Дисертації з теми "CARDIAC CONDITIONS"

Cardiac magnetic resonance (CMR) provides advantages over other cardiac imaging modalities when evaluating conditions associated with sudden cardiac death. CMR provides high-quality, cross-sectional images that enable accurate anatomical delineation, precise and reproducible measurements of right ventricular volumes and robust identification of non-compacted myocardium. Despite this, the diagnosis and prognosis of some conditions associated with sudden cardiac death remain challenging or indeed uncertain. This has implications for not just the decedent but also surviving family members in whom imaging screening for cardiovascular conditions may be of benefit. In this thesis, I assessed the ability of CMR to prognosticate patients with right ventricular abnormality and clinical suspicion of arrhythmogenic right ventricular cardiomyopathy (ARVC). Using our novel technique based on CMR signal intensity, I calculated left ventricular noncompacted mass and determined the correlation to long term outcomes. Finally, I evaluated the accuracy of post mortem CMR to identify causes of unexplained death, when compared to traditional autopsy, and its potential role in the coronial process.

The left atrium (LA) plays an important role in the modulation of LV filling and contributes to LV stroke volume with atrial contraction. Despite this important role, much research to date has been focused on the ventricles in disease, rather than the atria. In recent years there has been increasing interest and excitement in the function of the LA in normal and disease states – no longer is the LA secondary to the left ventricle (LV). The LA has three major functions: reservoir, conduit and contractile. The LA acts as a reservoir during ventricular systole as it fills with blood via the pulmonary veins and expands in size, subsequently, the mitral valve opens and the conduit phase is this passing of blood from the LA to the LV due to a small pressure gradient. Lastly, atrial systole, or the ‘atrial kick’, provides further augmentation of the LV stroke volume at the end of ventricular diastole. Methods for non-invasive assessment of these LA functions have been limited due to echocardiographic technology and the cumbersome nature data collection for these parameters. Prior techniques included assessment of LA size, phasic changes in LA size or volume as well as a variety of Doppler parameters which provided a cruder assessment of the LA functions. Strain is a unitless measurement of myocardial deformation and can be applied to assess the three LA functions in more detail. Contemporary strain research uses 2D-speckle tracking echocardiography (STE), where strain represents a fraction change in myocardial length relative to baseline and is expressed as a percentage. As strain technology surges forward with now dedicated LA strain software packages, the importance of the left atrium has become increasingly recognised. Improved strain technology has allowed easier and more widely available assessment of the three LA functions. Several studies have now documented normal LA strain values in large populations, and specifically, variations due to age and gender. Multiple literature reviews and guideline documents from cardiac imaging bodies have provided a standardised basis for acquisition of LA strain and the language used to describe LA functions and strain values. Previously, different gating techniques, software and terminology made comparison of literature more challenging. Interest and guidance from these peak bodies such as the European society of cardiovascular imaging confirms the importance of LA strain moving forward. There are many disease states which impact upon LA function and further study of LA strain in these areas may allow identification of subclinical atrial disease and impact on diagnostic or treatment pathways. In reviewing the literature, this thesis examines the current knowledge for clinical applications of LA strain in various pathologies/disease states. To contribute to current LA strain research, this thesis goes on to investigate the reproducibility of the LA strain technique, comparing strain readers of different expertise. This is an important step for uptake of LA strain into widespread use. The study showed LA strain was highly reproducible by a novice strain reader using multi-vendor analysis software and secondly, that there was good interobserver reproducibility between novice and experts. The thesis goes on to investigate the use of LA strain in a specific clinical scenario - cardiac amyloidosis (CA). Cardiac amyloidosis is a condition leading to amyloid protein deposition in cardiac tissue and subsequent organ dysfunction. Recent studies have shown that CA leads to LA dysfunction and abnormal LA strain and strain rate values. Given many different conditions can lead to reduction in LA strain, further investigation into changes and degree of LA dysfunction with CA compared to mimicking pathologies is of importance. Ventricular hypertrophy due hypertension can make differentiation of cardiac amyloidosis difficult using echocardiography alone – particularly when clinical history of hypertension is not previously known. The second original research study confirms a severe reduction in LA function in patients with cardiac amyloidosis, concordant with that seen in other studies. Additionally, LA function in CA was significantly worse compared to the hypertensive group, despite similar increases in LV wall thickness. Therefore, LA strain may provide incremental value in differentiating cardiac amyloidosis from increased LV wall thickness secondary to hypertension. Further investigation with larger cohorts and comparison between strain values in CA and other infiltrative pathologies should be considered to improve observe how specific this severe reduction in LA strain values is for CA compared to other infiltrative pathologies causing increased LV wall thickness. LA strain is a promising emerging tool, the applications of which will be further explored in this thesis.
Thesis (Masters)
Master of Philosophy (MPhil)
School of Medicine
Griffith Health
Full Text

The cardiomyocyte is a complex biological system where many mechanisms interact non-linearly to regulate the coupling between electrical excitation and mechanical contraction. For this reason, the development of mathematical models is fundamental in the field of cardiac electrophysiology, where the use of computational tools has become complementary to the classical experimentation. My doctoral research has been focusing on the development of such models for investigating the regulation of ventricular excitation-contraction coupling at the single cell level. In particular, the following researches are presented in this thesis: 1) Study of the unexpected deleterious effect of a Na channel blocker on a long QT syndrome type 3 patient. Experimental results were used to tune a Na current model that recapitulates the effect of the mutation and the treatment, in order to investigate how these influence the human action potential. Our research suggested that the analysis of the clinical phenotype is not sufficient for recommending drugs to patients carrying mutations with undefined electrophysiological properties. 2) Development of a model of L-type Ca channel inactivation in rabbit myocytes to faithfully reproduce the relative roles of voltage- and Ca-dependent inactivation. The model was applied to the analysis of Ca current inactivation kinetics during normal and abnormal repolarization, and predicts arrhythmogenic activity when inhibiting Ca-dependent inactivation, which is the predominant mechanism in physiological conditions. 3) Analysis of the arrhythmogenic consequences of the crosstalk between β-adrenergic and Ca-calmodulin dependent protein kinase signaling pathways. The descriptions of the two regulatory mechanisms, both enhanced in heart failure, were integrated into a novel murine action potential model to investigate how they concur to the development of cardiac arrhythmias. These studies show how mathematical modeling is suitable to provide new insights into the mechanisms underlying cardiac excitation-contraction coupling and arrhythmogenesis.
Il cardiomiocita è un sistema biologico complesso in cui molti meccanismi interagiscono non linearmente nel processo che accoppia l'eccitazione elettrica alla contrazione meccanica. Lo sviluppo di modelli matematici è quindi fondamentale nel settore dell'elettrofisiologia cardiaca, dove l'uso di strumenti computazionali è diventato complementare alla classica sperimentazione. La mia attività di ricerca si è concentrata sullo sviluppo di tali modelli allo scopo di investigare la regolazione dell'accoppiamento eccitazione-contrazione nella cellula ventricolare. In particolare, questa tesi presenta le seguenti attività: 1) Studio delle inaspettate deleterie conseguenze della somministrazione di un bloccante del canale sodio ad un paziente affetto da sindrome del QT lungo di tipo 3. I risultati sperimentali sono stati usati per riprodurre con un modello di corrente sodio gli effetti di mutazione e trattamento farmacologico, al fine di studiare come questi influenzino il potenziale d'azione umano. La nostra ricerca ha suggerito che l'analisi del fenotipo clinico non è sufficiente per somministrare un farmaco a pazienti che presentano mutazioni con indefinite proprietà elettrofisiologiche. 2) Sviluppo di un modello di inattivazione del canale calcio di tipo L nel cardiomiocita di coniglio allo scopo di riprodurre fedelmente i contributi di inattivazione voltaggio e calcio-dipendente. Il modello, applicato all'analisi delle cinetiche di tale corrente durante normale ed anormale ripolarizzazione, ha predetto lo sviluppo di attività aritmica in caso di inibizione del meccanismo calcio-dipendente, il cui effetto è predominante in condizioni fisiologiche. 3) Analisi delle conseguenze aritmogene dell'interazione tra le vie di segnalazione di stimolazione beta-adrenergica e proteina chinasi calcio-calmodulina dipendente. Le descrizioni dei due sistemi regolatori, entrambi aumentati in condizioni di insufficienza cardiaca, sono state integrate in un nuovo modello di potenziale d'azione murino, al fine di studiare come questi concorrono nell'insorgenza di aritmie. Questi studi mostrano come la modellistica matematica permetta di investigare i meccanismi che regolano l'accoppiamento eccitazione-contrazione e l'aritmogenesi.

The cardiomyocyte is a complex biological system where many mechanisms interact non-linearly to regulate the coupling between electrical excitation and mechanical contraction. For this reason, the development of mathematical models is fundamental in the field of cardiac electrophysiology, where the use of computational tools has become complementary to the classical experimentation. My doctoral research has been focusing on the development of such models for investigating the regulation of ventricular excitation-contraction coupling at the single cell level. In particular, the following researches are presented in this thesis: 1) Study of the unexpected deleterious effect of a Na channel blocker on a long QT syndrome type 3 patient. Experimental results were used to tune a Na current model that recapitulates the effect of the mutation and the treatment, in order to investigate how these influence the human action potential. Our research suggested that the analysis of the clinical phenotype is not sufficient for recommending drugs to patients carrying mutations with undefined electrophysiological properties. 2) Development of a model of L-type Ca channel inactivation in rabbit myocytes to faithfully reproduce the relative roles of voltage- and Ca-dependent inactivation. The model was applied to the analysis of Ca current inactivation kinetics during normal and abnormal repolarization, and predicts arrhythmogenic activity when inhibiting Ca-dependent inactivation, which is the predominant mechanism in physiological conditions. 3) Analysis of the arrhythmogenic consequences of the crosstalk between β-adrenergic and Ca-calmodulin dependent protein kinase signaling pathways. The descriptions of the two regulatory mechanisms, both enhanced in heart failure, were integrated into a novel murine action potential model to investigate how they concur to the development of cardiac arrhythmias. These studies show how mathematical modeling is suitable to provide new insights into the mechanisms underlying cardiac excitation-contraction coupling and arrhythmogenesis.
Il cardiomiocita è un sistema biologico complesso in cui molti meccanismi interagiscono non linearmente nel processo che accoppia l'eccitazione elettrica alla contrazione meccanica. Lo sviluppo di modelli matematici è quindi fondamentale nel settore dell'elettrofisiologia cardiaca, dove l'uso di strumenti computazionali è diventato complementare alla classica sperimentazione. La mia attività di ricerca si è concentrata sullo sviluppo di tali modelli allo scopo di investigare la regolazione dell'accoppiamento eccitazione-contrazione nella cellula ventricolare. In particolare, questa tesi presenta le seguenti attività: 1) Studio delle inaspettate deleterie conseguenze della somministrazione di un bloccante del canale sodio ad un paziente affetto da sindrome del QT lungo di tipo 3. I risultati sperimentali sono stati usati per riprodurre con un modello di corrente sodio gli effetti di mutazione e trattamento farmacologico, al fine di studiare come questi influenzino il potenziale d'azione umano. La nostra ricerca ha suggerito che l'analisi del fenotipo clinico non è sufficiente per somministrare un farmaco a pazienti che presentano mutazioni con indefinite proprietà elettrofisiologiche. 2) Sviluppo di un modello di inattivazione del canale calcio di tipo L nel cardiomiocita di coniglio allo scopo di riprodurre fedelmente i contributi di inattivazione voltaggio e calcio-dipendente. Il modello, applicato all'analisi delle cinetiche di tale corrente durante normale ed anormale ripolarizzazione, ha predetto lo sviluppo di attività aritmica in caso di inibizione del meccanismo calcio-dipendente, il cui effetto è predominante in condizioni fisiologiche. 3) Analisi delle conseguenze aritmogene dell'interazione tra le vie di segnalazione di stimolazione beta-adrenergica e proteina chinasi calcio-calmodulina dipendente. Le descrizioni dei due sistemi regolatori, entrambi aumentati in condizioni di insufficienza cardiaca, sono state integrate in un nuovo modello di potenziale d'azione murino, al fine di studiare come questi concorrono nell'insorgenza di aritmie. Questi studi mostrano come la modellistica matematica permetta di investigare i meccanismi che regolano l'accoppiamento eccitazione-contrazione e l'aritmogenesi.

