Anorexia nervosa (MA) is serious psychiatric disease associated with significant mortality. One of the main causes of mortality in these patients is cardiac complications. In 2003 - 2010 we examined 30 patients with established diagnosis of MA. Routinely used nutritional parameters are normal even in severe malnutrition in MA patients and we can ́t use them to diagnose or monitor nutritional status. Therefore we evaluated plasma aminoacids levels to detect minor changes of protein metabolism. According to our results we found mild hyperaminoacidemia and significant elevation of Gly/Val and Phe/Tyr ratio. In the second part of our research we performed non invasive examination s in risky patients with AN to consider possible cardiac complications. Results of ECG and echocardiography confirm results of the previous published studies. Original finding is significant decrease in flow mediated dilatation of brachial artery and its normalization after realimentation. We found also in ambulatory blood pressure monitoring significant decrease in blood pressure during the active period which was the consequence of changes in the heart rate variability. Decrease of the blood pressure in patients with AN in standing position was associated with increase of HF power in supine position and particularly with the lack of...

Purpose The vascular endothelium is an influential contributor to vasodilation at rest, yet its role during peak exercise is relatively unknown. The purpose of this study is to determine if exercise leg blood flow during dynamic submaximal and maximal exercise is related to resting vascular endothelial function. Methods Nineteen subjects (aged 23 ± 0.57 yr) completed multiple assessments of vascular endothelial function including passive leg movement (PLM), rapid onset vasodilation, (ROV) and flow-mediated dilation (FMD). Peak muscle blood flow was assessed during single leg knee extension (KE) exercise. Doppler ultrasound of the femoral artery was utilized to assess muscle blood flow. Results Peak exercise blood flow was linearly related with microvascular endothelial function determined by PLM (P < 0.001) and ROV (P < 0.001). Normalizing muscle blood flow for quadriceps mass did not change this significant association. Individuals with high vascular endothelial function had greater muscle blood flow during KE compared to those with low endothelial function (P = 0.05). Post hoc analysis indicated a significant difference in blood flow between high and low endothelial function groups at 20 W, 30 W, and peak flow (P = 0.042, 0.048, 0.001, respectively). Conclusion Peak muscle blood flow during dynamic exercise is correlated with vascular endothelial function, as measured by PLM and ROV, accounting for between 30 to 50% of the variance in this relationship. These data support the hypothesis that endothelial function significantly contributes to the peak blood flow response during dynamic exercise.

<p>Functional limitations place youth with cerebral palsy (CP) at an increased risk of physical inactivity and cardiovascular disease. The structure and function of the cardiovascular system of these adolescents has not been previously investigated. In the current cross-sectional study, endothelial function was assessed using flow-mediated dilation (FMD) in eleven adolescents with CP (age 13.2 ± 2.1 y) and compared to eleven healthy, age-and gender-matched control participants (12.4 ± 2.3 y). All participants with CP were ambulatory or ambulatory with assistive devices (lower leg brace) and classified as levels I-II according to the Gross Motor Function Classification System (GMFCS). Baseline arterial stiffness was examined through assessment of central and peripheral pulse wave velocity (cPWV, pPWV,) as well as carotid distensibility, a direct measure of central artery stiffness. A combination of B-mode ultrasound imaging and applanation tonometry was used to calculate carotid distensibility. Carotid intima-media thickness (IMT), a measure of vascular structure, was also quantified using B-mode ultrasound images and a semi-automated edge detection software program. cPWV was calculated using the distance (carotid to femoral via the subtraction method) and time delay between ventricular depolarization and the foot of the femoral waveform. pPWV was calculated from the femoral to dorsalis pedis artery using the distance between each site and time delay between the arrival of the foot of each corresponding waveform. Physical activity (PA) levels were assessed using a 7-day recall questionnaire. Anthropometric measurements as well as measures of resting systolic, diastolic and mean arterial blood pressures were similar in both groups. There were no group differences (p>0.05) in ivabsolute, relative or normalized FMD responses. Both groups also had similar values of carotid IMT as well as all measures of arterial stiffness including carotid distensibility, cPWV and pPWV (p>0.05). No group differences were found in the amount of time spent in light and moderate intensity PA; however, the control group participated in a significantly greater amount of vigorous intensity PA (CON: 196 ± 174 min. vs. CP: 38 ± 80 min). Pearson correlation coefficients with all participants revealed a significant positive relationship between age and cPWV (r=0.485 p=0.026) and negative relationship with carotid compliance (r=-0.436, p=0.048). These findings indicate that the arterial structure and function of youth with CP (GMFCS level I-II), examined in this study are not different from a healthy control group. Future research should include youth with CP of GMFCS levels III-V to gain further insight into the potential consequences of severe mobility impairments and functional limitations on levels of habitual PA and arterial health in this young, clinical population.</p> / Master of Science (MSc)

