Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirties priežastis visoje Europoje ir Lietuvoje. Literatūroje plačiai, tačiau nevienareikšmiai aptarta MS svarba širdies kraujagyslių ligų atsiradimui. Neatsakyta į vieną iš pagrindinių klausimų: kurie MS sudarantys rizikos veiksniai ar jų grupės daugiausia lemia širdies ir kraujagyslių ligų progresavimą. Mes savo darbe įvertinome arterijų funkcinių ir struktūrinių pokyčių bei kairiojo skilvelio miokardo masės indekso kitimų sąsajas su amžiumi, lytimi ir MS; taip pat atsižvelgėme ne tik į MS, bet ir į atskirų širdies bei kraujagyslių rizikos veiksnių nepriklausomą įtaką kardiovaskuliniam pažeidimui. Be to, bandėme nustatyti, koks MS sudarančių atskirų komponentų skaičius gali daugiausia lemti širdies ir kraujagyslių arterijų funkcinius ir struktūriniais kitimus bei kairiojo skilvelio miokardo masės didėjimą. Darbe nustatyta, kad sergantiesiems metaboliniu sindromu nepriklausomai nuo lyties ir amžiaus yra didesnis intimos medijos storis, šlaunies miego arterijų pulsinės bangos greitis ir kairiojo skilvelio miokardo masės indeksas. Didesnis miego arterijoje aterosklerozinių plokštelių skaičius rastas tik moterims su metaboliniu sindromu. Širdies ir kraujagyslių pažeidimų rizika sergantiems metaboliniu sindromu vyrams ir moterims taip pat buvo skirtinga. Vyrams su MS aptikta 2,14 karto didesnė kairiojo skilvelio hipertrofijos ir 4,9 karto – intimos medijos sustorėjimo tikimybė. Moterims metabolinis sindromas nesukelė intimos... [to full text] / Cardiovascular diseases (CVD) are the main cause of death all over the Europe and were the most prevalent disease in Lithuania in 2010. Based on some of the data, MS risk factors have different influence on changes of artery structure and function. MS and its components can influence differently the emergence of cardiovascular diseases and advance of complications in men and women. Furthermore, we tried to estimate the number of separate components constituting MS that can have the most significant influence on functional and structural changes in cardiovascular arteries and increase of the left ventricle myocardial mass index. The particularity of changes in different arterial stiffness indicators in patients with MS has not been determined yet in the literature, as well as prognostic value of MS when initiating early disorders in arterial structure and function and left ventricular hypertrophy. The research showed the following results: in subjects with metabolic syndrome irrespectively their gender and age higher intima-media thickness, femoral-carotid arteries pulse wave velocity and left ventricular myocardial mass index were found. However, higher number of atherosclerotic plaques in carotid artery was found only in females. Risk of cardiovascular disorders in males and females with metabolic syndrome is different. Nor in males, neither in females metabolic syndrome had no direct influence on pulse wave velocity, intima-media thickness, hypertrophy of left ventricle... [toliau žr. visą tekstą]

Širdies ir kraujagyslių ligos (ŠKL) yra pagrindinė mirties priežastis visoje Europoje ir Lietuvoje. Literatūroje plačiai, tačiau nevienareikšmiai aptarta MS svarba širdies kraujagyslių ligų atsiradimui. Neatsakyta į vieną iš pagrindinių klausimų: kurie MS sudarantys rizikos veiksniai ar jų grupės daugiausia lemia širdies ir kraujagyslių ligų progresavimą. Mes savo darbe įvertinome arterijų funkcinių ir struktūrinių pokyčių bei kairiojo skilvelio miokardo masės indekso kitimų sąsajas su amžiumi, lytimi ir MS; taip pat atsižvelgėme ne tik į MS, bet ir į atskirų širdies bei kraujagyslių rizikos veiksnių nepriklausomą įtaką kardiovaskuliniam pažeidimui. Be to, bandėme nustatyti, koks MS sudarančių atskirų komponentų skaičius gali daugiausia lemti širdies ir kraujagyslių arterijų funkcinius ir struktūriniais kitimus bei kairiojo skilvelio miokardo masės didėjimą. Darbe nustatyta, kad sergantiesiems metaboliniu sindromu nepriklausomai nuo lyties ir amžiaus yra didesnis intimos medijos storis, šlaunies miego arterijų pulsinės bangos greitis ir kairiojo skilvelio miokardo masės indeksas. Didesnis miego arterijoje aterosklerozinių plokštelių skaičius rastas tik