into BNP and NT-proBNP, resulting in the release of proBNP from the cell without being cleaved. Conversely, non-glycosylated proBNP is cleaved into BNP and NT-proBNP by corin or furin. We showed that non-glycosylation of proBNP and activation of furin are two important mechanisms in the acceleration of production of NPs during ADHF. We also showed that production of NT-proBNP was more closely linked to the rate of glycosylation of proBNP than to the production of BNP. Thus, our results strongly suggest that NT-proBNP should be used in future studies exploring the concept of "biomarker-guided therapy" in ADHF.To investigate new biomarkers, we explored plasma concentrations of 5 microRNAs (miR-l/-21/-23/-126/-423-5p), in patients with acute dyspnoea. None of these microRNAs were shown to have any diagnostic value. Conversely, miR-423-5p appears to be a prognostic marker for re-admission at 1 year. Secondly, we investigated the consequences of cardiac congestion on the liver. The hepatic markers studied were alkaline phosphatise and transaminases. Markers of cholestasis were associated with hepatic congestive while markers of cellular necrosis (transaminases) were related to arterial hypertension and low cardiac output. An increase in transaminases was associated with various criteria of excess mortality in the short term

No description available.

Hydrogen sulfide (H2S) is a gasotransmitter that has shown cardioprotective effects in the setting of myocardial injury such as acute myocardial infarction (MI) and pressure overload-induced heart failure. However, there are shortcomings in precision and control release from the use of traditional formulations of H2S in the form of inorganic salts. In this thesis, we sought to determine if the novel, orally active, slow-releasing H2S-compound SG1002 plays a role in attenuating MI-induced left ventricular (LV) dysfunction and adverse remodeling. We also evaluated the effect of SG1002 on changes in ECG parameters such as QT interval, in addition to 28-day survival post MI. SG1002 protects against ischemic cardiomyopathy in mice by mitigating LV dysfunction as measured by echocardiography and decreasing LV scar size as measured by histopathological methods. The improvement in survival might be due to the reduction in QT interval prolongation hence lessening the likelihood of forming lethal arrhythmias post MI. Western blot analyses of SG1002 treated mice showed restoration of VEGF levels indicating a pivotal role played by pro-angiogenic signaling in the improvement of cardiac function and attenuation of adverse remodeling. We propose that SG1002 can be a promising pharmacotherapeutic means for the treatment of ischemic heart failure.