Cardiovascular disease (CVD) and erectile dysfunction (ED) have common etiologies, such as increased adiposity and chronic diseases. Incident ED is known to be a sentinel of CVD, providing a unique opportunity for early lifestyle interventions to attenuate the progression of disease. The internal pudendal artery (IPA) plays an important role in controlling resistance to penile blood flow and thereby erections. Although morphological and functional disturbances in the IPA have been associated with ED, few studies have characterized changes in the IPA as it relates to increased adiposity and chronic diseases (e.g., chronic kidney disease [CKD]). Finally, although both vascular calcification and ED have been shown to be prevalent in patients with CKD, there has yet to be an assessment of associated mechanisms. The effect of lifestyle modifications on erectile function was evaluated in both experimental and clinical settings. Specifically, the studies assessed the effect of caloric restriction (CR) in rats and of chronic exercise in sedentary, overweight or obese male and female subjects. In rats, structural and functional changes of the IPA and erectile responses were characterized in relation to increasing adiposity and to CKD. Experimentally, the susceptibility of various vascular beds to calcification in CKD was determined. Clinically, erectile and female sexual function was assessed in patients with Stage 3 to 5 CKD, who had no history of CVD. In rats, CR blunted the accumulation of abdominal adiposity, and attenuated progression of both endothelial dysfunction and ED, independently of morphological changes in the IPA. Rats with CKD had an increased frequency of ED, greater endothelial dysfunction, and altered vascular morphology, yet vascular calcification per se did not account for ED. In the clinical study, sedentary and overweight or obese males with ED, but not females, had a significantly higher body mass index (BMI) and waist circumference. Chronic exercise significantly improved ED and female sexual dysfunction (FSD). Clinically, CKD was associated with ED and FSD as well as increased coronary artery calcification and endothelial dysfunction. These findings support the concept that early detection of cardiovascular abnormalities, using incident ED as a sentinel, should facilitate early interventions in otherwise asymptomatic populations. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-09-30 22:33:20.436

Preeclampsia is one of the leading causes of maternal and fetal mortality and morbidity. Furthermore, women who have had preeclampsia have an increased risk of cardiovascular events over the next 10-15 years. Indeed, preeclampsia is associated with a four-fold increase in the risk of hypertension and double the risk of fatal and non fatal ischaemic heart disease and stroke. In addition, offspring born to preeclampsia are more likely to have higher blood pressure from childhood and stroke in later life. The risk to mother and offspring is greatest when preeclampsia is diagnosed at an earlier gestation, suggesting a more severe form of preeclampsia. As the long term cardiovascular risk to both mother and child is known from delivery, the main interest of my research was to identify key phenotypic variations in mothers and children during the years between the episode of preeclampsia and emergence of established cardiovascular disease, which might explain the link between the two conditions. This information could then be used to devise ways to identify subjects at greatest risk of later cardiovascular disease and to establish intermediate endpoints for future preventative interventions. Therefore, in a case control study, women diagnosed with preeclampsia between 1998 and 2003 and their offspring were recruited and underwent comprehensive cardiovascular and metabolic phenotyping. Furthermore, young adults born preterm to hypertensive pregnancy were also investigated in their twenties. The research demonstrates that early-onset preeclampsia, diagnosed before 34 weeks gestation, is associated with blood pressure patterns in mothers 6-13 years after pregnancy that are distinct from those seen following later-onset disease. Furthermore, there is evidence of distinct differences in cardiac, vascular and metabolic profiles in these individuals with women having evidence of increased arterial stiffness, changes in cardiac function and reduced capillary density. Preterm offspring of hypertensive pregnancies similarly have higher blood pressure than seen in those born following late-onset disease and, in young adult life, have reduced endothelial function and changes in cardiac size proportional to this dysfunction. This research demonstrates adverse cardiac and vascular remodelling after preeclampsia in mothers and offspring that are evident before the development of clinical cardiovascular disease. The identified differences in cardiac and vascular function may be useful as surrogate endpoints in future preventive trials.