moterims su metaboliniu sindromu. Širdies ir kraujagyslių pažeidimų rizika sergantiems metaboliniu sindromu vyrams ir moterims taip pat buvo skirtinga. Vyrams su MS aptikta 2,14 karto didesnė kairiojo skilvelio hipertrofijos ir 4,9 karto – intimos medijos sustorėjimo tikimybė. Moterims metabolinis sindromas nesukelė intimos... [toliau žr. visą tekstą] / Cardiovascular diseases (CVD) are the main cause of death all over the Europe and were the most prevalent disease in Lithuania in 2010. Based on some of the data, MS risk factors have different influence on changes of artery structure and function. MS and its components can influence differently the emergence of cardiovascular diseases and advance of complications in men and women. Furthermore, we tried to estimate the number of separate components constituting MS that can have the most significant influence on functional and structural changes in cardiovascular arteries and increase of the left ventricle myocardial mass index. The particularity of changes in different arterial stiffness indicators in patients with MS has not been determined yet in the literature, as well as prognostic value of MS when initiating early disorders in arterial structure and function and left ventricular hypertrophy. The research showed the following results: in subjects with metabolic syndrome irrespectively their gender and age higher intima-media thickness, femoral-carotid arteries pulse wave velocity and left ventricular myocardial mass index were found. However, higher number of atherosclerotic plaques in carotid artery was found only in females. Risk of cardiovascular disorders in males and females with metabolic syndrome is different. Nor in males, neither in females metabolic syndrome had no direct influence on pulse wave velocity, intima-media thickness, hypertrophy of left ventricle... [to full text]

[pt] Esta dissertação tem por objetivo o desenvolvimento de um transdutor de pressão de alta sensibilidade, baseado nas características de fase da impedância de sensores de Magnetoimpedância Gigante. A configuração do dispositivo visa a aplicações biomédicas, tais como medições da onda de pulso arterial e de sua velocidade de propagação. Projetou-se um sistema de transdução de pressão em tensão, que contém um módulo intermediário baseado em um magnetômetro GMI. O protótipo implementado inclui uma estrutura mecânica, responsável pela transdução de pressão em campo magnético, e um circuito eletrônico, responsável pela conversão deste em uma tensão elétrica de saída. A conversão de pressão em campo magnético é feita por meio de uma fonte de campo magnético aderida a uma membrana elástica. Foram realizados estudos comparativos empregando agulhas magnetizadas e ímãs permanentes como fontes móveis de campo. Por sua vez, o elemento sensor GMI utilizado foi experimentalmente caracterizado, a fim de se obter suas curvas características de módulo e fase, em função do campo magnético. O circuito eletrônico de transdução foi projetado e avaliado de forma computacional e experimental. As principais características do mesmo são detalhadas ao longo do texto e as previsões teórico-computacionais são comparadas com os resultados experimentais obtidos. Por sua vez, parâmetros chave do protótipo desenvolvido são minuciosamente analisados, tais como: sensibilidade, linearidade e resposta em frequência. Também, avalia-se a densidade espectral de ruído do transdutor desenvolvido e estima-se sua resolução na banda de passagem. Os resultados obtidos indicam que o protótipo de baixo custo desenvolvido apresenta alta resolução e alta sensibilidade, além de uma banda de passagem compatível com a requerida pelas aplicações biomédicas nas quais deseja-se empregá-lo. Dessa forma, espera-se que o dispositivo desenvolvido contribua para o avanço tecnológico do ferramental utilizado no setor da saúde. / [en] This dissertation aims at the development of a high sensitivity pressure transducer, based on the phase impedance characteristics of Giant Magnetoimpedance sensors. The configuration is intended to employ the developed device in biomedical applications, such as in measurements of arterial pulse wave and pulse wave velocity. A transduction