Glucocorticoids increase PDK4 mRNA and protein expression, which phosphorylates PDH, thereby preventing the formed pyruvate from undergoing mitochondrial oxidation. This increase in PDK4 expression is mediated by the mandatory presence of FoxOs in the nucleus. Rat cardiomyocytes exposed to Dx produced a robust decrease in glucose oxidation. Measurement of FoxO compartmentalization demonstrated increase in nuclear, but resultant decrease in cytosolic content of FoxO1 with no change in the total content. The increase in nuclear content of FoxO1 correlated to an increase in nuclear phospho p38 MAPK together with a robust association between this transcription factor and kinase. Dx also promoted nuclear retention of FoxO1 through a decrease in phosphorylation of Akt, an effect mediated by heat shock proteins binding to Akt. Instead, Dx increased the association of Sirt1 with FoxO1, thereby causing a decrease in FoxO acetylation. Our data suggests that FoxO1 has a major PDK4 regulating function. Related to nutrient excess, FoxO1 has a role in regulating fatty acid (FA) uptake and oxidation, and triglyceride storage by mechanisms that are largely unresolved. We examined the mechanism behind palmitate (PA) induced TG accumulation in cardiomyocytes. PA treated cardiomyocytes showed substantial increase in TG accumulation, accompanied by amplification in nuclear migration of phospho-p38 and FoxO1, iNOS induction and translocation of CD36 to the plasma membrane. PA also increased Cdc42 protein and its tyrosine nitration, there by re-arranging the cytoskeleton and facilitating CD36 translocation. Cardiomyocyte cell death is a major contributing factor for diabetic cardiomyopathy, and multiple mechanisms have been proposed for its initiation. Diabetes increased the nuclear content of FoxO1 as a result of attenuated survival signalling. Increased nuclear FoxO1 augmented iNOS induction in the diabetic myocardium. The iNOS induced nitrosative stress increased the nitrosylation of GAPDH accompanied by its binding to Siah1 and translocation to the nucleus with an increased nuclear nitrosative stress. iNOS also nitrosylated caspase-3 there by hindering its ability to cleave PARP, a direct downstream target of Caspase-3. The resultant effect is activation of PARP with an nuclear compartmentalization of Apoptosis Inducing Factor (AIF) and resultant cell death.

Autologous explant-derived cardiac stem cell (EDC) therapies are a promising therapy for ischemic cardiomyopathy, but straightforward clinical translation is limited by traditional culture conditions which are often supplemented with ill-defined and xenobiotic components such as fetal bovine serum. Therefore, we investigated the influence of a commercially sourced serum-free (SF) xenogen-free medium on human EDC yield, phenotype, in vitro measures of EDC performance, and post-infarct cardiac repair using an immunodeficient mouse model of acute myocardial infarction. Despite reduced production of several pro-cardiogenic cytokines, SF EDCs promoted similar vessel formation, circulating stem cell recruitment and cardiogenic differentiation as compared to standard cultures. Transplant of SF EDCs into immunodeficient mice 1 week after myocardial infarction boosted post-ischemic repair beyond that of standard EDCs by enhancing viable myocardium within the infarct. These findings demonstrate that serum-free culture methods provide a superior cardiac-derived cell product with ready clinical translatability.

Mitochondria represent the main site of both ROS formation and degradation. One of the main source of mitochondrial ROS is represented by monoamine oxidases (MAOs). MAOs are flavoenzymes located in the outer mitochondrial membrane, which catalyse the oxidative deamination of biogenic amines yielding aldehydes, ammonia, and hydrogen peroxide (H2O2). It has been demonstrated that these products contribute to the oxidative stress occurring in hearts subjected to pathological conditions, such as cardiac reperfusion injury and decompensated hypertrophy. As MAO inhibitors significantly protect the heart in these models of cardiac injury, we focused our attention on the molecular mechanisms underlying MAO activation. To address this issue we investigated (i) the availability of MAO substrates under conditions of oxidative stress or injury and (ii) their main cellular sources in the whole heart. By mass spectrometry (MS) analysis we identified several amines that became available upon different ex vivo protocols of cardiac injury, and we focused our attention on N-tele-methylhistamine (NMH) and its precursor histamine, which were found the most abundant. Thus, we evaluated the contribution of myocyte and non-myocyte cells as possible sources of MAO substrates. For this purpose we firstly excluded synaptic terminals that innervate heart by mice injection of a neurotoxin, 6-hydroxydopamine (6-OH-DOPA). Our findings demonstrate the relevant contribution of synaptic terminals to increase the availability of MAO substrates in the ex vivo model of oxidative stress. Next we considered isolated cardiomyocytes, as these cells undergo MAO-dependent oxidative stress. We showed that cardiomyocytes can synthesize MAO substrates and to induce MAO activity when exposed to oxidative stress. Taken together, we establish for the first time a relevant interaction between histamine metabolism and MAO activity in cardiac injury, that does not involve a receptor-dependent pathway. These findings can explain how MAO activity is turned on when cells are stressed. Moreover, it also helps understanding how the increase in MAO activity amplifies an initial oxidative stress. It has been largely shown that inflammation is usually involved in cardiac diseases and monocytes (Mn), macrophages (MF) as well as mast cells are involved in the inflammatory response. We focused our attention on immune phagocytic cells since the role of MAO has not been conclusively defined. Firstly, we demonstrated that both the MAO isoforms were expressed in both M1 and M2 MF. We focused our attention on MAO A, as it resulted the most expressed and significant isoform, especially in M2 MF. Then, we characterized its pathway of induction considering two different stimuli: LPS, that is a pro-inflammatory signal and IL-4 plus IL-13 (IL-4+IL-13), that is a combination of anti-inflammatory cytokines. It is well known that during differentiation and polarization MF generate ROS, which leads to the activation of different signalling pathways. However, the mechanisms that induce ROS formation and activate this signalling remain unclear. Here we demonstrated that MAO contributes to macrophage differentiation and polarization through its H2O2 production. Taken together, these data demonstrate for the first time that MAO-A plays a role in M2 MF differentiation and activation, besides its role in amine oxidative degradation. These novel insights about MAO activity in phagocytic cells suggest that this enzyme could represent a new target to modulate MF differentiation and activation under pathological conditions to avoid the side effects related to inflammation such as fibrosis, cardiac remodelling, and oxidative stress amplification in post-ischemic reperfusion injury.
I mitocondri rappresentano il sito principale di origine e smaltimento delle specie reattive dell'ossigeno (ROS). Una delle più importanti fonti mitocondriali di ROS è rappresentata dalle monoammino ossidasi (MAO). Le MAO sono flavoenzimi situati nella membrana mitocondriale esterna, che catalizzano la deaminazione ossidativa di ammine biogeniche, producendo aldeidi, ammoniaca e perossido d'idrogeno (H2O2). È stato dimostrato che questi prodotti contribuiscono allo stress ossidativo che si verifica in cuori soggetti a condizioni patologiche, come ad esempio l'ischemia riperfusione e lo scompenso da ipertrofia. Dato che gli inibitori per le MAO proteggono significativamente il cuore in questi modelli di danno cardiaco, abbiamo focalizzato la nostra attenzione sui meccanismi molecolari alla base dell'attivazione di questi enzimi. A questo scopo è stata analizzata (i) la disponibilità dei substrati per le MAO in condizioni di stress ossidativo o danno cardiaco, e sono state valutate (ii) le principali fonti cellulari per questi substrati nel cuore. Mediante spettrometria di massa (MS) sono state identificate diverse ammine, rese disponibili in due differenti protocolli sperimentali d'induzione di stress cardiaco ex vivo. Particolare attenzione è stata data alla N-tele-Metilistamina (NMH) ed il suo precursore istamina, che rappresentavano la maggiore frazione di ammine sul contenuto totale nel cuore in queste condizioni di stress. Quindi, è stato valutato il contributo delle cellule miocitiche e non, come possibili fonti di substrati per le MAO. Anzitutto sono stati considerati i terminali sinaptici che innervano il cuore, e quindi eliminati iniettando gli animali con una neurotossina, la 6-idrossidopamina (6-OH-DOPA). I risultati così ottenuti dimostrano il contributo dei terminali nell'aumentare la disponibilità di substrati per le MAO nel modello ex vivo sottoposto a stress ossidativo. Sucessivamente, abbiamo considerato i cardiomiociti isolati, in quanto anch'essi subiscono lo stress ossidativo dipendente dalle MAO. Infatti abbiamo dimostrato che i cardiomiociti soggetti a stress ossidativo sono in grado di sintetizzare substrati per le MAO, promuovendo l'attività dell'enzima. Si stabilisce così per la prima volta un'importante relazione tra il metabolismo dell'istamina e l'attività dell'enzima MAO in condizioni di danno cardiaco, la quale non comporta alcuna dipendenza da un eventuale recettore istaminergico. Questi risultati spiegano come lo stress cellulare possa indurre l'attività enzimatica dell'enzima MAO amplificando l'iniziale stress ossidativo. È stato ampiamente dimostrato che l'infiammazione insorge durante le malattie cardiache e non solo, inoltre che le cellule infiammatorie coinvolte come monociti (Mn), macrofagi (MF) e mastociti sono particolarmente rilevanti ed attive. Pertanto la nostra attenzione è stata incentrata dalle cellule fagocitarie in cui il ruolo dell'enzima MAO non è stato ancora definito. In primo luogo, è stato dimostrato che entrambe le isoforme MAO (A e B) sono espresse sia nei MF M1 che M2. Poi ci siamo focalizzati su MAO A, in quanto è risultata essere l'isoforma principalmente espressa, soprattutto nei MF M2. In seguito è stato caratterizzato il suo meccanismo d'induzione, considerando due diversi stimoli: l'LPS e la combinazione delle citochine anti-infiammatorie IL-4 ed IL-13 (IL-4 + IL-13). È noto che, durante i processi di differenziamento e di polarizzazione, i MF generino ROS, che inducono l'attivazione di diverse vie di segnale. Tuttavia, i meccanismi che inducono la formazione di questi ROS non sono stati caratterizzati. In questo lavoro è stato dimostrato per la prima volta che l'isoforma A dell'enzima MAO svolge un ruolo rilevante nel differenziamento e nell'attivazione dei MF M2, mediante la produzione di H2O2. Questi nuovi risultati nelle cellule fagocitiche suggeriscono che questo enzima potrebbe rappresentare un nuovo bersaglio per modulare il differenziamento e l'attivazione dei MF. In particolare, in condizioni patologiche la loro modulazione potrebbe limitare gli effetti collaterali legati all'infiammazione, come ad esempio la fibrosi, il rimodellamento cardiaco, e l'amplificazione dello stress ossidativo nel danno da ischemia/riperfusione.

Background: Hypertrophic Cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are genetic cardiovascular diseases that cause sudden cardiac death. When an individual is diagnosed with an inherited disease such as HCM/LQTS it is critical that their biological relatives are notified of their increased risk. Newly diagnosed individuals in turn notify other at-risk family members through a successive process called cascade screening. This facilitates screening of at-risk biological relatives through genetic testing and/or clinical testing, and treatment for HCM/LQTS prior to development of life-threatening complications. However, for cascade screening to detect all potential cases the disease risk must be effectively communicated to all at-risk relatives. The responsibility for notifying family members of this risk largely falls to the first person diagnosed in the family (proband). Empiric evidence suggests that around half of at-risk relatives are not screened in accordance with cascade screening recommendations, potentially due to information about HCM/LQTS risk not being communicated effectively in their families. Factors have been identified that influence communication about genetic risk in families with non-cardiac disease; however, it is not known if or how these factors apply in families with genetic cardiac disease. These include network factors, which describe characteristics of relationships between family members and non-network factors, which describe characteristics of individuals including individual factors, disease factors, and sociocultural factors. There is a critical need to understand communication in families with HCM/LQTS in order to facilitate effective genetic risk communication in families, improve adherence to cascade screening recommendations, and prevent death and complications from cardiovascular diseases. Objectives: The purpose of this study was to improve our understanding of the relationships among network and non-network factors and communication of genetic risk for HCM/LQTS between probands and their relatives. I proposed the following aims: Aim 1: Describe family social network structures and communication paths about risk for HCM/LQTS from probands to their relatives. Aim 2: Identify which network and non-network factors are associated with who is told about risk for HCM/LQTS. Methods: The sample for this study included individuals with HCM or LQTS recruited through the University of Iowa Cardiology Clinics (UI) and the University of Wisconsin Inherited Arrhythmia Clinic (UW). Data were collected using a structured interview, family pedigree, and survey. Analysis included egocentric social network analysis, descriptive, bivariate, and multilevel logit regression modeling. Results: Participants in this study had an average of 24 living at-risk relatives in their families. Overall, just over half (52%) of these at-risk relatives had been reported to have been told about their risk. However, within families, the percentage of relatives told about their risk ranged from 0%-100%. Ninety percent of first-degree relatives were told about their risk, 61% of second-degree relatives were told and 33% of third-degree relatives were told. Recruitment site affiliation was determined to be a confounder and so analyses were calculated separately for UI and UW. In both the UI and UW samples, network factors including closer geographic distance, increased emotional closeness, increased relationship quality, increased frequency of communication, higher betweenness centrality, and closer degree of biological relation were independently associated with increased odds of communication of risk. In the UI sample, non-network factors that were independently associated with increased odds of communication of risk included younger age at diagnosis; having LQTS; having positive genetic test results; having an ICD; younger current age; being female; having increased role limitations due to physical functioning; feeling anxious about telling family members about risk; feeling communication was a burden; feeling that communication was a responsibility or duty; being happy to be able to share important information; and identifying financial issues, pregnancies, or upcoming marriages as playing a role in communication. In a multivariate model, increased frequency of communication, closer degree of biological relation, having an ICD, and identifying financial issues and pregnancies as contributors to communication were significantly associated with communication of genetic risk information. In the UW sample, non-network factors that were independently associated with increased odds of communication of risk included younger age, decreased emotional wellbeing, increased role limitations due to emotional wellbeing, and decreased energy and fatigue. In a multivariate model, increased frequency of communication and closer degree of biological relation were significantly associated with communication. Although over half of at-risk relatives were told about their risk, just over half of those (53.8%) were reported to have screened for disease, which represents 27% of all at-risk relatives. Of those tested, 35% were reported as diagnosed with HCM/LQTS. Conclusion: Communication of genetic risk for HCM/LQTS in families is inadequate and contributes to the problem of relatives not being screened for disease. Insight on the factors that influence communication in families at risk of sudden cardiac death can guide development of interventions, policies, and future research aimed at improving genetic risk communication and cascade screening, and preventing death and complications from inherited cardiac diseases. This research is applicable for genetic conditions where population based screening methods are not effective and rely on families to communicate risk and need for screening.