L'étude des mécanismes physiologiques au cours d'une plongée subaquatique estessentielle à la compréhension des accidents qui lui sont associées. Le plongeur subit denombreuses contraintes issues du milieu dans lequel il évolue. Parmi ces contraintes, qui leplus souvent se combinent, nous pouvons citer l'immersion, l'exposition au froid,l'hyperbarie, les variations des conditions d'oxygénation (hypoxie, hyperoxie) et l'exercicephysique. L'objectif de notre travail a été d'apprécier les modifications de la fonction cardiovasculaireet de son contrôle neuro-végétatif induites par ces contraintes rencontrées enplongée chez des sujets sains, novices en plongée, et également chez des chasseurs sousmarins. L'étude de la circulation artérielle et de la fonction endothéliale était basée surl'échographie (bi-dimensionnelle et Doppler). Des mesures de tonométrie d'applanation etautres mesures ultrasonores ont complété nos données hémodynamiques. L'étude du systèmeneurovégétatif était basée sur l'analyse de la variabilité de l'intervalle RR (contrôle cardiaque)et de la variabilité de la pression artérielle (contrôle vasculaire). Après un exercice aigu de pédalage de 45 minutes à haute intensité, l'augmentationpost-exercice du flux sanguin et de la vasodilatation endothéliale a été réduite aux musclesparticipant activement à l'exercice comparé aux muscles non actifs. Pour expliquer cesdifférences, la contribution de l'inflammation locale et du stress oxydatif élevé présents dansles muscles actifs de l'exercice pourrait avoir un rôle. / During a dive, subjects undergo environmental stressors such as immersion, coldexposure, hypoxia, hyperoxia and physical exercise. All these stressors may be responsible forchanges in cardiovascular system and consequently modified autonomic nervous control. Theaim of this work was to assess physiological changes induced by diving to better understandinjuries reported during this activity. Investigations were performed in healthy men and inspearfishermen. Hemodynamic changes and endothelial function were assessed by 2-Dimensional and Doppler echocardiography. Arterial wall compliance was estimated by pulsewave analysis. Autonomic nervous activity was assessed by power spectral density of heartrate variability (cardiac control) and blood pressure variability (vasomotor control). After an acute cycling exercise of 45 minutes in high intensity, the increase postexerciseof the blood flow and the endothéliale vasodilatation was reduced to musclesparticipating actively in the exercise compared with no active muscles. To explain thesedifferences, the contribution of the local inflammation and the important oxydative stress inthe active muscles of the exercise could have a role. Thermoneutral head-out water immersion induce hemodynamic and arterial changes. At rest, we observed a brachial arterial vasodilatation. This might be attributed to endothelialrequest inferred by increase of the peripheral arterial debit flow. Endothelial reactivity did notseem to be modified. With cycling exercise in low intensity,hemodynamic differencesobserved disappear. At rest, normobaric hyperoxia didn't affect blood pressure but induced an increase insystemic vascular resistances.

A cirurgia bariátrica confere proteção cardiometabólica à indivíduos obesos, contribuindo para uma redução do risco de mortalidade. No entanto, a extensão do benefício metabólico pode estar sujeita a mudanças no estilo de vida do paciente após a intervenção cirúrgica. Embora o exercício físico pareça melhorar os efeitos da cirurgia na sensibilidade à insulina, o mecanismo de ação subjacente permanece em grande parte sem explicação. Especula-se que mudanças potenciais na matriz extracelular do músculo esquelético (ECM) poderiam estar associadas à melhora da sensibilidade à insulina induzida pelo exercício físico em pacientes pós-bariátricos. Além disso, não se sabe se os benefícios da cirurgia bariátrica sobre a função endotelial, importante marcador precoce de aterosclerose, são sustentáveis sem alterações no estilo de vida, como a inclusão de exercícios físicos. Dessa forma, foram objetivos do presente estudo, investigar os efeitos do exercício físico sobre a sinalização intracelular envolvida na sensibilidade à insulina e remodelamento da matriz extracelular do músculo esquelético (Estudo 1) e sobre a função endotelial da artéria braquial de pacientes submetidos à cirurgia bariátrica (Estudo 2). Sessenta e duas mulheres foram randomizados após a cirurgia bariátrica para um programa de exercícios físicos de 6 meses ou tratamento padrão. No início do estudo, 3 e 9 meses após a cirurgia, a sensibilidade à insulina foi avaliada pelo teste oral