Pulmonary arterial hypertension (PAH) is a lethal disease, characterized by functional or structural abnormalities involving distal pulmonary arterioles that result in increased pulmonary vascular resistance (PVR) and ultimately right heart failure. Our objective is to establish a conditional transgenic system in mice, to test the hypothesis that lung EC apoptosis at the level of distal pulmonary arterioles is necessary and sufficient to cause a PAH phenotype. In a pilot study, the Fas-Induced Apoptosis (FIA) construct was expressed under the control of endothelial-specific Tie2 promoter in transgenic mice (i.e. EFIA mice). Administration of a small molecule dimerizing agent, AP20187, resulted in lung modest dose-dependent PAH, which was associated with proliferative vascular lesions localized to distal lung arterioles in a small proportion of mice. Due to the low level of transgene expression in preliminary EFIA lines, we re-designed the transgenic vector by incorporating a more robust endothelial promoter (superTie2). The new construct was transfected into HUVEC and BAEC and analyzed by monitoring immunofluorescence (DsRed). Data from the EFIA model suggests that EC apoptosis may be sufficient to induce a PAH phenotype with the characteristic lung vascular lesions. The EFIA model will allow us to better explore the mechanism that links distal lung EC apoptosis with reactive vascular cell proliferation in the pathogenesis of this devastating disease.

INTRODUÇÃO: A doença de Chagas tem patogênese não totalmente conhecida. Ao contrário das funções sistólica e diastólica do ventrículo esquerdo, a função do átrio esquerdo carece de informações. OBJETIVOS: Em portadores de doença de Chagas, com ou sem alterações eletrocardiográficas, com ou sem disfunção sistólica de ventrículo esquerdo, verificar se há diferença nos parâmetros de função atrial esquerda e se há correlação entre dados de função de átrio esquerdo e parâmetros ecodopplercardiográficos de função ventricular sistólica e diastólica de ventrículo esquerdo MÉTODOS: 85 indivíduos: 10 controles (GC), 26 na forma indeterminada (GI), 30 com alterações eletrocardiográficas somente (GII) e 19 com disfunção ventricular (GIII), submetidos a ecocardiograma para avaliação da função atrial e das funções sistólicas e diastólicas ventriculares. Para analise estatística foi utilizado teste de Kruskal-Wallis e o coeficiente de Spearman. RESULTADOS: Função de reservatório (FET: fração de esvaziamento total): Houve diferença entre os grupos (p < 0,0001), média menor no GIII comparado ao GC (p = 0,003), ao GI (p < 0,001) e GII (p < 0,001), sem diferença entre GC, GI e GII. Fluxo de veias pulmonares: na onda S houve diferença entre os grupos (p = 0,003), média menor no GIII comparada ao GC (p = 0,01). Função de conduto (FEP: fração de esvaziamento passivo): houve diferença entre os grupos (p = 0,004), média menor no GIII, sem significância estatística comparando entre os grupos (GIII e GC, p = 0,06, GI e GII, p = 0,06, e GII e GIII, p = 0,07). Função de bomba propulsora (FEA: fração de esvaziamento ativo): houve diferença entre os grupos (p = 0,0001), média menor no GIII comparado ao GC (p = 0,05), ao GI (p < 0,0001) e ao GII (p = 0,002). Correlações: E/e\'média e FET: fraca correlação negativa (r = - 0,263; p = 0,02), moderada correlação negativa no GIII (r = - 0,58; p = 0,02). E/e\'média e FEP: não houve correlação (r = - 0,09; p = 0,44). E/e\'média e FEA: moderada correlação negativa (r = -0,36; p = 0,002) e no GIII (r = - 0,57; p = 0,04). e\'média e FET: moderada correlação positiva (r = 0,53; p < 0,0001). e\'média e FEP: moderada correlação positiva (r = 0,49; p < 0,0001). e\'média e FEA: moderada correlação positiva (r = 0,39; p = 0,001). Fração de ejeção do VE e FET: moderada correlação positiva (r = 0,35; p = 0,003) e no GIII (r = 0,52; p = 0,04). Fração de ejeção do VE e FEP: moderada correlação positiva (r = 0,42; p < 0,0001). Fração de ejeção do VE e FEA: moderada correlação positiva (r = 0,35; p = 0,003). CONCLUSÕES: Em pacientes com