Intensive training is associated with hemodynamic changes that typically induce an enlargement of cardiac chamber. Despite LA dilatation in athletes has been interpreted as a benign adaptation, little evidence is available. The aim of this thesis is to demonstrate that LA size changes in response to alterations in loading conditions and to analyse atrial myocardial function in athletes through the application of novel echocardiographic techniques. We found that top-level athletes exhibit a dynamic morphological and functional LA remodelling, induced by training, with an increase in reservoir and conduit volumes, but stable active volume. Training causes an increase in biatrial volumes which is accompanied by normal filling pressures and stiffness. These changes in atrial morphology are not associated with respective electrical changes. Extending the evidence from adult athletes to children, we found that training-induced atrial remodelling can occur in the early phases of the sports career and is associated with a preserved biatrial function. Finally, in a meta-analysis study of the available evidence we demonstrated that atrial function and size are not affected by aging. In conclusions, athlete’s heart is characterized by a physiological biatrial enlargement. This adaptation occurs in close association with LV cavity enlargement, is dynamic and reversible. This increase in biatrial size is not intrinsically an expression of atrial dysfunction. Indeed, in athletes the atria are characterized by a preserved reservoir function, normal myocardial stiffness, and dynamic changes in response to different loading conditions.

The purpose of this thesis is to establish if there is any evidence to support the hypothesis that altered ventricular loading conditions after the cessation of exercise may cause "cardiac fatigue". The studies that have shown post-exercise "cardiac fatigue" have not controlled for either preload or afterload or both, before and after exercise. These studies may rather have identified the effects of alterations in peripheral vascular function on left ventricular function after prolonged exercise. The research study in this thesis is to evaluate if the loading conditions of the heart affect the echocardiographic measurements after exercise that may be misinterpreted as "cardiac fatigue". Echocardiography as a tool of cardiac evaluation cannot be done during exercise because of the technical difficulty of doing a cardiac ultrasound on a human being in motion. The studies that have investigated post exercise "cardiac fatigue" have therefore measured cardiac function after exercise and retrospectively assumed that the cardiac dysfunction was present during exercise since the cardiac demands are at their peak during exercise. However, the post exercise period may be associated with altered loading conditions that may cause changes in the echocardiographic measurements that are similar to cardiac abnormalities.

Ataxia-telangiectasia mutated kinase (ATM), a serine/threonine kinase primarily located in the nucleus, is typically activated in response to DNA damage. Individuals with mutations in ATM gene develop a disease called Ataxia telangiectasia (AT). These individuals are more susceptible to ischemic heart disease and metabolic disorder. Our lab has previously shown that ATM plays a critical role in β-adrenergic receptor (β-AR) - and myocardial infarction (MI)-stimulated myocyte apoptosis and cardiac remodeling. This study tested the hypothesis that ATM plays a critical role in cardiac autophagy and glucose metabolism following MI and ischemia, respectively. Early during MI (4 hours after its onset) and 4 hours post-treatment with ATM inhibitor KU-55933, ATM deficiency resulted in autophagic impairment in the heart and in cardiac fibroblasts, respectively. Such autophagic changes in the heart and in cardiac fibroblasts associated with the activation of GSK-3β and mTOR, and inactivation of Akt and AMPK. ATM deficiency also augmented autophagy in the infarct region of the heart 28 days post-MI as well as in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Autophagic changes in the infarct region during ATM deficiency associated with enhanced Akt, Erk1/2, and mTOR activation. Additionally, the lack of ATM accelerated glycolysis and gluconeogenesis and augmented TCA cycle metabolism under non-ischemic conditions. Following a 20 minute global ischemic period, the glycolytic pathway, not the gluconeogenic pathway, was down-regulated during ATM deficiency which was found to be associated with alterations in TCA cycle metabolism. Such metabolic rearrangements associated with changes in the phosphorylation of Akt, GSK-3β, and AMPK alongside alterations in Glut4 protein expression. Thus, ATM deficiency impairs autophagy early after the onset of MI and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 4 hours. In contrast, ATM deficiency appears to augment autophagy late post-MI in the infarct region of the heart and in cardiac fibroblasts treated with ATM inhibitor KU-55933 for 24 hours. Lack of ATM alters glucose and TCA cycle metabolism with and without ischemia. Such findings implicate ATM as a key player in autophagic changes in the heart in response to MI as well as in glucose metabolism under non-ischemic and ischemic conditions.

[spa] Los trastornos internalizantes (TIs) son las psicopatologías más prevalentes en adultos y generan un gran deterioro en muchas áreas de la persona y de sus familiares. La edad media de inicio de muchos de estos trastornos se encuadra dentro de la adolescencia, motivo por el cual esta etapa se considera un periodo de riesgo para el desarrollo de TIs. La probabilidad de que un TI se mantenga de la adolescencia hasta la edad adulta es elevada, ya que estos problemas no son suficientemente detectados por los sistemas de atención primaria. En este sentido, el estudio de los factores de vulnerabilidad relacionados con los TIs puede ayudar esclarecer la génesis y el mantenimiento de estos trastornos y, consecuentemente, ayudar a diseñar programas de prevención y de intervención basados en la evidencia empírica. Por lo que sabemos, la evidencia disponible sobre este tema en adolescentes es limitada. Tradicionalmente, el estudio de la psicopatología se ha centrado en concepciones lineales de la conducta humana. En respuesta a ello, la Teoría de los Sistemas Dinámicos (TSD), una perspectiva reciente dentro del ámbito de la psicología, puede ser útil a la hora de incrementar nuestro conocimiento sobre la conducta humana como lo que es: un fenómeno complejo y no lineal. El objetivo principal de esta tesis fue utilizar la TSD como marco teórico para dar respuesta a algunas de las lagunas existentes sobre la vulnerabilidad psicológica y fisiológica para el desarrollo de TIs en adolescentes. Se intentó dar respuesta a dos preguntas generales: a) ¿Se puede distinguir entre adolescentes sanos más y menos vulnerables a desarrollar TIs, mediante el uso de índices de complejidad afectiva y cardíaca?, b) ¿Cómo se relacionan la complejidad afectiva y cardíaca de los adolescentes sanos con otros factores de vulnerabilidad para los TIs ya establecidos, como el sexo, los síntomas de ansiedad o la desregulación emocional? Se diseñaron cinco estudios en condiciones ecológicas o de laboratorio con el objetivo de obtener una mejor representación de las dinámicas afectivas y cardíacas. En el estudio 1, una muestra de adolescentes sanos informó sobre sus niveles de estado de ánimo, ansiedad y preocupación, dos veces al día durante un periodo de 100 días. Los estudios 2 y 3 consistieron en registrar la actividad cardíaca de adolescentes sanos durante 120 minutos mientras llevaban a cabo actividades diarias dentro del contexto académico. La muestra del estudio 2 se dividió en dos grupos en función del sexo (chicos/chicas) y del nivel de ansiedad (alto/bajo). Para el estudio 3 se seleccionó una muestra aleatoria, independiente del nivel de ansiedad de los participantes. En los estudios 4 y 5 se registró la respuesta cardíaca de adolescentes sanos mientras se sometían a un protocolo de inducción de estrés social. El estilo de regulación emocional de los participantes también se evaluó en el estudio 4. Casi todos los exponentes de escala demostraron su fractalidad y multiestabilidad. Además, los exponentes de preocupación correlacionaron positivamente con el control intencional, y negativamente con la afectividad negativa y la necesidad de afiliación (estudio 1). En referencia a la complejidad cardíaca se encontró que ésta era inferior en las chicas en comparación con los chicos (estudios 2, 3 y 5), así como en aquellos adolescentes con una mayor tendencia a utilizar estrategias de regulación emocional negativas en general, pero solo cuando pasaron de la fase de estrés a la de recuperación (estudio 4). También se observó que, a menor complejidad cardíaca, mayor nivel de síntomas internalizantes (estudio 3). Finalmente, el sexo femenino predijo una menor complejidad cardíaca, al contrario que el estilo de regulación emocional negativo, que se observó que estaba positivamente relacionado con la complejidad cardíaca (estudio 4). En resumen, esta tesis doctoral demuestra que las fluctuaciones afectivas y cardíacas se encuentran bajo procesos de regulación complejos con memoria, que tienen en cuenta la información de diferentes escalas temporales para asegurar una adaptación más exitosa a la vida diaria. También se concluye que aquellos adolescentes más vulnerables a desarrollar un TI (chicas, mayores síntomas de ansiedad o estrategias de regulación emocional disfuncionales) parecen tener menores niveles de complejidad afectiva y cardíaca que aquellos adolescentes menos vulnerables. Por tanto, una complejidad/flexibilidad afectiva y cardíaca reducidas podrían constituir marcadores psicológicos y fisiológicos de un patrón desadaptativo a la hora de confrontar demandas internas y externas
[cat] Els trastorns internalitzants (TIs) són les psicopatologies amb major prevalença en adults i generen un gran deteriorament en moltes àrees de la persona i dels seus familiars. L’edat mitjana d’inici de molts d’aquests trastorns s’emmarca dins l’adolescència, motiu pel qual aquesta etapa és considerada un període de risc per al desenvolupament de TIs. La probabilitat que un TI es mantingui de l’adolescència fins a l’edat adulta és elevada, ja que aquests problemes no són suficientment detectats pels sistemes d’atenció primerenca. En aquest sentit, l’estudi de factors de vulnerabilitat relacionats amb els TIs pot ajudar a esclarir la gènesi i el manteniment d’aquests trastorns i, conseqüentment, ajudar a dissenyar programes de prevenció i d’intervenció basats en l’evidència empírica. Pel que sabem, l’evidència disponible sobre aquest tema en adolescents és limitada. Tradicionalment, l’estudi de la psicopatologia s’ha centrat en concepcions lineals de la conducta humana. En resposta a això, la Teoria dels Sistemes Dinàmics (TSD), una perspectiva recent dins l’àmbit de la psicologia, pot ser útil a l’hora d’incrementar el nostre coneixement sobre la conducta humana com el que és: un fenomen complex i no lineal.L’objectiu principal d’aquesta tesi va ser emprar la TSD com a marc teòric per a donar resposta a algunes de les llacunes existents sobre la vulnerabilitat psicològica i fisiològica per al desenvolupament de TIs en adolescents. Es va intentar donar resposta a dues preguntes generals: a) Es pot distingir entre adolescents sans més i menys vulnerables a desenvolupar TIs, mitjançant l’ús d’índexs de complexitat afectiva i complexitat cardíaca?, b) Com es relacionen la complexitat afectiva i cardíaca dels adolescents sans amb altres factors de vulnerabilitat per als TIs ja establerts, com el sexe, els símptomes internalitzants o la desregulació emocional? Es van dissenyar cinc estudis sota condicions ecològiques o de laboratori, amb l’objectiu d’obtenir una millor representació de les dinàmiques afectives i cardíaques. En l’estudi 1, una mostra d’adolescents sans va informar sobre els seus nivells d’estat d’ànim, ansietat i preocupació, dues vegades per dia durant un període de 100 dies. Els estudis 2 i 3 van consistir en l’enregistrament de l’activitat cardíaca d’adolescents sans durant 120 minuts mentre duien a terme les seves activitats diàries dins el context acadèmic. La mostra de l’estudi 2 es va dividir en dos grups en funció del sexe (nins/nines) i del nivell d’ansietat (alt/baix). Per a l’estudi 3 es va seleccionar una mostra aleatòria, independent del nivell d’ansietat dels participants. En els estudis 4 i 5 es va enregistrar la resposta cardíaca d’adolescents sans mentre es sotmetien a un protocol d’inducció d’estrès social. L’estil de regulació emocional dels participants també es va avaluar durant l’estudi 4. Quasi tots els exponents d’escala varen demostrar la seva fractalitat i multiestabilitat. A més a més, els exponents de preocupació correlacionaren positivament amb el control intencional, i negativament amb l’afectivitat negativa i la necessitat d’afiliació (estudi 1). En referència a la complexitat cardíaca, es va trobar que aquesta era més baixa en les nines en comparació amb els nins (estudis 2, 3 i 5), així com en aquells adolescents amb una major tendència a emprar estratègies de regulació emocional més negatives en general, però només quan passaren de la fase d’estrès a la de recuperació (estudi 4). També es va observar que a menor complexitat cardíaca, major nivell de símptomes internalitzants (estudi 3). Finalment, el sexe femení va predir una menor complexitat cardíaca, al contrari de l’estil de regulació emocional negatiu, que es va trobar que estava positivament relacionat amb la complexitat cardíaca (estudi 4). En resum, aquesta tesi doctoral demostra que les fluctuacions afectives i cardíaques es troben sota processos de regulació complexos amb memòria, que tenen en compte la informació de diferents escales temporals per assegurar una adaptació més exitosa a la vida diària. També es conclou que aquells adolescents més vulnerables a desenvolupar un TI (nines, majors símptomes internalitzants o estratègies de regulació emocional disfuncionals) semblen tenir menors nivells de complexitat afectiva i cardíaca que aquells adolescents menys vulnerables. Per tant, una complexitat/flexibilitat afectiva i cardíaca reduïdes podrien constituir marcadors psicològics i fisiològics d’un patró desadaptatiu a l’hora de confrontar demandes internes i externes.
[eng] The internalizing disorders (IDs) are the highest prevalent psychopathological conditions in adults and cause great impairment in several areas of the individual and their relatives. Since adolescence marks the median age of onset for many IDs, it is considered a risk period for their development. Unfortunately, these problems are not sufficiently detected in primary care and the probability of maintaining an ID from adolescence to adulthood is high. The study of related vulnerability factors can help to disentangle the genesis and the maintenance of IDs, and consequently to design empirically based prevention and intervention programs. As far as we know, the evidence in adolescent population is still scarce. Traditionally, the study of psychopathology has focused on linear conceptions of human behavior. The Dynamic System Theory (DST), a recent perspective in the field of Psychology, can be a useful strategy for understanding human behavior as it is, a complex nonlinear phenomenon. The main objective of the present thesis was to overcome some gaps regarding the psychological and physiological vulnerability for IDs in adolescents, using the DST as the main theoretical framework. Two general questions were tried to answer: a) Can cardiac and affective complexity indexes help to distinguish between healthy adolescents more vulnerable and less vulnerable to experience IDs?, b) How are affective and cardiac complexity from healthy adolescents related to other established IDs-related vulnerability factors, such as sex, internalizing symptomatology or emotion dysregulation? Five studies were designed in ecological or laboratory conditions, in order to obtain a better representation of cardiovascular and affective dynamics. In the study 1, a sample of healthy adolescents reported their daily mood, anxiety and worry levels twice a day over a period of 100 days. In the studies 2 and 3, the cardiac activity of healthy adolescents was recorded during 120 minutes while performing regular activities within the academic context. The sample of the study 2 was divided into two groups according to sex (male/female) and anxiety symptoms level (high/low). The sample of the study 3 was randomly selected, regardless of their level of anxiety symptoms. In the studies 4 and 5, the cardiac activity of healthy adolescents was recorded while performing a socially relevant stress induction protocol. The emotion regulation style of the participants from the study 4 was also assessed. Almost all scaling exponents proved their fractal nature and multistability. Furthermore, worry exponents were positively correlated with effortful control, and negatively associated with negative affectivity and affiliativeness (study 1). Regarding cardiac complexity, it was found to be lower in females in comparison to males (study 2, 3 and 5), as well as in adolescents prone to engage in more negative emotion regulation strategies in general, but only when they switched from stress to recovery (study 4). Prediction analyses showed that the lower the cardiac complexity, the higher the internalizing symptoms (study 3). Finally, the female sex predicted a lower cardiac complexity, but the negative emotion regulation style was positively related to cardiac complexity (study 4). In summary, this doctoral thesis proves that the affective and cardiac fluctuations of healthy adolescents are under complex regulation processes that have memory and take into account information from different time scales, to successfully adapt to their daily life. It is also concluded that healthy adolescents more vulnerable to IDs (females, higher internalizing symptoms or emotion dysregulation strategies) seem to have lower levels of affective and cardiac complexity than less vulnerable adolescents. Therefore, this attenuated cardiac and affective flexibility/complexity may constitute physiological and psychological markers of a maladaptive pattern to confront internal and environmental challenges.