system of pressure into voltage was designed, which contains an intermediate module based on a GMI magnetometer. The idealized prototype contains a mechanical structure, responsible for converting pressure into magnetic field, and an electronic circuit, responsible for converting the latter into a voltage output. The conversion of pressure into magnetic field is performed by means of a magnetic field source adhered to an elastic membrane. Comparative studies were carried out using magnetized needles and permanent magnets as field sources. In turn, the GMI sensor element was experimentally characterized in order to evaluate how its impedance magnitude and phase are affected by the magnetic field. The influence of the cable length used to interconnect the GMI sensor to the electronic circuit is also discussed. The electronic transduction circuit was designed and analyzed by computational and experimental evaluations. The main features of the circuit are detailed throughout the text and the theoretical and computational predictions are compared with the obtained experimental results. Furthermore, the key parameters of the developed prototype are meticulously analyzed, such as: sensitivity, linearity and frequency response. Also, the spectral noise density of the developed transducer is evaluated and its resolution in the passband is estimated. The obtained results indicate that the developed prototype presents low cost of manufacture and operation, high resolution, high sensitivity and a passband compatible with the requirements imposed by the biomedical applications of interest. In this way, it is intended that the device developed in the present Dissertation contributes to the technological enhancement of measurement equipment used in health sector.

INTRODUÇÃO:A rigidez arterial aumentada é um importante determinante do risco cardiovascular e um forte preditor de morbimortalidade. Além disso, estudos demonstram que o enrijecimento vascular pode estar associado a fatores genéticos e metabólicos. Portanto,os objetivos do presente estudo são determinar a herdabilidade da velocidade de onda de pulso (VOP) e avaliar a associação do perfil lipídico e do controle glicêmico com o fenótipo de rigidez arterial em uma população brasileira.MÉTODOS:Foram selecionados 1675 indivíduos (ambos os gêneros com idade entre 18 e 102 anos) distribuídos em 109 famílias residentes no município de Baependi-MG. A VOP carótida-femoral foi avaliada de forma não invasiva através de um dispositivo automático.As variáveis lipídicas e a glicemia de jejum foram determinadas pelo método enzimático colorimétrico. Os níveis de hemoglobina glicada (HbA1c) foram determinados pelo método de cromatografia líquida de alta eficiência. As estimativas da herdabilidade da VOP foram calculadas utilizando-se a metodologia de componentes de variância implementadas no software SOLAR. RESULTADOS: A herdabilidade estimada para a VOP foi de 26%, sendo ajustada para idade, gênero, HbA1c e pressão arterial média. Os níveis de HbA1c foram associados a rigidez arterial, onde a elevação de uma unidade percentual da HbA1c representou um incremento de 54% na chance de risco para rigidez arterial aumentada. As variáveis lipídicas (LDL-c, HDL-c, colesterol não- HDL-c, colesterol total e triglicérides) apresentaram fraca correlação com a VOP. Além disso, uma análise de regressão linear estratificada para idade (ponto de corte >= 45 anos) demonstrou uma relação inversa entre LDL-c e VOP em mulheres com idade >= 45 anos. CONCLUSÃO: Os resultados indicam que a VOP apresenta herdabilidade intermediária (26%); a HbA1c esta fortemente associada a rigidez arterial aumentada; o LDL-c é inversamente relacionado com a VOP em mulheres com idade >= 45 anos, possivelmente devido às alterações metabólicas associadas à falência ovariana / INTRODUCTION: Increased central arterial stiffness is an important determinant of cardiovascular risk and a strong predictor of morbimortality. Moreover, studies showed that vascular stiffening can be associated with genetic and metabolic factors. Thus, the aims of this study are to estimate the heritability of pulse wave velocity (PWV) and to assess the association of lipid