miocardiopatia chagásica com disfunção sistólica de ventrículo esquerdo, houve comprometimento das funções de reservatório, de conduto e bomba propulsora do átrio esquerdo e aqueles com função sistólica normal não apresentaram alterações nessas funções / BACKGROUND: Chagas disease (CD) pathogenesis is not fully known. Unlike the systolic and diastolic function of the left ventricle, the left atrial function still lacks information. OBJECTIVES: The aim of this study was to observe differences in patients with CD regarding the parameters of left atrial function and correlate them with Doppler echocardiographic parameters CASUISTIC AND METHODS: 85 subjects: 10 controls (GC), 26 in the indeterminate form (GI), 30 with ECG changes and normal left systolic function (GII) and 19 with left ventricular dysfunction (GIII) underwent echocardiography to assess left atrial and ventricular systolic and diastolic functions RESULTS: Reservoir function (TEF: total emptying fraction): there was a difference between groups (p <0.0001), lower mean in GIII compared to CG (p = 0.003), GI (p <0.001) and GII (p <0.001) with no difference between GC, GI and GII. Pulmonary veins flow: the S wave was no difference between groups (p = 0.003), lower mean in GIII compared to the CG (p = 0.01). Conduit function (PEF: passive emptying fraction): there was a difference between groups (p = 0.004), lower mean in GIII, without statistical significance between groups (GIII and GC, p = 0.06, GI and GII, p = 0.06, and GII and GIII, p = 0.07). Pump function (AEF: active emptying fraction): there was a difference between groups (p = 0.0001), lower mean in GIII compared to CG (p = 0.05), GI (p <0.0001) and GII (p = 0.002). Correlations: E/e\'mean and TEF: weak negative correlation (r = - 0.263, p = 0.02), moderate negative correlation in GIII (r = - 0.58, p = 0.02). E/e\'mean and PEF: no correlation (r = - 0.09, p = 0.44). E/e\'mean and AEF: moderate negative correlation (r = -0.36, p = 0.002) and GIII (r = - 0.57, p = 0.04). e\'mean and TEF: moderate positive correlation (r = 0.53, p <0.0001). e\'mean and PEF: moderate positive correlation (r = 0.49, p <0.0001). e\'mean and AEF: moderate positive correlation (r = 0.39, p = 0.001). LV ejection fraction and TEF: moderate positive correlation (r = 0.35, p = 0.003) and GIII (r = 0.52, p = 0.04). LV ejection fraction and PEF: moderate positive correlation (r = 0.42, p <0.0001). LV ejection fraction and AEF: moderate positive correlation (r = 0.35, p = 0.003). CONCLUSIONS: In patients with Chagas\' cardiomyopathy with left ventricular systolic dysfunction, there was impairment of the functions of reservoirs, conduit and pump of the left atrium

- 4 - Abstract Adaptation to hypoxia or exercise training has cardioprotective effects against acute ischemic injury, but can potentially negatively influence heart function. Possible negative changes depend on the degree of hypoxia and exercise training intensity. It is therefore necessary to evaluate the effects of the specific adaptation protocols used. The ideal technique is echocardiography, which enables non-invasive, repeated and long-term measurements of the same individual allowing to study the development of changes in the course of adaptation. The aim of this study was to determine the effects of selected protocols of adaptation to intermittent hypobaric hypoxia (corresponding to the altitude of 4,000 to 8,000 meters above sea level, for 15 weeks in total) and exercise training (running speed 30 m.min-1 for 60 min a day, 4 weeks in total) on the left ventricle geometry and systolic function in rats. We assessed basic echocardiographic parameters of the ventricle geometry and function such as fractional shortening, ejection fraction, stroke volume, cardiac output etc. The adaptation of rats to intermittent hypobaric hypoxia lead neither to the impairment of systolic function nor to the development of left ventricle hypertrophy compared to controls; signs of moderate hypertrophy were observed only...

No description available.