Sudden cardiac death is the second biggest cause of death in the UK and at least 12 young people aged 14 to 35 die each week from undetected cardiac conditions. Cardiac screening, 12-led ECG test, has been speculated to have 90% effectiveness for illness detection. The UK National Screening Committee does not mandate population screening because there is not enough evidence for the cost-effectiveness and psychological costs to the individual. Yet, measuring the effectiveness of a screening relies on its participants. Literature to date offers some explanations for participation and non-participation; however, there is no literature for parents' decision-making processes for cardiac screening for adolescents aged 14-17. Therefore, this research has emerged from the need to understand the cognitive and affective processes that explain the decisions whether or not to take part in cardiac. screening. In pmiicular, Weinstein's (1988) Precaution Adoption Process Model (P APM) is used to identify of the stages of engagement for a non-apparent, a relatively unknown health risk, and investigated role of affect in decision-making. Initially, we explored retrospective accounts of non-pmiicipant families with a qualitative study and found that parents m·e primary decision-makers and organisations providing screening have a fundamental role for communicating credibility, task impOliance and salience under unceliainty. FUlihelIDore, we have explored decision-making with a concurrent think aloud study and found that "feelings-of-risk" provide a first step in engagement with health risk. Collectively, we assessed these findings with a prospective mixed methods study in which parents of adolescents were staged according to P APM. The results indicate that the respondents' trust and confidence in the organisation and the screening procedure provides the first steps from being unaware, unengaged and needing more information whilst "feelings-of-risk" is integral for deciding whether or not to have screening. The reasons for non-pmiicipation is characterised as being unfamiliar (unaware), having low trust in the processes of the organisation (unengaged), low decisional certainty (need info), low concern (not intend) and having practical baniers (non-pmiicipant intenders). The implications ofthe results are considered for theory, research and practice.

Abstract Coronary artery disease is the leading cause of death in the world. The outcome of patients at a very high operative risk undergoing coronary artery bypass surgery has not been thoroughly investigated. Cohorts of patients underwent coronary surgery between January 1997 and December 2013 at the Oulu University Hospital, Finland. Data was acquired from electronic patient records. Statistical analysis was performed on the collected data to evaluate outcome and identify predictors of adverse events. Very high-risk patients who underwent isolated coronary artery bypass surgery had a high 30-day mortality (16.2%), but their 5-year survival was satisfactory (66.8%). Survivors of out-of-hospital cardiac arrest were compared to a control group. Immediate postoperative mortality was slightly higher in out-of-hospital cardiac arrest patients (6.3% vs. 0%, p = 0.24), but the overall 5-year survival rates were similar (80.7% vs. 84.5%). Patients with preoperative stage 3 chronic kidney disease have a higher mortality than patients with stage 1-2 chronic kidney disease. Kidney function decline/year was predictive of all-cause mortality, cardiovascular mortality and also tended to predict fatal and non-fatal cardiovascular events. The E-CABG postoperative complication grading system was used to stratify the severity and prognostic impact of postoperative complications and was shown to predict early and late mortality for these patients. The outcome of emergency coronary artery bypass surgery was studied in a multi-center setting. Increasing emergency classes, left ventricular ejection fraction ≤30%, on-pump surgery, and participating centers were independent predictors of in-hospital mortality. Survival rates at 1, 3 and 5 years were 86.4%, 81.6%, and 76.1%. Despite the high preoperative risk of these patients, the long-term outcome for coronary surgery is satisfactory. Patients with stage 3 chronic kidney disease may experience a significant decline in kidney function and poor outcome. Early referral to a nephrologist may be beneficial for these patients. The E-CABG complication grading system seems to be a promising tool for stratifying the severity and prognostic impact of complications occurring after coronary surgery
Tiivistelmä Sepelvaltimotauti on johtavia kuolinsyitä Maailmassa. Ohitusleikkauksen tuloksia ei ole täysin selvitetty erittäin korkean riskin potilailla. Potilaat leikattiin vuosina 1997-2013. Potilastiedot hankittiin sairauskertomuksista ja kuolinsyytiedot kansallisista rekistereistä. Erittäin korkean riskin potilaiden välitön kuolleisuus ohitusleikkauksen jälkeen on korkea (30 päivän kuolleisuus 16,2 %). Viiden vuoden kuluttua leikkauksesta elossa oli 66,8% leikatuista. Ohitusleikkausta edeltävästi elvytettyjä potilaita verrattiin kontrolliryhmään. Välittömät leikkauksen jälkeinen kuolleisuus oli 6,3% vs. 0% (p = 0,24). Viiden vuoden kuluttua leikkauksesta elossa oli tutkimusryhmästä 80,7% ja kontrolliryhmästä 80,7%. Leikkausta edeltävästi keskivaikean munuaisten vajaatoiminnan omaavilla potilailla on korkeampi kuolleisuus verrattuna potilaisiin, joiden munuaistoiminta on normaalia tai lievästi heikentynyt. Munuaisten vajaatoiminnan eteneminen ennusti kokonaiskuolleisuutta, sydän- ja verisuonikuolleisuutta ja enteili sydän- ja verisuonitapahtumia. E-CABG leikkauksen jälkeisten komplikaatioiden luokittelujärjestelmällä luokiteltiin leikkauksen jälkeisten komplikaatioiden vaikeusastetta ja ennusteellista vaikutusta. E-CABG luokat ja pisteytys ennustivat 1kk, 3kk kuolleisuutta ja kuolleisuutta pidemmällä aikavälillä. Päivystysohitusleikkauksen tuloksia tutkittiin monikeskusasetelmassa. Sairaalakuolleisuutta ennustivat päivystysleikkausluokitteluluokan vakavuus, vasemman kammion ejektiofraktio ≤30%, perfuusiossa tehty leikkaus ja leikkaava keskus. Potilaiden elossaololuvut olivat 1, 3 ja 5 vuoden kohdalla 86,4%, 81,6%, and 76,1%. Leikkaustulokset erittäin korkean riskin potilailla ohitusleikkauksesta ovat kohtuullisia leikkausta edeltävään riskiarvioon suhteutettuna. Näin ollen tämän potilasryhmän sepelvaltimotaudin hoito leikkaamalla on perusteltua. Keskivaikean munuaisten vajaatoiminnan omaavien potilaiden munuaissairauden etenemiseen seuranta-aikana liittyy kuolleisuutta ja sydän- ja verisuonitapahtumia. Aikaisessa vaiheessa tehty nefrolgin konsultaatio voi parantaa näiden potilaiden munuaisfunktiota. E-CABG komplikaatioiden luokittelujärjestelmä vaikuttaa lupaavalta työkalulta ohitusleikkauksen jälkeisten komplikaatioiden luokitteluun ja ennustevaikutuksien arviointiin

Background: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia. There is a need for new pharmacological treatment strategies since the current antiarrhythmic drugs have a modest efficacy and may have severe side effects. Cardioversion (CV) of AF offers an opportunity to study related conditions in sinus rhythm (SR) and during AF. Since catheter ablation of AF is a symptomatic treatment, it is important to have tools for measurement of arrhythmia-related symptoms. Aims: To evaluate the effect of atorvastatin on maintaining SR after CV of persistent AF. To assess if highsensitivity C-reactive protein (hsCRP) predicts the recurrence of AF after CV in a population randomized to treatment with either atorvastatin or placebo. To quantify the symptomatic effect of left atrial catheter ablation of AF. To assess if the restoration of SR by CV, in a population with persistent AF, affects sleep apnea. Methods: Paper I: A total of 234 patients were randomized to treatment with either high dose atorvastatin or placebo prior to CV. Paper II: In a pre-specified substudy which included 128 of the patients in study I, hsCRP was analyzed before and after CV. Paper III: Umea 22 Arrhythmia Questions (U22) is a questionnaire that quantifies paroxysmal tachycardia symptoms. A total of 105 patients underwent first-time pulmonary vein isolation and answered U22 forms at baseline and follow-up 304 (SD 121) days after ablation. Paper IV: Polysomnography was performed before and after CV in 23 patients with persistent AF scheduled for elective CV. Results: Paper I: An intention-to-treat analysis with the available data, by randomization group, showed that 57 (51%) in the atorvastatin group and 47 (42%) in the placebo group were in SR 30 days after CV (OR 1.44, 95%CI 0.85–2.44, P=0.18). Paper II: HsCRP did not significantly predict recurrence of AF at 30 days. However, after adjusting for treatment with atorvastatin, hsCRP predicted the recurrence of AF (OR 1.14, 95% CI 1.01–1.27). Six months after CV, hsCRP at randomization predicted recurrence of AF in both univariate analysis (OR 1.30, 95% CI 1.06–1.60) and in multivariate logistic regression analysis (OR 1.33, 95% CI 1.06– 1.67). Paper III: The U22 scores for well-being, arrhythmia as cause for impaired well-being, derived timeaspect score for arrhythmia, and discomfort during attack detected relevant improvements of symptoms after the ablation. U22 showed larger improvement in patients undergoing only one procedure than in patients who later underwent repeated interventions. Paper IV: Obstructive sleep apnea occurred in 17/23 patients (74%), and central sleep apnea in 6/23 patients (26%). Five patients had both obstructive and central sleep apnea. SR at follow-up was achieved in 16 patients. The obstructive apnea-hypopnea index, central apneahypopnea index, and the number of patients with obstructive or central sleep apnea did not differ before and after restoration of SR. Conclusions: Atorvastatin is not a treatment option with regards to maintaining SR after CV in patients with persistent AF. HsCRP was associated with AF recurrence 1 and 6 months after successful CV of persistent AF. U22 quantifies the symptomatic improvement after AF ablation with adequate internal consistency and construct validity. Both obstructive and central sleep apneas are highly prevalent in patients with persistent AF. Obstructive sleep apneas are unaffected by the CV of AF to SR.