profile and glycemic control with arterial stiffness in a sample from the Brazilian population. METHODS: For this study, 1675 individuals (both genders aged from 18 to 102 years) were selected and they were distributed within 109 families residents in the municipality of Baependi - MG. The PWV was measured with a non-invasive automatic device. Lipid profile parameters and fasting glucose were determined by enzymatic colorimetric method. HbA1c levels were determined by high-performance liquid chromatography. Variance component approaches implemented in the SOLAR software were applied to estimate the heritability of PWV. RESULTS: Heritability estimates for carotid-femoral PWV was 26%, after adjustment for age, gender, HbA1c, and mean blood pressure. HbA1c levels were associated with arterial stiffness and the elevation of a single unit percentage of HbA1c represented an increase of 54 % in the odds of increased arterial stiffness. The lipid variables (LDL-c, HDL-c, non-HDL-c, total cholesterol and triglycerides) presented weak correlation with PWV. In addition, a linear regression analysis stratified by age (cutoff >= 45 years) showed an inverse relation between LDL-c and PWV in women aged 45 or older. CONCLUSION: Our findings indicate that PWV demonstrated an intermediate heritability (26%); HbA1c proved to be a good marker for risk stratification for increased arterial stiffness; LDL-c was inversely related with PWV in women aged 45 or older, possibly due to the metabolic alterations associated with ovarian failure

Submitted by Fabio Sobreira Campos da Costa (fabio.sobreira@ufpe.br) on 2016-04-12T15:21:22Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) / Made available in DSpace on 2016-04-12T15:21:22Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de Zoraya versão definitiva 131015 aceita.pdf: 2706371 bytes, checksum: 83da3cf5bbbffb2d66214831901498f3 (MD5) Previous issue date: 2015-02-27 / Esta tese teve como objetivo estudar um marcador de aterosclerose subclínica, a rigidez aórtica, medida através da velocidade de onda de pulso aórtica, diante da importância de se identificar os pacientes com risco maior de desenvolver doenças cardiovasculares (DCV), hoje, uma das principais causas de morbidade e mortalidade, não relacionada à síndrome da imunodeficiência adquirida (AIDS) em pessoas vivendo com o vírus da imunodeficiência humana (PVHIV). Entre setembro de 2011 e janeiro de 2013, a população do estudo composta por homens e mulheres vivendo com o vírus da imunodeficiência humana (HIV), participantes da coorte HIV/AIDS-PE, no nordeste do Brasil, iniciada em 2007, foi submetida a dois desenhos de estudos visando identificar os fatores de risco cardiovasculares tradicionais e emergentes associados com a rigidez aórtica e sua progressão.Visando identificar fatores de riscos cardiovasculares emergentes, incluindo a perda de massa óssea, realizamos um estudo transversal em mulheres vivendo com HIV que haviam realizado densitometria mineral óssea, no período entre Outubro de 2010 a Novembro de 2011. A densidade mineral óssea (DMO), foi medida pela absorciometria de energia dupla de raio-x de (DXA) nas regiões da coluna lombar, colo de fêmur e fêmur total e a rigidez aórtica, foi medida pela velocidade de onda de pulso aórtica (VOPa). O resultado principal deste estudo foi a correlação negativa significante entre a DMO do colo de fêmur e do fêmur total com a VOPa mesmo ajustada para idade, síndrome metabólica e pressão arterial média. Sugerindo que mulheres vivendo com HIV com perda de massa óssea deverão ser avaliadas para doença cardiovascular aterosclerótica. Para investigar a progressão da rigidez aórtica, foram acompanhados por uma média de 2,9 anos, homens e mulheres vivendo com HIV que haviam realizado a primeira avaliação da rigidez aórtica entre Abril e Novembro de 2009. O achado mais importante deste estudo foi a verificação de uma acelerada progressão da rigidez aórtica associada a fatores de risco tradicionais, idade, sexo masculino e hipertensão arterial e uma correlação negativa com a duração da infecção em uma população sob bom controle virológico. Os dados favorecem intensificar medidas para melhor controle da hipertensão