Ultraljudsundersökning av arteria carotis interna (ICA) och arteria carotis externa (ECA) utförs på fysiologiska kliniker för att bland annat bedöma blodflödeshastigheten i kärlen. Det kan i sin tur användas vid diagnostik av plack och stenoser. Behandling av stenos är viktigt eftersom det kan leda till stroke och transitorisk ischemisk attack (TIA). Syftet med den här studien är att jämföra den maximala blodflödeshastigheten i ECA och ICA, samt om den skiljer sig mellan höger och vänster sida. I studien inkluderades 36 deltagare i åldern 20–27 år. Resultatet analyserades med ett parat t-test samt med en korrelationsanalys. En statistisk signifikant skillnad identifierades vid jämförelse av ICA och ECA på samma sida. Ingen signifikant skillnad observerades vid sidojämförelse av vänster och höger ECA respektive ICA. En korrelation påvisades mellan vänster och höger ECA samt mellan vänster och höger ICA. Ytterligare en signifikant korrelation identifierades mellan ECA bilateralt och ICA dx. Slutsatsen med studien är att det finns en statistisk skillnad mellan flödeshastigheten i ICA och ECA och därav går det inte att använda samma referensvärden till båda kärlen. / Ultrasound examination of the internal carotid artery (ICA) and the external carotid artery (ECA) is performed in physiological clinics to assess the blood flow velocity in the vessels. Furthermore, it can be used in the diagnosis of plaque and stenoses. Treatment of stenosis is important as it can lead to stroke and transient ischemic attack (TIA). The purpose of this study is to compare the maximum blood flow velocity in ECA and ICA and allocate a possible difference between the right and left side. The study included 36 participants between the ages of 20–27. The result was analyzed using a paired t-test and a correlation analysis. A statistical significance was identified when comparing ICA and ECA on the same side. No significant difference was found when comparing left and right ECA and ICA. One correlation was detected between left and right ECA and between left and right ICA. Another correlation was identified between ECA bilaterally and ICA dexter. The conclusion of this study is that there is a significant difference between the flow velocity in ICA and ECA and therefore it is not possible to use the same reference values ​​for both vessels.

No description available.

L’hypertension systolique isolée (HSI) est le résultat de changements au niveau de la paroi vasculaire qui ont pour conséquence d’augmenter la rigidité artérielle. Ces modifications surviennent surtout au niveau des grosses artères comme l’aorte et sont associées au vieillissement. La fragmentation des fibres élastiques, leur calcification (élastocalcinose) et la fibrose font partie des changements majeurs observés avec l’âge. En plus de ces changements, le vieillissement vasculaire provoque des modifications au niveau des cellules qui composent la paroi. Les cellules endothéliales sécrètent moins de monoxyde d’azote (NO) provoquant une dysfonction endothéliale et les cellules musculaires lisses vasculaires (CMLVs) synthétisent maintenant des protéines matricielles et osseuses. Situé entre le sang et les CMLVs, l’endothélium contrôle le tonus vasculaire par la sécrétion de plusieurs substances vasoactives qui interagissent entre elles afin de maintenir l’homéostasie du système vasculaire. Parmi celles-ci, on note l’endothéline (ET), un puissant vasoconstricteur et le NO, un gaz vasorelaxants. Ce dernier est aussi reconnu pour bloquer la production d’ET par un mécanisme dépendant du guanosine monophosphate cyclique (GMPc). Comme il y a une interaction entre le NO et l’ET, et que cette dernière est impliquée dans la calcification artérielle, le NO pourrait être impliqué dans la modulation de l’élastocalcinose et de la rigidité artérielle par l’inhibition de l’ET et la modification de la composition de la paroi. Cet effet, qui se produirait au delà des effets vasorelaxants du NO, offre un potentiel thérapeutique intéressant pour l’HSI. Afin d’évaluer l’implication du NO dans la calcification vasculaire et la rigidité artérielle, un modèle animal d’HSI a été utilisé (modèle warfarine vitamine K, WVK). Ce modèle d’élastocalcinose est basé sur l’inhibition de la maturation d’une protéine anti-calcifiante, la matrix Gla protein (MGP), par la warfarine. Afin de déterminer l’implication physiologique du NO dans l’initiation et la progression de l’élastocalcinose, sa production a été inhibée par un analogue de la L-arginine, le L-NG-nitroarginine methyl ester (L-NAME). Lors des processus d’initiation de la calcification, le L-NAME a prévenu l’élastocalcinose sans toutefois modifier la vitesse de l’onde de pouls (PWV). Suite au traitement L-NAME, l’expression de la NO synthase inductible (iNOS) a été diminuée alors qu’elle a été augmentée lors du traitement WVK. Elle pourrait donc être impliquée dans les processus de calcification vasculaire. De plus, la NO synthase endothéliale (eNOS) semble également impliquée puisqu’elle a été augmentée dans le modèle WVK. Cette hausse pourrait être bénéfique pour limiter l’élastocalcinose alors que l’expression de la iNOS serait délétère. Lors de la progression de la calcification, le L-NAME a augmenté l’élastocalcinose et le PWV. Dans ce contexte, l’ET serait impliquée dans