de tolerância à glicose (TOTG), análise da função endotelial e amostras de músculo esquelético foram obtidas a partir do vasto lateral. As amostras de músculo esquelético foram submetidas a análises abrangentes, incluindo expressão de genes e proteínas, fenótipo do músculo esquelético, transcriptoma e identificação de novas vias de sinalização celular. O treinamento físico após a cirurgia bariátrica melhorou a sensibilidade à insulina no músculo esquelético. Esta resposta foi mediada por alterações moleculares e fenotípicas na ECM. A cirurgia bariátrica per se foi incapaz de solucionar completamente a resistência à insulina e a expansão da ECM no músculo esquelético. Candidatos relevantes modulados pelo exercício emergiram como alvos terapêuticos para o tratamento da resistência à insulina do músculo esquelético, nomeadamente a via TGF \'beta\' 1 SMAD 2/3 e seu antagonista folistatina. Em resumo, empregamos uma abordagem \"top-down approach\" para fornecer evidências de que a ECM do músculo esquelético desempenha um papel fundamental nos efeitos sobrepostos da cirurgia bariátrica e do exercício físico sobre a sensibilidade à insulina em mulheres obesas. Além disso, este estudo demonstrou que o treinamento físico evitou a reversão da melhora da função endotelial por meio da melhora do padrão de fluxo sanguíneo e redução de marcadores inflamatórios. Em conclusão, ao revelar um novo mecanismo pelo qual o exercício pode contrabalançar a resistência à insulina em pacientes pós-bariátricos (isto é, atenuar a espessura da ECM) e preservar a função endotelial, este estudo endossa que o exercício físico deve ser adotado como relevante medida terapêutica a fim de garantir os melhores resultados cardiometabólicos em pacientes submetidos à cirurgia bariátrica / Bariatric surgery provides cardiometabolic protection to obese individuals, contributing to a reduction in mortality risk. However, the extent of metabolic benefit may be subject to changes in the patient\'s lifestyle after surgical intervention. Although exercise seems to improve the effects of surgery on insulin sensitivity, the underlying mechanism of action remains largely unexplained. It is speculated that potential changes in the skeletal muscle extracellular matrix (ECM) could be associated with improved insulin sensitivity induced by physical exercise in post-bariatric patients. In addition, it is not known whether the benefits of bariatric surgery on endothelial function, an important marker of early atherosclerosis, are sustainable without changes in lifestyle, such as the inclusion of physical exercise. Thus, the aims of the present study were to investigate the effects of exercise on intracellular signaling involved in insulin sensitivity and skeletal muscle ECM remodeling (Study 1) and the effects of exercise on the brachial artery vasodilator response of patients undergoing bariatric surgery (Study 2). Sixty-two women were randomized after bariatric surgery to a 6-month exercise program or standard of treatment. At the beginning of the study, 3 and 9 months after surgery, insulin sensitivity was assessed by the oral glucose tolerance test (OGTT), endothelial function analysis and skeletal muscle samples were obtained from the vastus lateralis. Skeletal muscle samples were subjected to comprehensive analysis, including gene and protein expression, skeletal muscle phenotype, transcriptome and identification of new cell signaling pathways. Exercise training after bariatric surgery improved insulin sensitivity in skeletal muscle. This response was mediated by molecular and phenotypic changes in ECM. Bariatric surgery per se was unable to completely resolve insulin resistance and skeletal muscle ECM expansion. Relevant exercise-modulated candidates emerged as therapeutic targets for the treatment of skeletal muscle insulin resistance, namely the TGF&#946;1/SMAD 2/3 pathway and its follistatin antagonist. In summary, we employed a \"top-down approach\" to provide evidence that skeletal muscle ECM plays a key role in the overlapping effects of bariatric surgery and exercise on insulin sensitivity in obese women. In addition, this study demonstrated that physical training avoided reversal of endothelial function improvement by improving blood flow pattern and reducing inflammatory markers. In conclusion, in revealing a new mechanism by which exercise can counterbalance insulin resistance in post-bariatric patients (i.e., attenuate ECM thickness) and preserve endothelial function, this study endorses that exercise should be adopted as a relevant therapeutic measure in order to guarantee the best cardiometabolic results in patients undergoing bariatric surgery.