Tissues are not solely composed of cells. The extracellular matrix is important for the cell well-being and cell-cell communication. The glycosaminoglycan hyaluronan (HYA) is a widely distributed extracellular matrix (ECM) component. The molecule has prominent physicochemical properties, foremost viscoelastic and osmotic, but participates in many biological processes such as cell migration, proliferation, tissue turnover, wound healing and angiogenesis. HYA is synthesised by either of three different hyaluronan-synthesising enzymes, HAS1-3, and its main ligand is the transmembrane receptor CD44. In the heart and vessels the matrix components are of great importance for endurance and elasticity which are prerequisites for a normal function. The aims of the study were to describe the distribution of HYA and its receptor CD44 in normal cardiovascular tissue and to investigate the ECM composition in myocardial hypertrophy. Normal conditions were studied in a rat model. These studies showed that the tunica adventitia in almost all vessels stained strongly for HYA. The expression in the tunica intima and media on the venous side, differed between the vessels and was almost absent on the arterial side. In the adult animals only minute amounts of CD44 were detected. The expression of both HYA and CD44 was increased in newborn rats. In the heart HYA was unevenly distributed in the interstitium. Strong HYA-staining was seen in the valves and in the adventitia of intramyocardial vessels. Almost no CD44-staining was observed. Notably, there was no obvious difference between newborn and adult animals. In an experimental rat model of pressure-induced cardiac hypertrophy the mRNA-levels of HAS1, HAS2, CD44, basic Fibroblast Growth Factor (FGF-2) and Fibroblast Growth Factor Receptor-1 (FGFR-1) were elevated on day 1 after aortic banding. HAS2, CD44 and FGFR-1 were at basal levels on day 42. The HYA-concentration was significally elevated on day 1. HYA was detected in the interstitium by histochemistry and CD44 was detected mainly in and around the intramyocardial vessels. The HYA-staining was increased in myectomi specimens from patients with HCM compared to controls. HYA was detected in the interstitium, in fibrous septas and in the adventitia of intramyocardial vessels. No CD44 was detected in HCM or in control specimens. Our results indicate that HYA and CD44 play an active role in the maturing vessel tree and that the ECM content of HYA is increased in experimental myocardial hypertrophy and human hypertrophic cardiomyopathy.

Includes abstract.
Includes bibliographical references (leaves 92-98).
The objectives of this study were to assess the feasibility of this system for measuring in vivo mechanical loading on pectorally implanted pacemakers, to compare differences in mechanical loading experienced by pacemakers in different pectoral implant positions (i.e. sub-muscular and sub-coetaneous) and to formulate a concept of an interspecific transfer function for predicting the in vivo mechanical loads on sub-muscularly implanted pacemakers in humans, by using data obtained from baboons.

The endocrine heart synthesises and secretes two polypeptide hormones: the natriuretic peptides (NP) atrial natriuretic factor (ANF) and B-type natriuretic peptide (BNP). The biological actions of these hormones serve both acutely and chronically to reduce systemic blood pressure and hemodynamic load to the heart, thus contributing to the maintenance of cardiorenal homeostasis. Considerable effort has been focused on the elucidation of the mechanistic underlying ANF and BNP gene expression and secretion but much remains to be determined regarding specific molecular events involved in the cardiocyte secretory function. These hormones are produced by the atrial muscle cells (cardiocytes), which display a dual secretory/muscle phenotype. In contrast, ventricular cardiocytes display mainly a muscle phenotype. Comparatively little information is available regarding the genetic background for this important phenotypic difference with particular reference to the endocrine function of the heart. We postulated that comparison of gene expression profiles between atrial and ventricular muscles would help identify transcripts that underlie the phenotypic differences associated with the endocrine function of the heart as well as identify signaling pathways involved in its regulation. The cardiac atrial and ventricular transcriptomes were analyzed using oligonucleotide microarrays under normal or chronically induced aortocaval shunt volume-overload conditions. Transcriptional differences were validated by RT-PCR and transcripts of interest were knocked-down by RNAi. Comparison of gene expression profiles in the rat heart revealed a total of 1415 differentially expressed genes between normal atrial and ventricular tissues. Functional classification and pathway analysis identified numerous transcripts involved in mechanosensing, vesicle trafficking, hormone secretion, and G protein signaling. Volume-overloaded animals exhibited a progressive increase in cardiac mass over the four-week time course, an increase in expression of known hypertrophic genes, as well as the differential expression of 700 genes within the atria. Volume-overload specifically downregulated the accessory protein for heterotrimeric G protein signaling RASD1 in the atria. In vitro, knockdown of RASD1 in the atrial-derived HL-1 cells, significantly increased ANF secretion, demonstrating a previously unknown negative modulator role for RASD1. The data developed in this investigation provides insight into the expression profiles of genes particularly centered on the secretory function of the heart under normal and chronic hemodynamic overload conditions. Genome-wide expression profile analysis identified RASD1 as being differentially expressed between cardiac tissues as well as being modulated by chronic volume overload. RASD1 emerges as a tonic inhibitor of ANF secretion. The novel function identified herein for RASD1 in the atria is of considerable interest given the fact that secretory impairment of the cardiac natriuretic hormones can negatively impact cardiovascular homeostasis.

KCNE1 (E1) peptide is the founding member of the KCNE family (1-5), which is a class of type I transmembrane ß-subunits. KCNE1 peptides assemble with and modulate the gating, ion conducting properties and pharmacology of a variety of voltage-gated K+ channel a-subunits, including KCNQ1 (Q1). Mutations that interfere with the function of either E1 and/or Q1 and disrupt the assembly and trafficking of KCNE1- KCNQ1 channel complexes give rise to diseases such as Romano-Ward (RW) and Jervell Lange Nielsen Syndrome (JLNS), two different forms of Long QT Syndrome (LQTS). Using enzymatic deglycosylation assays, immunofluorescence techniques and quantitative cell surface labeling, we showed that KCNE1 peptides are retained in the early stages of the secretory pathway as immaturely N-linked glycosylated proteins. KCNE1 co-assembly with KCNQ1 leads to E1 progression through the secretory pathway and glycan maturation, resulting in cell surface expression. N-linked glycosylation of some membrane proteins is critical for proper folding, co-assembly and subsequent trafficking through the biosynthetic pathway. Previous studies have shown that genetic mutations that disrupt one of the two N-linked glycosylation sites on KCNE family members lead to LQTS (T7I, KCNE1 and T8A, KCNE2) (Schulze-Bahr et al., 1997; Sesti et al., 2000a; Park et al., 2003). Having confirmed that KCNE1 proteins acquire N-linked glycans, we examined the kinetics and efficiency of N-linked glycan addition to KCNE1. We showed that KCNE1 has two distinct N-linked glycosylation sites. The N-terminal sequon is a traditional co-translational site. The internal sequon (which is only ~ 20 residues away from the N-terminal sequon) acquires N-linked glycans primarily after protein synthesis (post-translationally). Surprisingly, mutations that prevent N-glycosylation at the cotranslational site also reduce the glycosylation efficiency of post-translational glycosylation at the internal sequon, resulting in a large population of unglycosylated KCNE1 peptides that are retained in the early stages of the secretory pathway and do not reach the cell surface with their cognate K+ channel. We showed that KCNE1 post-translational N-glycosylation in the endoplasmic reticulum is a cellular mechanism that ensures E1 proteins acquire the maximal number of glycans needed for proper channel assembly and trafficking. Our findings provide a new biogenic mechanism for human disease by showing that the JLNS mutation, T7I, not only inhibits glycosylation of the N-terminal sequon, but also indirectly prevents the glycosylation of the internal sequon, giving rise to a large population of assembly incompetent hypoglycosylated KCNE1 peptides. To further investigate the two N-linked glycosylation sites on KCNE1, we generated structure-function deletion scans of KCNE1 and performed positional glycosylation scanning mutagenesis. We examined the glycosylation pattern of glycosylation mutants in an effort to define the glycosylation window important for proper KCNE1 assembly and trafficking. Our findings suggested a nine amino acid periodicity to serve as a desirable glycosylation site and a better substrate for N-glycosylation. Appendix II shows work on the characterization of the C-terminally HA-tagged KCNE1 protein, which was used throughout the experiments presented in Chapter II, Chapter III and Chapter IV. Analysis of the C-terminally HA-tagged KCNE1 protein revealed that in heterologous expression systems KCNE1 had an internal translational start site, a methionine at position 27. A proteolytic cleavage site was also identified at the arginine cluster spanning residues 32 through 38 bearing the two known Long QT mutations (R32H and R36H) (Splawski et al., 2000; Napolitano et al., 2005). My work in Professor Craig C. Mello’s lab during the first four years of my graduate study is presented in Appendix I. The highly conserved Wnt/Wingless glycoproteins regulate many aspects of animal development. Wnt signaling specifies endoderm fate by controlling the fate of EMS blastomere daughters in 4-cell stage Caenorhabditis elegans embryos. A suppressor genetic screen was performed using two temperature sensitive alleles of mom-2/Wnt to identify additional regulators of the Wnt/Wingless signaling pathway during C. elegans endoderm specification. Five intragenic suppressors and three extragenic suppressors of mom-2/Wnt embryonic lethality were identified. We cloned ifg-1, eIF4G homologue, as one of the extragenic suppressors suggesting an intriguing connection between the Wnt signaling pathway and the translational machinery.

Objectives: Contemporary data are lacking with respect to the incidence rates of, factors associated with, and impact of cardiac arrest from ventricular fibrillation or tachycardia (VF-CA) on hospital survival in patients admitted with an acute coronary syndrome (ACS). The objectives of this multinational study were to characterize trends in the magnitude of in-hospital VF-CA complicating an ACS and describe its impact over time on hospital prognosis. Methods: The study population consisted of 59,161 patients enrolled in the Global Registry of Acute Coronary Events Study between 2000 and 2007. Overall, 3,618 patients (6.2%) developed VF-CA during their hospitalization for an ACS. Incidence rates of VF-CA declined over time, albeit in an inconsistent manner. Patients who experienced VF-CA were on average older and had a greater burden of cardiovascular disease, yet were less likely to receive evidence-based cardiac therapies than patients in whom VF-CA did not occur. Hospital death rates were 55.3% and 1.5% in patients with and without VF-CA, respectively. There was a greater than 50% decline in the hospital death rates associated with VF-CA during the years under study. Patients with a VF-CA occurring after 48 hours were at especially high risk for dying during hospitalization (82.8%). Conclusions: Despite reductions in the magnitude of, and short-term mortality from, VF-CA between 2000 and 2007, VF-CA continues to exert a significant adverse effect on survival among patients hospitalized with an ACS. Opportunities exist to improve the identification and treatment of ACS patients at risk for VF-CA to reduce the incidence of, and mortality from, this serious arrhythmic disturbance.

L'orientation des fibres myocardiaque est à la base du comportement électro-mécanique du cœur, et connue pour être altérée dans diverses maladies cardiaques telles que la cardiopathie ischémique et l'hypertrophie ventriculaire. Cette thèse porte principalement sur l'imagerie in vivo du tenseur de diffusion (diffusion tensor imaging—DTI) en vue d’obtenir la structure des fibres myocardiques du cœur humain dans des conditions de respiration libre. L'utilisation de DTI pour l'étude du cœur humain in vivo est un grand défi en raison du mouvement cardiaque. En particulier, l’acquisition DTI avec respiration libre sans recourir au gating respiratoire est très difficile à cause des mouvements à a fois respiratoire et cardiaque. Pour aborder ce problème, nous proposons de nouvelles approches consistant à combiner des acquisitions à retards de déclenchement multiples (trigger delay—TD) et des méthodes de post-traitement. D’abord, nous réalisons des acquisitions avec multiples TD décalés en fin de diastole. Ensuite, nous développons deux méthodes de post-traitement. La première méthode s’attaque au problème d’effets de mouvement physiologique sur DTI cardiaque in vivo en utilisant les techniques de recalage et de PCATMIP (Principal Components Analysis filtering and Temporal Maximum Intensity Projection). La deuxième méthode traite le problème de mouvement par l’utilisation d’un algorithme de fusion d’images basé sur l’ondelette (wavelet-based image fusion-WIF) et d’une technique de débruitage PCA (Principal Components Analysis). Enfin, une comparaison des mesures DTI entre la méthode PCATMIP et la méthode WIF est réalisée ; les champs de tenseurs sont calculés, à partir desquels les propriétés de l’architecture des fibres in vivo sont comparées. Les résultats montrent qu’en utilisant les approches proposées, il est possible d’étudier l’impact du mouvement cardiaque sur les paramètres de tenseur de diffusion, et d’explorer les relations sous-jacentes entre les propriétés de tenseur de diffusion mesurées et le mouvement cardiaque. Nous trouvons aussi que la combinaison des acqusiitions avec des TD multiples décalés and des post-traitements d’images peut compenser les effets de mouvement physiologique, ce qui permet d’obtenir l’architecture 3D du cœur humain dans des conditions de respiration libre. Les résultats suggèrent de nouvelles solutions au problème de perte du signal due au mouvement, qui sont prometteuses pour obtenir les propriétés de l’architecture des fibres myocardiques du cœur humain in vivo, dans des conditions cliniques
The orientation of cardiac fibers underlies the electro-mechanical behavior of the heart, and it is known to be altered in various cardiac diseases such as ischemic heart disease and ventricular hypertrophy. This thesis mainly focuses on in vivo diffusion tensor imaging (DTI) to obtain the myocardial fiber structure of the human heart under free-breathing conditions. The use of DTI for studying the human heart in vivo is challenging due to cardiac motion. In particular, free-breathing DTI acquisition without resorting to respiratory gating is very difficult due to both respiratory and cardiac motion. To deal with this problem, we propose novel approaches that combine multiple shifted trigger delay (TD) acquisitions and post-processing methods. First, we perform multiple shifted TD acquisitions at end diastole. Then, we focus on two different post-processing methods. The first method addresses physiological motion effects on in vivo cardiac DTI using image co-registration and PCATMIP (Principal Components Analysis filtering and Temporal Maximum Intensity Projection). The second method is a wavelet-based image fusion (WIF) algorithm combined with a PCA noise removing method. Finally, a comparison of DTI measurements between the PCATMIP and WIF methods is also performed; tensor fields are calculated, from which the in vivo fiber architecture properties are compared. The results show that using the proposed approaches, we are able to study the cardiac motion effects on diffusion tensor parameters, and investigate the underlying relationship between the measured diffusion tensor properties and the cardiac motion. We also find that the combination of multiple shifted TD acquisitions and dedicated image post-processing can compensate for physiological motion effects, which allows us to obtain 3D fiber architectures of the human heart under free-breathing conditions. The findings suggest new solutions to signal loss problems associated with bulk motion, which are promising for obtaining in vivo human myocardial fiber architecture properties in clinical conditions