l’amplification de la calcification vasculaire entrainant une hausse de la rigidité artérielle. Comme le NO endogène limite la progression de la calcification et conséquemment la rigidité artérielle, il semble être protecteur. L’efficacité d’une modulation de la voie du NO dans le modèle WVK a été étudiée par l’administration d’un donneur de NO, le sinitrodil, ou d’un inhibiteur de la phosphosdiestérase 5 (PDE5), le tadalafil. La modulation de la voie du NO semble être bénéfique sur la rigidité artérielle, mais seulement de façon aiguë. En effet, le sinitrodil a modifié de transitoirement la rigidité au niveau de l’aorte possiblement par la modulation du tonus vasculaire sans toutefois avoir des effets sur la composition de la paroi. Comme le modèle WVK n’affecte pas la fonction endothéliale, les concentrations endogènes de NO semblent être optimales puisque le sinitrodil provoque une augmentation de l’élastocalcinose possiblement par le développement d’une tolérance. Tout comme le sinitrodil, le tadalafil a modulé de manière aiguë la rigidité artérielle sans modifier la composition de la paroi. Globalement, ces travaux ont permis de mettre en évidence les effets bénéfiques du NO endogène pour limiter le développement de l’HSI, suggérant qu’une dysfonction endothéliale, tel qu’observé lors du vieillissement, a un impact négatif sur la maladie. / Isolated systolic hypertension (ISH) is the result of complex changes in the vascular wall and consequently the increase of arterial stiffness. These modifications occur mainly in conductance arteries, like the aorta, and are associated with aging. The fragmentation of elastic fibers, calcification (elastocalcinosis), and fibrosis are major changes with age. In addition to these changes in the extracellular matrix, vascular aging also induces vascular cell wall modifications. These include decreased production of nitric oxide (NO) by endothelial cells, which induces endothelial dysfunction, and the production of matrix and bone proteins by vascular smooth muscle cells (VSMCs). Located between the blood and VSMCs, the endothelium controls vascular tone by secreting various vasoactive factors. These factors interact with each other to maintain the hemodynamic of the vascular system. Among these factors, the vasoconstrictor endothelin (ET) and the vasodilator NO. The latter has been shown to block ET production via a cyclic guanosine monophosphates-(cGMP) dependent mechanism, whereas ET has been implicated in arterial calcification. Therefore, NO might be involved in the modulation of elastocalcinosis and arterial stiffness by inhibiting ET and modifying the vascular wall composition. This effect of NO could offer interesting therapeutic potential for ISH. To evaluate the implication of NO in the vascular calcification and arterial stiffness, an animal model of ISH was used. This model of elastocalcinosis is based on the inhibition of the maturation of the anti-calcific protein, matrix Gla protein (MGP), by warfarin (WVK model). To gain insight into the physiological role of endogenous NO in the initiation and progression of elastocalcinosis, its production was inhibited by the administration of L-NAME. Interestingly, elastocalcinosis was prevented by L-NG-nitroarginine methyl ester (L-NAME) administration without any modifications of the pulse wave velocity (PWV) during the initiation of the calcification processes. After the L-NAME treatment, the expression of inducible NO synthase (iNOS) was decreased, whereas upon treatment with warfarin alone the expression of iNOS was increased, which could be implicated in vascular calcification and arterial stiffness. In addition, endothelial NO synthase (eNOS) seems to be implicated in this process as its expression was also increased upon WVK treatment. This increase could be beneficial to limit elastocalcinosis, whereas the increase in iNOS expression could be harmful. L-NAME administration during the progression of calcification increased elastocalcinosis and PWV. In an endothelial dysfunction context, ET has been shown to be involved in the amplification process of vascular calcification causing an increase in arterial stiffness. As NO limits the progression of calcification and consequently arterial stiffness, endogenous NO seems to be protective in the aorta. The efficacy of exogenous modulation of the NO pathway in the WVK model was studied upon administration of the NO donor, sinitrodil, or the phosphodiesterase type 5 inhibitor (PDE5), tadalafil. The exogenous modulation of the NO pathway seemed to be beneficial for arterial stiffness, but only in an acute manner. Indeed, sinitrodil modified the acute stiffness in the aorta potentially by vascular tone modulation, without having any effect on vascular wall composition. Since endothelial function was not affected upon WVK model, endogenous NO concentrations seem to be optimal. Thus, exogenous NO potentially caused an increase of elastocalcinosis by inducing tolerance to NO. As well as sinitrodil, tadalafil modulated the arterial stiffness in an acute manner without modifying the composition of the vascular wall. Broadly, these studies provide evidence that endogenous NO can limit ISH development, suggesting that endothelial dysfunction, as observed in aging, has a negative impact on this pathology.