Bei der klinischen Beschreibung einer Sepsis sind Symptome vorhanden, die allesamt auf eine endotheliale Beteiligung schließen lassen. Hierzu zählt die Infektion an sich, die Regulation der Gefäßpermeabilität, der Gerinnung, der Interaktion mit zirkulierenden Zellen, des Gefäßtonus und des Sauerstoffverbrauchs. In systematischer Weise werden die Einflüße reaktiver Sauerstoff- und Stickstoffderivate für diese endothelialen Funktionen beschrieben. Beide Molekülgruppen können toxische Wirkungen als unspezifisch im Sinne der Onkose induzieren, die komplex von den jeweiligen Produktionsraten und Umgebungsbedingungen abhängig sind. Es scheint bei einer NO. induzierten Toxizität eine kooperative Wirkung mit reaktiven Sauerstoffderivaten zu geben, wohingegen eine primär durch reaktive Sauerstoffderivate induzierte Toxizität von niedrig dosiertem NO. inhibiert werden kann. Daneben kann der Tod einer Zelle auch als eine teleologisch sinnvolle Form geregelt eintreten. Dieser sogenannte programmierte Zelltod, die Apoptose, scheint durch exogene Zufuhr reaktiver Sauerstoff- oder Stickstoffderivate eher wenig wahrscheinlich. Dagegen scheint die endogene Produktion reaktiver Sauerstoffderivate enger mit proapoptotischen Veränderungen assoziiert zu sein. Die endogene endotheliale Produktion von NO. hat in bisherigen Untersuchungen widersprüchliche Bedeutung für die Apoptose und muß weiteren Untersuchungen vorbehalten bleiben. Ob eine durch Sepsis induzierte endotheliale Apoptose oder Onkose bei Menschen vorliegt wird diskutiert. Unabhängig von der Induktion zum Sterbeprozeß haben reaktive Sauerstoff- und Stickstoffderivate eine signalgebende Funktion in Endothelzellen, die nach exogener Zugabe aber auch durch eine endogene Produktion systematisch zusammengefaßt werden. Zahlreiche Sepsiserreger, oder deren Sekretions-, bzw. Abbauprodukte können primär mit Endothelzellen interagieren. Bereits diese frühen Interaktion gehen mit einer Dysregulation reaktiver Sauerstoff- und Stickstoffderivate einher. Vor allem im Rahmen eines früh auftretenden septischen Schocks wird eine enorm erhöhte Gefäßpermeabilität deutlich. Untersuchungen zur endothelialen Permeabilität legen zumindest in vitro eine Dysregulation reaktiver Sauerstoff- und Stickstoffderivate nahe. Die Regulation des Gefäßtonus ist ganz offensichtlich bei septischen Patienten gestört. Welcher Beitrag hierfür auf eine gestörte Endothelfunktion zurückzuführen ist wurde in zahlreichen tierexperimentellen Modellen untersucht. Endothelzellen sind in der Lage, den Sauerstoffverbrauch ganzer Organe zu regeln und Implikationen für die Pathophysiologie der Sepsis werden diskutiert. Endotheliale Dysfunktionen bei septischen Patienten scheinen aufgrund tierexperimenteller Modellvorstellungen naheliegend, sind aber nur ansatzweise bei Menschen belegt. Es ist unklar, welche endothelialen Funktionsdefizite bei septischen gut definierten Patienten überhaupt sicher zu quantifizieren sind, oder wie lange sie anhalten und sich über die Zeit ändern. Auch ist nicht belegt, ob lösliche Marker ein Funktionsdefizit anzeigen, oder lediglich Ausdruck einer allgemeinen Schädigung eines Organismus sind. Eine Dysbalance der endothelialen Produktion reaktiver Sauerstoff- und Stickstoffderivate liegt allerdings sehr wahrscheinlich vor. / The definition of sepsis includes clinical signs which all are related to endothelial dysfunctions. Infections agents can primarily target endothelial cells. The regulation of vascular permeability and coagulation, the interaction with circulating cells, vasoregulation and oxygen consumption are endothelial dependent. Systematically it is described how reactive oxygen species and reactive nitrogen species act as mediators for these diverse functions. Both reactive oxygen and nitrogen species are well known for their toxic potencies leading to oncosis. Their interaction is very complex. Nitric oxide induced toxic reactions increase in the presence of reactive oxygen species, whereas reactive oxygen species induced toxicity is decreased by low doses of nitric oxide. Apoptosis as opposed to oncosis hardly is induced by exogeneous reactive oxygen or nitrogen species in endothelial cells. However, endogeneous production of reactive oxygen species is more likely to serve proapoptotic functions. Whether patients suffering from sepsis show increased signs of apoptotic endothelium is discussed. Signalling events by low doses of exogeneous reactive oxygen and nitrogen species as well as by endogeneous production