arterial e da imunodeficiência. / This thesis aimed to study a marker of Subclinical Atherosclerosis, aortic stiffness measured by aortic pulse wave velocity, given the importance of identifying the patient with higher risk of developing cardiovascular diseases, today, one of the leading causes of morbidity and mortality, not related to AIDS. Between September 2011 and January 2013, the study population comprised of men and women living with human immunodeficiency virus (HIV), HIV/AIDS cohort participants-PE, in northeastern Brazil, initiated in 2007, have undergone two designs of studies aimed at identifying the factors of traditional and emerging cardiovascular risk associated with aortic stiffness and its progression. Aiming to identify emerging cardiovascular risk factors, including the loss of bone mass, we performed a cross-sectional study in women living with HIV who had performed bone mineral densitometry in the period between October 2010 to November 2011. Bone mineral density was measured by dual-energy x-ray absorptiometry (DXA) in regions of the lumbar spine, neck femur and total femur and aortic stiffness was measured by aortic pulse wave velocity (aPWV). The main result of this study was the significant negative correlation between the BMD of the femoral neck and total femur aPWV even adjusted for age, metabolic syndrome and mean arterial pressure. Suggesting that women living with HIV with low of bone mass should be assessed for atherosclerotic cardiovascular disease. To investigate the progression of aortic stiffness, were accompanied by an average of 2.9 years, men and women living with HIV who had carried out the initial evaluation of aortic stiffness between April and November 2009 .The most important finding of this study was the verification of an accelerated progression of aortic stiffness associated with traditional risk factors, age, male and hypertension and a negative correlation with duration of infection in a population under good viral control. The data favor the aggressive measures of intensify and immunodeficiency hypertension.

The aim of this diploma thesis is to assess the applicability of pulse wave propagation monitoring in the cardiovascular system in the field of prediction and early diagnosis of abdominal aortic aneurysm (AAA). The very first part is focused on description of heart and blood vessels with its pathological changes in presence of aneurysm. For this reason, current methods of monitoring and surgical treating of AAA were mentioned. Due to their difficult clinical use widely in the population, new methods based on pulse wave monitoring were presented. Using an analytical approach we estimated the difference in the arrival of the pulse wave at measurable locations between healthy and pathological aorta in the order of miliseconds. By experimental monitoring using photoplethysmographic sensors, we observed significant changes of pulse wave velocity with respect to the mechanical properties of the artery wall (mainly associated with age), which we tried to implement by hyperelastic material models used in computational simulations of pulse wave proagation on simplified geometries by fluid structure interaction method. These analyzes should verify applicability of FSI simulations in further development of diagnostic methods of AAA.

This thesis deals with the methodology of use of whole-body impedance cardiography for evaluation of pulse wave velocity. The first three chapters explain selected hemodynamic properties of the arterial system related to the issue of pulse wave propagation. At the same time the ordinary methods for estimation, its disadvantages and merits has been summarized. Points at issue of whole-body impedance evaluation methodology for pulse wave velocity are researched in second part of this thesis. In order that analysis the procedure for correct methodology has been determined. Particularly determination of reference proximal point for calculation of transit time towards aortic valve, and design and accuracy of transit distance measurement were discussed. Based on the obtained data, a calculation of representative pulse wave velocity to eight limb locations was performed.