La paroi vasculaire est composée de cellules endothéliales, de cellules musculaires lisses vasculaires et de fibroblastes qui sont entourés d’un réseau structuré et complexe de protéines, la matrice extracellulaire. Les interactions réciproques entre la matrice et les cellules sont nécessaires à la croissance, au développement et au remodelage. Or, différents contextes pathologiques entraînent la perturbation de ces interactions et sont la cause de différentes maladies. Au cours du vieillissement, la matrice extracellulaire des grosses artères élastiques est modifiée. Ainsi, les lamelles élastiques de la paroi vasculaire se fragmentent ou sont dégradées, en plus de calcifier. De même, l’accumulation de protéines plus rigides, comme le collagène, entraîne le développement de la fibrose. Ces modulations vont mener à l’augmentation de la rigidité artérielle et au développement de l’hypertension systolique isolée. En utilisant un modèle animal de calcification basé sur l’inhibition d’une protéine anti-calcifiante, la matrix Gla protein, avec la warfarine, nous avons étudié la séquence des événements impliqués dans le développement de l’hypertension systolique isolée. Nous avons observé l’activation précoce et transitoire de MMP-9, puis du TGF-ß, précédant la modulation phénotypique des cellules musculaires lisses vasculaires, la calcification et les changements hémodynamiques. L’inhibition des métalloprotéinases et du TGF-ß a permis de prévenir la calcification vasculaire. Nous avons également étudié le rôle joué par une enzyme de la matrice extracellulaire, la transglutaminase 2, dans le développement de la calcification associée à l’hypertension systolique isolée. À l’aide d’un nouvel inhibiteur de cette enzyme, qui a permis de prévenir la calcification, nous avons établi que la transglutaminase était un élément clé dans le processus pathologique. Ces travaux ont permis de démontré l’intérêt de nouvelles avenues thérapeutiques ciblant directement la matrice extracellulaire, particulièrement la MMP-9, le TGF-ß et la transglutaminase 2, dans la pathologie de l’hypertension systolique isolée. / Within the vascular wall, endothelial cells, vascular smooth muscle cells and fibroblasts are surrounded by a complex and structured network of secreted macromolecules and proteins, the extracellular matrix. Reciprocal interactions between matrix and cells are essential to growth, development and remodeling. However, in pathological situations, the alteration of these interactions can lead to the development of different disease states. With aging, the extracellular matrix of large elastic arteries undergoes several modifications. The elastic lamellae are fragmented or degraded and calcify, whereas more rigid proteins, such as collagen, accumulate and cause fibrosis. These alterations are associated with the stiffening of arteries, which results in the development of isolated systolic hypertension. In order to study the sequence of events occuring in the development of this pathology, we used an animal model of calcification based on the inhibition of a matrix Gla protein, which physiologically prevents calcification, with warfarin. We observed an acute and transient activation of MMP-9 and TGF-ß, which preceded the phenotypic modulation of vascular smooth muscle cells, calcification and changes to hemodynamic parameters. Moreover, the inhibition of MMPs and TGF-ß prevented vascular calcification. We also studied the role of an extracellular matrix enzyme, transglutaminase 2, in the development of vascular calcification associated with isolated systolic hypertension. Using a novel inhibitor of this enzyme, we established a key role for transglutaminase 2 in this pathological process. This thesis demonstrates the relevance of directly targeting the extracellular matrix, particularly MMP-9, TGF-ß and transglutaminase 2, as a novel therapeutic avenue in the treatment of isolated systolic hypertension.