in endothelial cells unrelated to death signals are summarized. The known signalling pathways are integrated into specific dysregulated endothelial functions of septic patients. Early interactions of endothelium with infectious agents involve reactive oxygen and nitrogen species. Clinically apparent early signs of septic shock include increased vascular permeability and vasoregulatory disturbance. The involvement of endothelium and reactive oxygen and nitrogen species in these functions is summarized. New data have become available showing that endothelium is able to regulate whole organ oxygen consumption in which reactive oxygen and nitrogen species are involved. These data are discussed. From these in vitro and animal studies it seems evident that endothelial dysfunctions are central features of sepsis. However it remains to be clearly shown that definite endothelial dysfunctions are present and measurable in well defined patient groups, how long these suggested dysfunctions are present or change along the course of septic episodes. The involvement of dysregulated production of reactive oxygen and nitrogen species is most likely.

O objetivo do presente estudo foi avaliar comparativamente os efeitos dos treinamentos físicos aeróbico contínuo (TC) e aeróbico intervalado (TI) na tolerância ao esforço e na resposta vasomotora, analisando as vias de produção de espécies reativas de oxigênio (EROs) e a biodisponibilidade de óxido nítrico (NO), em aorta torácica isolada de ratos infartados pós-ligadura da coronária esquerda (IM). As sessões de treino de ambos TC e TI foram equalizados pelo gasto calórico total, distância total percorrida e intensidade média do VO2pico. Após 48 h da última sessão de treino, os ratos foram sacrificados e feita a retirada da aorta torácica para as analises funcionais e bioquímicas. Resultados: o IM promoveu disfunção endotelial aórtica, evidenciada por um menor relaxamento à ACh e maior constrição à NE. O grupo IM-SED apresentou menor capacidade funcional (menor tolerância ao esforço e menor VO2pico). Por outro lado, ambos os grupos IM-TC e IM-TI aumentaram a vasodilatação à ACh e diminuíram a vasoconstrição à NE. Além disso, ambos os TC e TI foram eficientes em aumentar a tolerância ao esforço e VO2pico nos grupos IM. Estes efeitos benéficos do TC e TI na função endotelial aórtica estavam associados ao aumento da via de produção de NO (ativação da eNOS por maior expressão da Akt total e fosforilada) e diminuição da produção de superóxido (redução da NOX- 1), acarretando em maior biodisponibilidade de NO. Deste modo, podemos concluir que ambos os TC e TI foram igualmente efetivos em atenuar o estresse oxidativo, restaurar a função endotelial aórtica e aumentar a capacidade funcional de ratos infartados / The aim of this study was to evaluate comparatively the effects of continuous aerobic physical training (CT) and aerobic interval training (IT) on exercise tolerance and vasomotor response, analyzing the process of production of reactive oxygen species (ROS) and nitric oxide (NO) bioavailability in thoracic aorta isolated from postinfarcted rats induced by left coronary artery ligation (MI). The training sessions of both CT and IT were equalized by total caloric expenditure, total distance running and average intensity of VO2peak. 48 h after the last training session, rats were sacrificed and the thoracic aorta was removed for the functional and biochemical analysis. Results: MI caused aortic endothelial dysfunction, evidenced by a lower relaxation to ACh and increased constriction to NE. The IM-SED group had lower functional capacity (lower exercise tolerance and lower VO2peak). Moreover, both groups CT and IT increased vasodilation to ACh and reduced vasoconstriction to NE. Furthermore, both CT and IT were effective in increasing exercise tolerance and VO2peak in IM groups. These beneficial effects of CT and IT on aortic endothelial function were associated with increased NO production pathway (activation of eNOS by increased expression of total and phosphorylated Akt), and decreased superoxide production (reduction of NOX-1), resulting in increased bioavailability of NO. Thus, we conclude that both IC and IT were equally effective in attenuating oxidative stress, restore aortic endothelial function and increase the functional capacity of infarcted rats