La stabilité métabolique des cellules cardiaques est dépendante d'une organisation fonctionnelle qui favorise le transfert des liaisons phosphate depuis les sites de synthèse de l'ATP (mitochondries) jusqu'aux sites d'utilisation de l'énergie. Au niveau mitochondrial, cette fonction est principalement assurée par l'Interactosome Mitochondrial, comprenant les complexes respiratoires, l'ATP synthasome fonctionnellement couplé à la créatine kinase mitochondriale et le pore de la membrane mitochondriale externe VDAC qui régit la diffusion des nucléotides adényliques sous le contrôle de protéines du cytosquelette. Il est communément admis que la situation d'ischémie/reperfusion (IR) du myocarde affecte l'organisation intracellulaire des cardiomyocytes, les phosphorylations oxydatives (OxPhos), ainsi que le transfert de l'énergie cellulaire.L'objectif de ce travail était d'étudier les mécanismes de régulation de la fonction mitochondriale par les interactions entre la tubuline BII et la membrane mitochondriale externe (MME) d'une part et l'organisation de supercomplexes respiratoires (SCR) d'autre part. Différents types de muscles striés (cardiaque et squelettique) ont été utilisés pour étudier le lien entre la tubuline BII et la perméabilité de la MME pour les nucléotides adényliques. De plus, le rôle de la tubuline BII et de l'organisation des SCR ont été étudiés dans la situation physiopathologique de l'IR cardiaque.Dans les cardiomyocytes, comme dans les cellules issues de muscles squelettiques oxydatifs de rats adultes, la tubuline BII est colocalisée avec les mitochondries et la perméabilité de la MME pour l'ADP est faible. A l'aide du système pyruvate kinase/phosphoénolpyruvate, destiné à piéger l'ADP extramitochondrial, nous avons montré que l'affinité apparente d'OxPhos pour l'ADP est directement liée à la perméabilité de la MME. Ainsi, dans le muscle cardiaque comme dans les muscles squelettiques oxydatifs, un fort Km apparent pour l'ADP est associé à une faible perméabilité de la MME à l'ADP et à une forte expression de tubuline BII, présente sous une forme non-polymérisée. A l'inverse, dans les muscles glycolytiques, la très faible teneur en tubuline BII non-polymérisée est associée à une forte perméabilité de la MME aux nucléotides adényliques (faible Km apparent pour l'ADP).Les effets de l'ischémie (20 ou 45 minutes) et de la reperfusion cardiaque (30 minutes) ont été étudiés sur un modèle de coeur isolé perfusé de rat. Les principaux résultats sont que la séquence d'IR induit un réarrangement de la tubuline BII, associé à une réduction du Km apparent pour l'ADP, une baisse du contrôle de la respiration par la créatine et une diminution de la capacité d'OxPhos. Les modifications observées étaient dépendantes de la durée de l'ischémie et variables d'un cœur à l'autre. De plus, le groupe soumis à 20 minutes d'ischémie était caractérisé par la présence de SCR incluant le complexe I et l'absence de perte de cytochrome c (suggérant l'absence d'apoptose cellulaire). A l'inverse, 45 minutes d'ischémie suivies de reperfusion ont conduit à une perte de cytochrome c et à un remodelage de l'ultrastructure mitochondriale, sans modification de l'organisation des SCR.En conclusion, nos résultats soulignent l'importance des interactions mitochondrie-cytosquelette, et plus particulièrement celles impliquant la tubuline BII, dans la compartimentation intracellulaire des nucléotides adényliques et les transferts d'énergie dans les muscles striés oxydatifs. Par ailleurs, la séquence d'IR myocardique induit une désorganisation de la tubuline BII, qui contribue à la dysfonction mitochondriale. Enfin, l'absence de réorganisation des SCR quand la lésion d'IR est irréversible (45 minutes d'ischémie) suggère que le réarrangement des SCR observé après 20 minutes d'ischémie pourrait être l'un des mécanismes adaptatifs mis en jeu pour prévenir la dysfonction mitochondriale à la suite d'une séquence d'IR
Cardiac metabolic stability is highly dependent on the intracellular functional organization which favors compartmentalized phosphoryl flux transfer between sites of mitochondrial ATP synthesis and sites of ATP hydrolysis (mainly myofibrillar ATPases). At the level of mitochondria, this function is provided by Mitochonrial Interactosom (IM) which includes respiratory complexes, ATP Synthasom coupled functionally to Mitochondrial Creatine Kinase (MtCK) and Voltage-Dependent Anion Channel (VDAC) regulating ATP/ADP diffusion through its interaction with cytoskeleton proteins. Cardiac ischemia/reperfusion (IR) injury alters intracellular organization, oxidative phosphorylation (OxPhos) and compartmentalized intracellular phosphoryl flux transfer.The aim of this work was to study the regulation of mitochondrial activity by B tubulin II interaction with MOM and by respiratory supercomplex (RSC) organization, under physiological conditions as well as in ischemia/reperfusion in striated muscles. For this purpose, different types of striated muscles (cardiac and skeletal) were used for studying the link between B tubulin II and MOM permeability to adenine nucleotides. In addition, the role of B tubulin II and RSC organization was studied in the pathophysiological context of cardiac ischemia/reperfusion.In cardiac and oxidative skeletal muscles from adult Wistar rats, B tubulin II is colocalized with mitochondria and associated with low MOM permeability to ADP. Using pyruvate kinase and phosphoenolpyruvate trapping system for ADP, we show that the apparent affinity of OxPhos for ADP can be directly linked to the permeability of MOM. High apparent Km for ADP in cardiac and oxidative skeletal muscle is associated with low MOM permeability to ADP and high expression of non-polymerized B tubulin II. Very low expression of non-polymerized B tubulin II in glycolytic muscles is associated with high MOM permeability for adenine nucleotides (low apparent Km for ADP).The effect of the IR-injury was studied by subjecting isolated and perfused Wistar rat hearts to total ischemia (for 20 min and 45 min) followed by 30 min of reperfusion (I20R and I45R groups, respectively). The IR-injury induced intracellular rearrangement of B tubulin II was associated with decreased apparent Km for ADP, creatine-control of respiration and reduced OxPhos capacity. Observed changes were dependent on the duration of ischemia and were heterogeneously present across hearts. Additionally, in the I20R group we evidenced an increase in the content of the RSC embodying complex I in the absence of cytochrome c release (evidencing the absence of apoptosis). Forty five minutes of ischemia followed by reperfusion resulted in increased cytochrome c release and mitochondrial cristae remodeling without alteration of RSC organization.The results of this study highlight the importance of cytoskeleton-mitochondria interactions, and particularly that of B tubulin II, for adenine nucleotide intracellular compartmentalization and phosphoryl flux transfer in oxidative striated muscles. In addition, cardiac IR was shown to induce B tubulin II disorganization contributing to mitochondrial dysfunction. The absence of the RSC reorganization after irreversible IR injury (45 minutes of ischemia) suggests that the rearrangement of RSC observed after 20 minutes of ischemia could be an adaptive mechanism to overcome the IR-induced alterations of mitochondrial function

Thesis (PhD)-- Stellenbosch University, 2013.
ENGLISH ABSTRACT: This dissertation considers automatic segmentation of the left cardiac ventricle in short axis magnetic resonance images. The presence of papillary muscles near the endocardium border makes simple threshold based segmentation difficult. The endo- and epicardium are modelled as two series of radii which are inter-related using features describing shape and motion. Image features are derived from edge information from human annotated images. The features are combined within a Conditional Random Field (CRF) – a discriminatively trained probabilistic model. Loopy belief propagation is used to infer segmentations when an unsegmented video sequence is given. Powell’s method is applied to find CRF parameters by minimising the difference between ground truth annotations and the inferred contours. We also describe how the endocardium centre points are calculated from a single human-provided centre point in the first frame, through minimisation of frame alignment error. We present and analyse the results of segmentation. The algorithm exhibits robustness against inclusion of the papillary muscles by integrating shape and motion information. Possible future improvements are identified.
AFRIKAANSE OPSOMMING: Hierdie proefskrif bespreek die outomatiese segmentasie van die linkerhartkamer in kortas snit magnetiese resonansie beelde. Die teenwoordigheid van die papillêre spiere naby die endokardium grens maak eenvoudige drumpel gebaseerde segmentering moeilik. Die endo- en epikardium word gemodelleer as twee reekse van die radiusse wat beperk word deur eienskappe wat vorm en beweging beskryf. Beeld eienskappe word afgelei van die rand inligting van mens-geannoteerde beelde. Die funksies word gekombineer binne ’n CRF (Conditional Random Field) – ’n diskriminatief afgerigte waarskynlikheidsverdeling. “Loopy belief propagation” word gebruik om segmentasies af te lei wanneer ’n ongesegmenteerde video verskaf word. Powell se metode word toegepas om CRF parameters te vind deur die minimering van die verskil tussen mens geannoteerde segmentasies en die afgeleide kontoere. Ons beskryf ook hoe die endokardium se middelpunte bereken word vanaf ’n enkele mens-verskafte middelpunt in die eerste raam, deur die minimering van ’n raambelyningsfout. Ons analiseer die resultate van segmentering. Die algoritme vertoon robuustheid teen die insluiting van die papillêre spiere deur die integrasie van inligting oor die vorm en die beweging. Moontlike toekomstige verbeterings word geïdentifiseer.

Ce travail de thèse s'intéresse principalement à la régulation de la respiration mitochondriale in situ dans les cellules de muscle cardiaque et squelettiques. L'oxygraphie, la spectrophotométrie et la microscopie confocale sur cellules isolées ou fibres musculaires perméabilisées à la saponine ont été utilisées ainsi que la modélisation mathématique. Dans les cellules musculaires, les mitochondries sont organisées de manière très précise tel un ‘cristal'. Cet arrangement intracellulaire serait la base d'une organisation à la fois structurale et fonctionnelle au sein desquelles les mitochondries sont couplées fonctionnellement par le cytosquelette aux autres organelles : réticulum sarcoplasmique et myofibrilles : les ICEUs (ou unités énergétiques intracellulaires). Au sein des cellules cardiaques, il existe 2 niveaux de régulation de la respiration mitochondriale par l'ADP exogène : la perméabilité de la membrane mitochondriale externe (VDAC) et des restrictions localisées de diffusion de l'ADP au voisinage des mitochondries. La β-tubuline participe indirectement à ces mécanismes de régulation de même que la protéine STOP, une protéine associée aux microtubules. Ces données expérimentales sont utiles pour expliquer les aspects métaboliques de la loi de Frank-Starling dans le cœur. Cette notion d'ICEU peut servir de diagnostic lors de l'étude clinique du métabolisme énergétique chez des transplantés pulmonaires avant et après un programme d'entraînement à domicile
The aim of this work was to study the regulation of mitochondrial respiration in situ in cardiac and skeletal muscle cells. Oxygraphy, spectrophotometry and confocal microscopy on saponin-permeabilized muscle cells or fibers were used as well as mathematic modelisation. In muscle cells, mitochondria are ordered very precisely in ‘a crystal like pattern'. This intracellular arrangement could be the basis of a structural and functional organisation within which mitochondria are functionally coupled by cytoskeleton to the other organelles: sarcoplasmic reticulum and myofibrils: ICEUs (intracellular energetic units). In cardiac cells, there are two levels of regulation of mitochondrial respiration by exogenous ADP: permeability of the outer mitochondrial membrane (VDAC) and localized restrictions of ADP diffusion in the neighbourhood of mitochondria. β-tubulin and STOP protein, a microtubule-associated protein, participate indirectly to these mechanisms of regulation. These experimental data are useful for explaining the metabolic aspects of the Frank-Starling law of the heart. The notion of ICEU can be diagnostically used in clinical study of energetic metabolism of lung recipients transplants before and after a home-interval training program

Heart disease is a complex and heterogeneous disease. Notably, studies have demonstrated gender differences in the expression and types of cardiovascular disease, such as dilated cardiomyopathy (DCM), a major underlying cause of heart failure. Previously we showed that loss of A-Kinase Anchoring Protein 13 (Akap13), a unique proto-oncogene and estrogen receptor modulator, resulted in enlarged embryonic hearts, defective cardiac sarcomere formation, and embryonic lethality in mice. Data have also shown cAMP-dependent Protein Kinase A (PKA) to be involved in DCM pathophysiology. Given the established role of AKAP13 in cell signaling, its ability to bind and modulate ligand-activated nuclear hormone receptors and transcription factors, and its association with actin and other cytoskeletal components, we hypothesized that a functional AKAP13 protein was required for cardiomyocyte function in the adult heart; defective function of AKAP13 could promote DCM. To this end, we established an inducible, cardiac-specific Akap13 conditional knockout (Akap13cKO) mouse model using a Cre-lox recombination strategy with two separate Cre-recombinase expressing mouse models (α-MHC-MerCreMer and Tnnt2-rtTA; TetO-Cre). Cardiac functional examination of Akap13cKO mice revealed significant biventricular dilated cardiomyopathy with compensatory hypertrophic remodeling of the left ventricle and left atrial enlargement, decreased left and right ventricular systolic function, and abnormal left ventricular diastolic function. Of note, female Akap13cKO mice displayed a more pronounced cardiac phenotype and were more likely to die post-recombination.