L'imagerie par résonance magnétique (IRM) est un outil remarquable pour le diagnostic clinique, aussi bien pour l'imagerie cérébrale que pour l'imagerie cardiaque et abdominale. En IRM cardiaque, deux problèmes sont récurrents : la non reproductibilité des cycles cardiaques et le mouvement respiratoire. L'IRM cardiaque morphologique est généralement faite avec une séquence composée d'une préparation longue, visant à annuler le signal du sang pour accentuer le contraste au niveau du myocarde, et de l?acquisition à proprement parler. Ces acquisitions sont généralement faites en mésodiastole (phase de relaxation passive du coeur) ce qui permet de satisfaire les contraintes liées à l'annulation du sang et d'éviter les problèmes liés aux non reproductibilités des cycles cardiaques car la mésodiastole est longue. Il est donc difficile de satisfaire les contraintes liées à l?annulation du sang pour faire les acquisitions en télésystole (phase où le coeur est contracté) à cause des non reproductibilités cardiaques car la télésystole est courte. Afin de passer outre ces limitations et de pouvoir acquérir ces mêmes images morphologiques en télésystole, nous proposons une nouvelle méthode adaptative qui permet à la fois de placer la fenêtre d'acquisition de manière optimale et de satisfaire les contraintes liées à l'annulation du sang. Une application de cette méthode a également été mise en place pour estimer et comparer les temps de relaxation transversale (T2) entre télésystole et mésodiastole. Pour la gestion prospective du mouvement respiratoire, le point crucial est d'estimer les mouvements en temps réel en perturbant au minimum les signaux de résonance magnétique. Pour ce faire nous proposons une méthode basée sur l'estimation paramétrique des mouvements en temps réel à partir des signaux physiologiques disponibles (ceintures respiratoires et ECG). Cette méthode a été testée et les résultats montrent son intérêt et sa fiabilité par rapport aux erreurs faites au niveau du mouvement. Une méthode de reconstruction incluant les mouvements a également été utilisée pendant ces travaux afin de faire de l'imagerie en télésystole en respiration libre et d'utiliser d'autres types de capteurs respiratoires comme certains signaux de résonance magnétique. Ainsi pendant ces travaux, des méthodes adaptatives ont été mises en place afin de mieux gérer le mouvement et de prendre en compte les spécificités de chaque patient. Ces travaux ouvrent la voie de l'imagerie par résonance magnétique adaptative pleinement fonctionnelle dans un contexte clinique / Magnetic resonance imaging (MRI) is a valuable tool for the clinical diagnosis for brain imaging as well as cardiac and abdominal imaging. In cardiac MRI, there are two challenging issues: the non reproducibility of cardiac cycles and respiratory motion. Morphological cardiac MRI is generally performed with a pulse sequence composed of a long preparation, to cancel the blood signal and thus enhance the contrast of the myocardium, and the acquisition itself. These acquisitions are performed during the mid-diastolic rest (relaxation period of the heart) to satisfy constraints to cancel the blood signal and to avoid problems linked to the cardiac non reproducibility because the mid-diastolic rest is long. Consequently, to acquire images in end-systolic rest (when the heart is fully contracted) while taking into account constraints to cancel the blood signal is not straight forward due to cardiac non reproducibility because the end-systolic rest is short. To overcome these limitations and to acquire images in end-systolic rest, a new adaptive method is introduced that allows to optimally placing acquisition windows while taking constraint for the cancellation of the blood signal into account. This method was applied to measure and compare transverse relaxation time (T2) between end-systolic and mid-diastolic rests. For prospective respiratory motion correction, the crucial point is to estimate motion in real-time without perturbing MR signal used for imaging. In order to solve this issue, a new method is introduced aiming at estimating motion parameters in real-time based on physiological signals such as respiratory bellows and ECG. This method is evaluated and results show its interest and its reliability regarding motion estimation errors. A reconstructions algorithm is also used in order to perform cardiac imaging during the end-systolic rest in free breathing and to use different kind of respiratory motion sensors such as MR signals. Hence, during this research work, several adaptive method were developed to get a better management of motion and to take into account specificity of each patient. These works open the way of fully functional adaptive magnetic resonance imaging in a clinical situation