Le coeur et les vaisseaux sanguins sont directement issus de l'endothélium et dépendent de sa fonction. Le coeur ne représente pas la seule force motrice de notre système circulatoire, la plupart des stratégies thérapeutiques actuelles des maladies cardiovasculaires sont encore focalisées sur le coeur, négligeant l'ensemble du système circulatoire et le système endothélial. Par exemple, le développement de Dispositifs d'Assistance Cardiaque (DAC) est influencé par le coeur, conçu pour suivre,obéir et doit être synchronisé avec un organe malade.De nombreux « signaux » de nature différente sont capables d’activer les cellules endothéliales : les forces de cisaillement créées par le flux sanguin parallèle à la surface de la paroi des vaisseaux, mais également les forces perpendiculaires provoquées par l’étirement de la paroi artérielle par les variations de la pression et la qualité cyclique de ces forces. L’activation de cellules endothéliales est due à la pulsatilité du flux mais aussi à l’action de substances vasoactives et des médiateurs de l’inflammation.Dans notre travail de thèse, nous proposons une nouvelle approche thérapeutique,basée sur une révision fondamentale de l'ensemble du système circulatoire: exposer les défauts de la gestion courante des maladies cardiovasculaires (MCV). Notre nouveau concept se concentre sur la dynamique des flux sanguins pour stimuler,restaurer et maintenir la fonction endothéliale, et compris le coeur lui-même. Nous avons développé et évalué une nouvelle génération de DAC pulsatiles, testée in vitro et in vivo.Pendant le déroulement de cette thèse nous avons effectué les études suivantes:1. Etude d’un prototype de cathéter pulsatile. Il est testé de manière isolée dans un modèle expérimental d’ischémie aiguë du myocarde et dans un modèle d’hypertension pulmonaire aiguë.2. Etude d’un prototype de tube pulsatile à double lumière. Il est testé in-vitro dans un circuit de circulation extracorporelle, et in vivo comme assistance ventriculaire gauche.73. Etude d’un prototype de combinaison pulsatile. Il est testé sur un modèle animal présentant une défaillance aiguë du ventricule droit. Des prototypes de masques et de pantalons pulsatiles sont en développement.En conclusion, notre approche est basée sur l’activation de la fonction endothéliale plutôt qu’en une assistance cardiaque directe. Ce concept permet une meilleure gestion thérapeutique des maladies circulatoires et cardio-pulmonaires. / The “Heart” is still considered as the main organ to be dealt with, in case ofcardiovascular disease. Nevertheless, the heart is not the only driving force in ourcirculatory system. In fact, the heart and blood vessels are the direct issues of theendothelium and depend on its function. Moreover, almost all current therapeuticstrategies are still focusing on the heart and neglecting the entire circulatoryendothelialsystem. For example, development of cardiac assist devices (CAD) is stillrestrained by the heart, designed to follow, obey and must be synchronized with adiseased organ.Many "signals" of different nature are capable of activating endothelial cells: the shearforces created by the blood flow parallel to the surface of the vessel wall, but alsoforces caused by stretching perpendicular to the artery wall by the cyclic pressuregradient and the quality of these forces. The activation of endothelial cells is due tothat pressurized flow dynamic forces, but also to the action of vasoactive substancesand inflammatory mediators.In this thesis we are proposing a new therapeutic approach, based on a fundamentalrevision of the entire systems: exposing those defects of current management ofcardiovascular diseases (CVD). A concept that focuses on flow dynamics to stimulate,restore and maintain endothelial function including the heart itself. This includespreliminary results of new generations of pulsatile CAD that promote endothelial shearstress (ESS) enhancement. Devices prototypes were tested.During this thesis, pulsatile devices prototypes were tested in vivo, in vitro as well aswith pre-clinical volunteers as follow:1. A pulsatile catheter prototype was tested in 2 pediatric animal models (piglets) of:acute myocardial ischemia; and acute pulmonary arterial hypertension.2. A pulstile tube prototype was tested in vitro (mock circuit) and in vivo (piglets) as aleft ventricular assist device (ongoing).3. Pulsatile suit prototypes were tested: in vivo (piglets) for acute right ventricularfailure treatment. Prototypes of pulsatile mask and trousers are currently in plannedfor pre-clinical studies.9Conclusion, Think endothelial instead of cardiac is our policy for better management ofCVD.