Ce travail a été réalisé en cotutelle entre l'Université Nationale de Technologie de Ternopil Ivan Pul'uj (TNTU, Ukraine) et l’Université Blaise Pascal (France). Il appartient au domaine scientifique de la biomécanique et de l'informatique. Le but de l'étude est de développer les modèles et les méthodes de traitement des signaux biomécaniques cardiaques par les systèmes de diagnostic assisté par ordinateur avec une précision accrue, informativité et de la complexité de calcul inférieure. La méthode d'analyse statistique du rythme cardiaque a été mise au point. Cette méthode possède une plus grande précision et informativité par rapport aux méthodes connues d'analyse du rythme cardiaque. Dans cette thèse, le logiciel existant de l'analyse des signaux cardiaques biomécaniques a été améliorée par l'ajout de nouveaux modules logiciels, qui mettent en œuvre les nouvelles méthodes de l'analyse du rythme cardiaque et de l'analyse morphologique des signaux cardiaques biomécaniques
This work has been performed under the co-tutelle agreement between Ternopil Ivan Pul’uj National Technical University in Ternopil (TNTU, Ukraine) and the University Blaise Pascal in Clermont-Ferrand (France). It belongs to the scientific field of biomechanics and informatics. The aim of the study is to develop the mathematical models and methods of the processing of biomechanical heart signals in computer-based diagnostic systems with increased accuracy, informativeness and lower computational complexity. The method of statistical analysis of heart rhythm was developed, which is characterised by higher accuracy and informativeness compared with the known methods of heart rhythm analysis. In this thesis, the existing software of the analysis of biomechanical heart signals was improved by means of adding new software modules that implement the new methods of the analysis of heart rhythm and morphologic analysis of biomechanical heart signals

Previous research has shown that cognitive reappraisal, an emotion regulation strategy, has beneficial effects on emotion experience during strategy engagement. The present study extends this work by investigating whether cognitive reappraisal impacts the anticipation of an aversive event during, and five days following, strategy engagement. Emotion profiles, including psychophysiological and self-report indices, were also examined to assess whether reappraisal inhibits affective responses. Participants underwent habituation and simple discriminatory fear conditioning. Stimuli were pictures of a snake and a spider. Two days later participants returned to the laboratory and were either i) cued to engage in cognitive reappraisal while imagining the stimuli ii) exposed to the stimuli with no reappraisal instructions iii) exposed to the stimuli while engaging in cognitive reappraisal or iv) had an experience unrelated to the stimuli (control condition). Participants returned to the lab five days later and were exposed to both pictures paralleling initial habituation and conditioning protocols. It was found that cognitive reappraisal during exposure reduced expectancy of the UCS faster than exposure alone and resulted in lower mean skin conductance response (SCR) for those low, but not high, in fear of snakes. Five days later participants in the intervention conditions, compared to the control condition, demonstrated less anticipation of the UCS and smaller emotion-modulated startle magnitudes to the UCS. These findings suggest that cognitive reappraisal may be an effective tool for reducing anticipation of an aversive event and can result in enduring fear inhibition. This may have important implications for the treatment of individuals with anxiety disorders. The present study also examined the relationship between cardiac vagal control, indexed by respiratory sinus arrhythmia (RSA), and subsequent sympathetic arousal during fear conditioning, indexed by SCR. Results demonstrate that participants with low, compared to high, resting RSA had larger SCRs during habituation and conditioning trials. In addition, participants with lower RSA showed greater SCR reactivity following UCS presentation to both conditioned stimuli, suggesting that those with the lower RSA initially differentiated less between the UCS paired and unpaired images. These findings are consistent with theories that associate faster recovery from emotionally demanding situations with greater cardiac vagal control.

INTRODUCCIÓN: El empoderamiento del paciente es un concepto clave incorporado en los diferentes modelos de atención a la cronicidad. La gestión de la cronicidad requiere a un paciente empoderado que participe y asuma la responsabilidad de su cuidado con el objetivo de mejorar sus resultados en salud, de prevenir complicaciones y de aumentar su calidad de vida. En nuestro país no hay instrumentos validados que permitan medir el constructo empoderamiento. Esta carencia se contrapone con la exigencia por parte de los planes de salud de buscar e implementar estrategias que permitan el empoderamiento de los pacientes crónicos y con la necesidad de disponer de herramientas para medir resultados de empoderamiento. OBJETIVOS: Adaptar al contexto español y evaluar las propiedades psicométricas del cuestionario Patient empowerment in long-term conditions que evalúa el nivel de empoderamiento de los pacientes con enfermedad crónica. El objetivo secundario es identificar los factores que predicen el empoderamiento basal y las trayectorias de cambio (mejoría o deterioro) en pacientes con insuficiencia cardíaca. MÉTODOS: Se realizó el proceso de adaptación transcultural mediante: 1) Traducción directa; 2) síntesis y conciliación de las versiones por un comité de expertos; 3) traducción inversa; 4) conciliación de la traducción inversa con la autora del cuestionario original, y 5) análisis de la comprensibilidad mediante entrevistas cognitivas a una muestra de pacientes. Para la evaluación de las propiedades psicométricas se realizó un diseño observacional y prospectivo, en el que se analizaron a 124 pacientes con diagnóstico de Insuficiencia Cardíaca. Se recogieron variables sociodemográficas, clínicas y psicosociales, además de cuestionarios de calidad de vida, autocuidado, autoeficacia y empoderamiento, en tres evaluaciones distintas (basal, 2 semanas y 12 semanas). La fiabilidad se evaluó mediante la consistencia interna (alfa de Cronbach) y la reproducibilidad test-retest (coeficiente de correlación intraclase). La validez se estudió mediante análisis factorial y validez convergente-divergente. La sensibilidad al cambio se analizó mediante el tamaño del efecto. Para el segundo objetivo se construyó la variable evolución de empeoramiento que se definió como la diferencia entre el valor de CEPEC a 3 meses y el valor basal. Se realizaron pruebas bivariadas, modelo lineal general multivariante, modelo de regresión logística univariante y multivariante, RESULTADOS: Las versiones de traducción directa no presentaron grandes diferencias entre ellas. La versión de la traducción inversa fue aceptada por la autora del cuestionario original. En las entrevistas cognitivas, los pacientes señalaron algún tipo de dificultad en 5 ítems. Los resultados de las propiedades psicométricas mostraron un alfa de Cronbach excelente (> 0.9) y un coeficiente de correlación intraclase moderado (0.47). Las puntuaciones del cuestionario se correlacionaron con calidad de vida (0.46) y autoeficacia (0.43). Los resultados del análisis factorial obtenidos no fueron acordes con el modelo original. El tamaño del efecto fue moderado (0.67). Las variables que se relacionan con empoderamiento basal fueron peor clase funcional (p=0.008), valores elevados de NT-proBNP (p=0,04) y ansiedad (p<0,001). Las variables predictoras de empeoramiento en la trayectoria de empoderamiento fueron la edad (p<0,001), la clase funcional (p=0,02), Test de Barthel (p=0,01), Test de Pfeiffer (p<0,001) y ansiedad (p= 0,03) CONCLUSIONES: La versión española del cuestionario es equivalente semántica y conceptualmente al instrumento original. Los resultados preliminares de las propiedades psicométricas sugieren que son apropiadas en términos de consistencia interna y validez, y moderadas en términos de reproducibilidad y sensibilidad al cambio. El análisis factorial mostró un ajuste insuficiente. Los factores predictores de bajo nivel de empoderamiento basal son peor estado funcional de salud y síntomas de ansiedad. Las variables que pueden predecir una disminución en el nivel de empoderamiento, son el propio nivel basal de empoderamiento, la edad y el nivel de dependencia para las actividades de la vida diaria.
INTRODUCTION: The management of chronicity requires an empowered patient to participate and assume responsibility for their care with the aim of improving the health outcomes, preventing complications and increasing the quality of life. OBJECTIVES: 1) To validate the Spanish version of the questionnaire “Patient empowerment in long- term conditions” which evaluates the patients’ level of empowerment of chronic diseases. 2) To identify factors which predict basal empowerment and changes (improvement or deterioration) in patients with Heart Failure (HF). METHODS: The process of transcultural adaptation was carried out through: direct translation; committee of experts; reverse translation and cognitive interviews. For the evaluation of the psychometric properties the internal consistency will be assessed through Cronbach’s alpha coefficient; construct validity through Pearson’s correlation coefficient; and sensibility to change through effect size coefficient. For the second objective, bivariate tests were performed, general multivariate linear model, univariate and multivariate logistic regression model. RESULTS: The direct translation versions did not show great differences between them, the expert committee introduced changes in 23 items. In the cognitive interviews, the patients indicated some type of difficulty in 5 items. The results of the psychometric properties showed Cronbach's alpha > 0.9 and an intraclass correlation coefficient 0.47. Questionnaire scores correlated with quality of life (0.46) and self-efficacy (0.43). The factorial analysis were not consistent with the original model. The effect size was 0.67. The variables related to baseline empowerment were worse functional class (p = 0.008), high values of NT-proBNP (p = 0.04) and anxiety (p <0.001). The predictors of worsening in the empowerment trajectory were age (p <0.001), functional class (p = 0.02), Barthel test (p = 0.01), Pfeiffer test (P <0.001) and anxiety (p = 0.03). CONCLUSIONS: Preliminary results of psychometric properties suggest that it is appropriate in terms of internal consistency and validity, and moderate in terms of reproduction and sensitivity to change. The factor analysis showed an insufficient adjustment. The predictors of the low level of empowerment are: baseline status, functional health status and anxiety symptoms. The variables that can predict a decrease in the level of empowerment are: age and level of dependency for activities of daily living.

La modélisation du vivant, en particulier la modélisation de l'activité cardiaque, est devenue un défi scientifique majeur. Le but de cette thématique est de mieux comprendre les phénomènes physiologiques et donc d'apporter des solutions à des problèmes cliniques. Nous nous intéressons dans cette thèse à la modélisation et à l'étude numérique de l'activité électrique du cœur, en particulier l'étude des électrocardiogrammes (ECGs). L'onde électrique dans le cœur est gouvernée par un système d'équations de réaction-diffusion appelé modèle bidomaine ce système est couplé à une EDO représentant l'activité cellulaire. Afin simuler des ECGs, nous tenons en compte la propagation de l'onde électrique dans le thorax qui est décrite par une équation de diffusion. Nous commençons par une démonstrer l'existence d'une solution faible du système couplé cœur-thorax pour une classe de modèles ioniques phénoménologiques. Nous prouvons ensuite l'unicité de cette solution sous certaines conditions. Le plus grand apport de cette thèse est l'étude et la simulation numérique du couplage électrique cœur-thorax. Les résultats de simulations sont représentés à l'aide des ECGs. Dans une première partie, nous produisons des simulations pour un cas normal et pour des cas pathologiques (blocs de branche gauche et droit et des arhythmies). Nous étudions également l'impact de certaines hypothèses de modélisation sur les ECGs (couplage faible, utilisation du modèle monodomaine, isotropie, homogénéité cellulaire, comportement résistance-condensateur du péricarde,. . . ). Nous étudions à la fin de cette partie la sensibilité des ECGs par apport aux paramètres du modèle. En deuxième partie, nous effectuons l'analyse numérique de schémas du premier ordre en temps découplant les calculs du potentiel d'action et du potentiel extérieur. Puis, nous combinons ces schémas en temps avec un traîtement explicite du type Robin-Robin des conditions de couplage entre le cœur et le thorax. Nous proposons une analyse de stabilité de ces schémas et nous illustrons les résultats avec des simulations numériques d'ECGs. La dernière partie est consacrée à trois applications. Nous commençons par l'estimation de certains paramètres du modèle (conductivité du thorax et paramètres ioniques). Dans la deuxième application, qui est d'originie industrielle, nous utilisons des méthodes d'apprentissage statistique pour reconstruire des ECGs à partir de mesures ('électrogrammes). Enfin, nous présentons des simulations électro-mécaniques du coeur sur une géométrie réelle dans diverses situations physiologiques et pathologiques. Les indicateurs cliniques, électriques et mécaniques, calculés à partir de ces simulations sont très similaires à ceux observés en réalité.