INTRODUÇÂO: A hipertensão arterial sistêmica (HAS) é uma condição clínica com alta prevalência, sendo considerada como o principal fator de risco modificável para o desenvolvimento de insuficiência cardíaca (IC). Dentre os mecanismos relacionados à progressão da HAS para a IC, a hiperatividade simpática e a disfunção endotelial devem ser consideradas. OBJETIVO: Avaliar a modulação do sistema nervoso autônomo (central e periférico), e a função endotelial em pacientes hipertensos com diferentes graus de disfunção diastólica (DD) do ventrículo esquerdo (VE). CASUÍSTICA E MÉTODO: Quarenta e cinco pacientes com HAS, sem outras co-morbidades foram submetidos ao exame de ecoDopplercardiograma tecidual, e foram alocados em três grupos: (GHT) sem alteração funcional ou estrutural cardíacas (n=15, 7 homens, 48±2 anos, IMC 28±1 Kg/m2), (GDD-ar) com diagnóstico prévio de IC diastólica e com DD padrão alteração de relaxamento do VE (n=15, 7 homens, 53±2 anos, IMC 29±1 Kg/m2) e (GDD-pr) com diagnóstico prévio de IC diastólica com padrão pseudonormal ou restritivo de DD do VE (n=15, 9 homens, 51±2 anos, IMC 27±1 Kg/m2). Voluntários saudáveis normotensos (n=14, grupo GNT) pareados para idade, sexo e IMC também foram avaliados. Curvas de pressão arterial (PA) foram registradas de modo contínuo e não invasivo (Finometer®) durante 15 minutos em repouso, na posição supina. Simultaneamente, a atividade nervosa simpática muscular (ANSM) foi registrada por meio da técnica de microneurografia. A variabilidade da freqüência cardíaca (VFC) e da pressão arterial sistólica (VPAS) foi estimada pelo método FFT. Em um segundo momento foi realizada a avaliação da função endotelial, por meio de ultrassonografia da artéria braquial associada à manobra de hiperemia reativa e após administração de trinitrato sublingual. As análises estatísticas foram realizadas pelo teste exato de Fisher e ANOVA, os resultados expressos em média ± erro padrão ou em mediana (valores mínimos e máximos). RESULTADOS: Não houve diferenças de gênero, idade e IMC entre os grupos, como também no uso das diferentes classes de drogas anti-hipertensivas entre os hipertensos. Os parâmetros estruturais cardíacos foram semelhante entre os grupos, com exceção da massa de VE do grupo GDD-pr [98 (66-162) g/m2] foi maior, p<0,05, quando comparada ao grupo GNT [85 (56-95) g/m2]. A PA sistólica (PAS) não foi diferente entre GHT, GDD-ar e GDD-pr [(138 (110-149), 133 (104-190) e 148 (118-171) mmHg, respectivamente]. Os grupos GDD-ar e GDD-pr apresentaram PAS maiores, p<0,05,quando comparados ao grupo GNT [121(108-133) mmHg]. A PA diastólica foi semelhante entre os grupos. Os grupos mostraram semelhantes valores para a modulação autonômica cardíaca avaliada pela VFC. A modulação simpática periférica representada pelo componente LF PAS da VPAS (mmHg2) foi aumentada nos grupos GDD-ar (12,2±1,3) e GDD-pr (11,7±1,2) quando comparados ao grupo GNT (6,7±0,6), p<0,05, mas não quando comparada ao grupo GHT (9,3±1,1). O prejuízo baroreflexo (índice alfa LF, ms/mmHg) foi observado nos grupos GDD-ar (4,6±0,6) e GDD-pr (5,07±0,7) quando comparados ao grupo GNT (8,2±1), p<0,05, mas não quando comparados ao grupo GHT (6,05±0,5). ANSM (espículas/min) foi maior significativamente nos grupos GDD-ar (33±1) e GDD-pr (32±1) quando comparada aos grupos GHT (26±1) e GNT (15±1) p<0,05. Ainda, o grupo GHT apresentou aumento da ANSM quando comparado ao grupo GNT, p<0,05. Os grupo GDD-ar e GDD-pr apresentaram valores semelhantes de ANSM. Com relação à avaliação da função endotelial, os grupos hipertensos apresentaram menor dilatação dependente do endotélio, sendo que somente no grupo GDD-ar [0,67 (0,0-8,7)%] houve significância estatística quando comparado ao GNT [6,3 (2,6-8,2)%]. Na avaliação da vasodilatação independente do endotélio os grupos apresentaram respostas