Pulse wave velocity (PWV) and augmentation index (AI) are independent predictors of cardiovascular health. However, the comparability of multiple oscillometric modalities currently available for their assessment was not studied in detail. In the present study, we aimed to evaluate the relationship between indices of arterial stiffness assessed by diastolic and suprasystolic oscillometry. In total, 56 volunteers from the general population (23 males; median age 70 years [interquartile range: 65–72 years]) were recruited into observational feasibility study to evaluate the carotid-femoral/aortic PWV (cf/aoPWV), brachial-ankle PWV (baPWV), and AI assessed by 2 devices: Vicorder (VI) applying diastolic, right-sided oscillometry for the determination of all 3 indices, and Vascular explorer (VE) implementing single-point, suprasystolic brachial oscillometry (SSBO) pulse wave analysis for the assessment of cfPWV and AI. Within- and between-device correlations of measured parameters were analyzed. Furthermore, agreement of repeated measurements, intra- and inter-observer concordances were determined and compared for both devices. In VI, both baPWVand cfPWVinter-correlatedwell and showed good level of agreement with bilateral baPWVmeasured byVE (baPWV[VI]– baPWV[VE]R: overall concordance correlation coefficient [OCCC]¼0.484, mean difference¼1.94 m/s; cfPWV[VI]–baPWV[- VE]R: OCCC¼0.493, mean difference¼1.0m/s). In contrast, SSBO derived aortic PWA (cf/aoPWA[VE]) displayed only weak correlation with cfPWV(VI) (r¼0.196; P¼0.04) and ipsilateral baPWV (cf/ aoPWV[VE]R–baPWV[VE]R: r¼0.166; P¼0.08). cf/aoPWA(VE) correlated strongly with AI(VE) (right-sided: r¼0.725, P<0.001). AI exhibited marginal between-device agreement (right-sided: OCCC¼ 0.298, mean difference: 6.12%). All considered parameters showed good-to-excellent repeatability giving OCCC > 0.9 for 2-point-PWV modes and right-sided AI(VE). Intra- and inter-observer concordances were similarly high except for AI yielding a trend toward better reproducibility in VE (interobserver–OCCC[VI] vs [VE]¼0.774 vs 0.844; intraobserver OCCC[VI] vs [VE]¼0.613 vs 0.769). Both diastolic oscillometry-derived PWV modes, and AI measured either with VI or VE, are comparable and reliable alternatives for the assessment of arterial stiffness. Aortic PWV assessed by SSBO in VE is not related to the corresponding indices determined by traditional diastolic oscillometry.

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.

The mechanical properties of the arterial wall are of great importance for blood pressure regulation and cardiac load. With increasing age, large arteries are affected by increased wall stiffness. Furthermore, atherosclerotic manifestations may increase the stiffness even further, both processes acting as independent cardiovascular risk factors affecting the arterial system in a heterogeneous way. The aims of this thesis was to characterize the local mechanical properties of brachial artery (BA) with the aid of ultrasound technique and to evaluate the influence of 1) age, gender, sympathetic stimulation and examination site; 2) type 1 diabetes (DM) and its association to circulatory biomarkers; and 3) to evaluate the general properties of the arterial system with the aid of pulse wave velocity (PWV) as well as pulse wave analysis (PWA) in systemic lupus erythematosus (SLE) and correlate the findings to disease activity and circulatory biomarkers. In the most proximal arterial segment of the upper arm a pronounced age-related decrease in wall distensibility, increase in intima-media thickness (IMT), and a slight increase in diameter were seen. Sympathetic stimulation had no influence on wall mechanics. More distally in BA, no change in diameter, and only minor increase in IMT and decrease in distensibility were seen. No gender differences were found. These findings suggest that the principle transit zone between elastic and muscular artery behaviour is located in the proximal part of the upper arm. Women with uncomplicated insulin-dependent DM had similar diameter, IMT and distensibility in their distal BA as controls, whereas flow-mediated dilatation (FMD) was slightly, and nitrate mediated dilatation (NMD) markedly reduced. NMD was negatively correlated with higher HbA1c levels. Vascular smooth muscle cell function seems to be an early manifestation of vascular disease in women with DM, influenced by long-term hyperglycaemia. Women with SLE had increased aortic PWV compared to controls, a finding positively associated with increased levels of complement factor 3 (C3), but not with disease activity. The increased stiffness of central arteries may be one factor contributing to the increased cardiovascular risk seen in SLE.