Les analyses des fonctions ventriculaires gauche (VG) et droite (VD) et des pressions de remplissage sont des éléments importants dans le contexte des défaillances cardio-circulatoires graves car elles ont des conséquences diagnostiques et pronostiques avec un impact sur les prises de décisions thérapeutiques. Toutefois, l'évaluation de la fonction myocardique en cas de choc reste difficile pour des raisons physiopathologiques et technologiques. Les paramètres de fonction ventriculaire longitudinale (FVL) pourraient avoir un intérêt dans ce domaine car ils permettent une évaluation directe d'une composante majeure de la mécanique ventriculaire. Ces paramètres ont été évalués chez les défaillances chroniques stables et ont montré leurs intérêts diagnostiques et pronostiques. Ils restent très peu étudiés dans les contextes aigues et graves
Despite advances in management and therapies, cardiogenic shock remains a clinical challenge with high mortality rates.The analysis of left and right ventricular functions and filling pressures are important in this context because they had diagnostic and prognostic consequences with impact in therapeutic decisions. Nevertheless, the assessment of myocardial function remains difficult for physiopathologic and technical reasons. The parameters of longitudinal ventricular function (LgVF) could have an interest in this context because they permit a direct assessment of a major component of ventricular mechanics whereas ejection fraction remains a global evaluation. These indices were assessed in chronic and stable heart failure patients and were found to have prognostic and diagnostic interests. Though, they were not evaluated in the context of acute and severe cardio-circulatory failures

The short-term regulation of blood pressure is influenced by many influences, some being represented by cardiovascular signals and their changes. Because of the complexity of this system, the linear methods for its analysis are not sufficient. Non-linear methods for time series analysis have been devised quite a lot. In the course of this work, the analysis of the relations of several signals was evaluated as the most suitable conditional entropy and the resulting indexes of affinity and directionality. This method was applied to a set of heart-rate signals and systolic and diastolic pressure signals measured on eight adults and nine children. Relationships were analyzed but unfortunately after the statistical test was held the expected information links between the individual signals were not established. The indices were very small - in the hundredths of bits. Finally, optimization of the algorithm of the whole method has been performed and the newly modified function already shows significantly better results, for example strong information binding from the time-series of systolic pressure to a series of diastolic pressures.

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OBJECTIVE Evaluate the heart rate variability (HRV) of individuals with Type 2 diabetes, in the supine and in response to active postural maneuver from the supine to orthostatic position, by means of linear and non linear analysis and correlate these data. RESEARCH DESIGN AND METHODS Sixteen men with type 2 diabetes (DM) and sixteen control subjects (CG), age-range from 40 to 65 year were studied. The R-R intervals were recorded with a Polar RS800CX for 10 minutes in supine and 10 minutes in the orthostatic position. We assessed HRV using spectral (LFnu, HFnu and LF/HF), symbolic (0V%, 1V%, 2LV% and 2ULV%) analysis, Shannon (SE) and conditional entropy (complexity Index - CI and Normalized Complexity Index- NCI). RESULTS The DM presented higher sympathetic modulation (LFnu) in the supine position than the CG. In active postural maneuver for the variables LFnu and HFnu, DM showed no significant responses. Irrespective of position DM presented lower complexity than CG for SE. The same did not occur with conditional entropy, however, in both groups a reduction in values of entropies was observed with postural change. The reduction in complexity observed by SE was related to an increase in sympathetic modulation (0V%). CONCLUSION Our study showed that DM had higher sympathetic modulation in the supine position, which may be related to less complexity of HRV in this population. In addition, DM did not present the expected response of the autonomic nervous system to active postural maneuver for the variables LFnu and HFnu.
OBJETIVO Avaliar a variabilidade da frequência cardíaca (VFC) de indivíduos com diabetes mellitus tipo 2, na posição supina e em resposta a manobra postural ativa de supino para ortostático, por meio de análise linear e não linear e correlacioná-las. MÉTODOS Foram avaliados dezesseis homens com diabetes mellitus tipo 2 (DM) e dezesseis sujeitos controle (GC), na faixa etária de 40 a 65 anos. Os intervalos R-R (iRR) foram captados por um Polar RS800CX durante 10 minutos na posição supina e 10 minutos na posição ortostática. Avaliou-se a VFC utilizando análises espectral (BFun, AFun e BF/AF), simbólica (0V%, 1V%, 2LV% e 2ULV%), entropia de Shannon (ES) e condicional (índice de complexidade - IC e índice de complexidade normalizado - ICN). RESULTADOS O DM apresentou maior modulação simpática (BFun) na posição supina do que o GC. Na manobra postural ativa para as variáveis BFun e AFun o DM não mostrou resposta significativa. Independentemente da posição DM apresentou menor complexidade (menor ES) do que o GC. O mesmo não ocorreu com a entropia condicional, entretanto em ambos os grupos foi observada redução nos valores das entropias com a mudança postural. A redução da complexidade observada pela ES foi relacionada ao aumento da modulação simpática (0V%). CONCLUSÃO Nosso estudo mostrou que DM apresentou maior modulação simpática na posição supina, a qual pode estar relacionada com a menor complexidade da VFC nessa população. Além disso, DM não apresentou resposta esperada do sistema nervoso autonômico à manobra postural ativa para as variáveis BFun e AFun.

This thesis presents three original and complementary approaches to enhance the quality of Statistical Shape Models (SSMs), that improve the accuracy of medical image segmentation in challenging applications. First, we enhance the statistical richness of SSMs by developing a technique capable of merging the shape representations and statistical properties of several pre-existing models with no original or additional raw data. Second, we enhance the geometrical quality of SSMs by developing a framework for modeling simultaneously both global and local characteristics of highly complex and/or multi-part anatomical shapes. Last, we improve the specificity of SSMs for specific subjects by integrating individual-specific non-imaging metadata such as demographic, clinical and behavioral variables into the SSM construction and image segmentation tasks. These techniques are demonstrated and validated by considering various imaging modalities such as magnetic resonance imaging (MRI) and computed tomography (CT), and different complex anatomies, including the human heart, brain and spine.
Esta tesis presenta tres propuestas originales y complementarias para mejorar la calidad de los modelos estadísticos de formas (SSMs) que mejoran la precisión de la segmentación de la imagen médica en aplicaciones difíciles. Proponemos, primero, mejorar la riqueza estadística de los SSMs por medio de una técnica para unir la representación de forma y las propiedades estadísticas de muchos modelos pre-existentes sin observaciones adicionales. Segundo, mejorar la representacion geométrica de los SSMs modelando simultáneamente las características globales y locales del objecto o de multiples anatomias. Por último, mejorar la especificidad de los SSMs mediante la integración de metadatos del paciente no derivados de la imagen, tales como, variables demográficas, conductuales y de entorno clínico, en la construcción de los modelos. Estas técnicas son demostradas y validadas en imágenes de resonancia magnética (MRI) y tomografía computarizada (CT) y en anatomias como el corazón, el cerebro y la espina dorsal humanos.

L’obésité et le surpoids ont été décrits comme une pandémie. L’obésité et le vieillissement vont conduire à des complications cardiovasculaires. De plus, l’obésité favoriserait un vieillissement cardiaque prématuré chez les adultes jeunes. L’hypothèse de ce travail est qu’un régime riche en graisses, démarré avant l’âge adulte, poursuivi sur une longue durée, pourrait entraîner un vieillissement « accéléré » cardiovasculaire et métabolique. Nous avons démontré, dans un modèle murin vieillissant, qu’un régime riche en graisses conduit à des troubles métaboliques ainsi qu’à une augmentation de la masse grasse et à une détérioration du métabolisme au niveau du tissu adipeux blanc. Ces troubles sont associés à des altérations au niveau cardiaque, malgré l’absence de modifications de la pression artérielle et de la fréquence cardiaque. Le vieillissement, chez les souris obèses, va conduire à un remodelage du ventricule gauche accompagné par une dysfonction systolique. Au niveau tissulaire cardiaque, le vieillissement et le régime précoce conduisent à l’augmentation de l’expression de gènes de fibrose confirmant ainsi le phénotype hypertrophique. Le vieillissement associé à un régime riche en graisses précoce conduit également à une up-régulation de GDF11. GDF11 peut alors être considéré comme un marqueur de vieillissement cardiaque accéléré. Ces résultats peuvent suggérer des voies thérapeutiques ou préventives, où l’inhibition de GDF11 améliorerait le pronostic et la survie cardiovasculaire des sujets obèses. L’étude de ce modèle nous a ainsi permis de mettre en évidence qu’un régime riche en graisses conduit à un vieillissement accéléré au niveau cardiaque
Obesity and being overweight have been described as a global pandemic. Both obesity and aging will lead to cardiovascular complications. In addition, it has been highlighted that obesity promotes premature cardiac aging in young adults. The hypothesis of this work is that a high fat diet begun before adulthood, pursued over a long period of time, could lead to “accelerated” cardiovascular and metabolic aging. We have demonstrated, in an aging mouse model, that an early high fat diet leads to metabolic disorders and to an increase in fat mass and a deterioration in metabolism of white adipose tissue. These disorders are associated with alterations in cardiac morphology and function, despite an absence of changes in blood pressure and heart rate. Ageing, in obese mice, leads to ventricular remodeling accompanied by systolic dysfunction. In cardiac tissue, aging and early diet lead to an increased expression of fibrosis genes confirming the hypertrophic phenotype. Aging associated with an early high fat diet led also to an up-regulation of GDF11. GDF11 may then be considered as a marker of accelerated cardiac aging. These results may suggest therapeutic or preventive pathways, where inhibition of GDF11 improves prognosis and survival in obese subjects with cardiovascular disease. The study of this model has allowed us to demonstrate that a high fat diet leads to accelerated aging at the level of the heart

Le vieillissement cardiaque est fortement associé à l’apparition d’une fibrose pouvant entrainer une dysfonction progressive du remplissage et de l’éjection ventriculaire. Le dépistage du remodelage et du vieillissement cardiovasculaire sont primordiaux afin de proposer des stratégies de prévention et de prises en charge spécifiques visant à retarder l’apparition ou ralentir la progression d’une insuffisance cardiaque à fraction d’éjection préservée. Les outils cliniques, biologiques ou d’imagerie sont insuffisamment performants à l’heure actuelle pour dépister ces modifications précoces ou prédire l’apparition de remodelage ultérieur de façon efficace. La réalisation d’une méta-analyse avec revue de la littérature, nous a permis de montrer la valeur de la déformation myocardique comme marqueur du remodelage cardiovasculaire dans le post-infarctus, mais nous a aussi éclairé sur la complexité du phénomène et le manque de preuves sur sa potentielle valeur additionnelle en pratique clinique. Après avoir validé les différents outils de quantification du remodelage dans nos cohortes, nous avons montré l’importance d’une expertise précise de la morphologie et de la fonction cardiaque lors d’un évènement aigu pour prédire un remodelage ultérieur. Nous avons précisé le rôle de la déformation myocardique dans la quantification de la taille de l’infarctus, sa sévérité et son éventuelle extension au ventricule droit. Enfin, nous avons mis en relation les paramètres de contractilité et de fonction vasculaire en montrant la valeur du couplage ventriculo artériel mesuré en IRM. Ces travaux ouvrent la voie pour une stratégie d’évaluation d’imagerie précoce en post-infarctus pouvant orienter les thérapeutiques de revascularisation et/ou de réhabilitation
Cardiovascular aging is strongly associated with myocardial fibrosis and progressive LV systolic/diastolic dysfunction including vascular stiffening. Cardiac remodeling with left ventricular parietal stress and hypertrophy take place over several years and can ultimately lead to the occurrence of heart failure. Clinical, biological or imaging tools are currently insufficient to detect early changes or to predict the onset of subsequent remodeling in an effective manner. However, if subclinical structural and functional cardiac abnormalities are not detected by conventional echocardiographic techniques, they may be evaluated by others imaging tools with the measurement of myocardial deformation parameters. We performed a systematic review suggesting that deformation imaging is associated with left ventricular volume and function changes regardless the mechanisms and deformation direction. But added strain predictive value over other clinical, biological and imaging variables remains to prove. After validation of various remodeling indices, we proved the add value of a comprehensive assessment of ventricule geometry and function to evaluate remodeling after an acute event. We confirmed the central role of myocardial deformation for infarct size quantification and detect right ventricle extension. Finally, we used vascular function measured by MRI to demonstrate the relation between ventriculo-arterial coupling and remodeling. Further studies are needed to assess the gain in information provided by strain and these new biomarkers