semelhantes. CONCLUSÃO: A presença de disfunção diastólica, em qualquer grau, está associada à maior ANSM e modulação simpática periférica (LF PAS) e a menor sensibilidade do baroreflexo. A modulação simpática cardíaca não apresentou diferença entre os grupos em repouso. Outros estudos são necessários para esclarecer a relação entre causa - efeito de tais achados / INTRODUTION: The hypertension (HP) is a clinical condition with high prevalence, considered as a main modifiable risk factor for developing heart failure (HF). Among the mechanism related to the progression for HP to the HF, the sympathetic hyperactivity and endothelial dysfunction should be considered. OBJECTIVE: Evaluate the autonomic nervous system modulation (central and peripheral), and endothelial function in hypertensive patients with different pattern of diastolic dysfunction (DD) of the left ventricle (LV). METHOD: Forty-five hypertensive patients without comorbities were submitted to tissue Doppler echocardiography and allocated into three groups: (GHT) without cardiac functional or structural abnormalities (n=15, 7 men, 48±2 years, BMI 28±1 Kg/m2); (GDD-ar) with prior diastolic HF and impaired relaxation pattern of DD of LV (n=15, 7 men, 53±2 years, BMI 29±1 Kg/m2), and (GDD-pr) with prior diastolic HF and pseudonormal and restrictive patterns of DD of LV (n=15, 9 men, 51±2 years, BMI 27±1 Kg/m2). Normotensive healthy volunteers matched for age, sex and body mass index were also evaluated. Curves of blood pressure (BP) were recorded non-invasively and continuously (Finometer®) for 15 minutes at rest in the supine position. Simultaneously, muscle nerve sympathetic activity (MNSA) was recorded by microneurography technique. The heart rate and systolic blood pressure variability (HRV and SPBV) was estimated by FFT method. Afterwards, an evaluation of endothelial function through brachial artery ultrasound maneuver associated with reactive hyperemia and after sublingual administration of trinitrate was conducted. Statistical analysis was performed by Fishers exact test and ANOVA, the results are expressed as mean±standard deviation or median (minimum and maximum values). RESULTS: There were no differences in gender, age and BMI between the groups, as well as in the use of different classes of antihypertensive drugs among hypertensive patients. Cardiac structural parameters were similar between groups, except for LV mass in GDD-pr group [98 (66-162) g/m2] which was higher, p<0.05, when compared to the GNT group [85 (56-95) g/m2]. The systolic blood pressure (SBP) was similar between GHT, GDD-ar and GDD-pr groups [(138 (110-149), 133 (104-190) e 148 (118-171) mmHg, respectively]. The GDD-ar and GDD-pr groups had higher SBP, p<0.05, when compared to GNT group [121(108-133) mmHg]. The diastolic BP was similar between groups. The groups showed similar values for cardiac autonomic modulation assessed by HRV. The peripheral sympathetic modulation represented by the LF component of SBP (SBPV, mmHg2) was increased in GDD-ar group (12,2±1,3) and GDD-pr group (11,7±1,2) compared to the GNT group (6,7±0,6), p<0.05, but not when compared to GHT group (9,3±1,1). The impairment of the baroreflex (LF alpha índex, ms/mmHg) was observed in the GDD-ar (4,6±0,6) e GDD-pr (5,07±0,7) groups compared to the GNT group (8,2±1), p<0.05, but not when compared to GHT group (6,05±0,5). MNSA (burst/min) was significantly higher in GDD-ar (33±1) e GDD-pr (32±1) groups compared to GHT group (26±1) and GNT group (15±1) p<0.05. Also the GHT group showed increased MNSA when compared to GNT group, p<0.05. The GDD-ar and GDD-pr groups showed similar values of MNSA. Regarding the assessment of endothelial function, hypertensive groups had lower endothelium-dependent dilatation, but only in GDD-ar group [0,67 (0,0-8,7)%] was statistically significant when compared to GNT group [6,3 (2,6-8,2)%]. In the evaluation of endothelium-independent vasodilatation all groups showed similar responses. CONCLUSION: The presence of diastolic dysfunction of any pattern is associated with higher MNSA and peripheral sympathetic modulation (LF SBP) and lower sensitivity of the baroreflex. Cardiac sympathetic modulation did not differ between groups at rest. Further studies are needed to clarify the relationship between cause-effect of such findings