A hipertensão arterial sistêmica (HAS) pós-transplante é frequente e está associada com aumento da morbimortalidade cardiovascular e subsequente disfunção do enxerto, sendo relatada como consequência ao uso de imunossupressores, especialmente os inibidores da calcineurina. Este estudo pretende avaliar o impacto da hipertensão arterial sobre a rigidez arterial calculada utilizando o índice ambulatorial de rigidez arterial (IARA) como desfecho substituto obtido pela monitorização ambulatorial da pressão arterial (MAPA) em pacientes transplantados de coração. Trata-se de um estudo prospectivo, observacional, analítico, com grupo controle, realizado no Hospital de Messejana Dr. Carlos Alberto Studart Gomes, hospital público do estado do Ceará, especializado em doenças cardiopulmonares e de referência em transplante de coração. Foram selecionados pacientes adultos transplantados do coração, os quais passaram por exames clínicos e complementares, e um grupo controle com pacientes não transplantados hipertensos. Todos foram submetidos a MAPA e obtenção do IARA com o objetivo de estimar o risco de rigidez arterial. Foram realizados testes estatísticos de significância e regressão logística para controle de confundimento. A média de idade dos transplantados foi de 55 anos, contra 48 dos não transplantados. A hipertensão prévia foi mais frequente em não transplantados, mas diabetes e doença arterial coronariana foram mais frequentes em transplantados. A média diastólica dos transplantados (82) é significativamente maior que a dos não transplantados (74) e o descenso sistólico é praticamente inexistente em pacientes transplantados (-0,18) que no grupo-controle (9,45). A condição de transplantado do paciente não é determinante de rigidez arterial, mas a hipertensão arterial sistólica na primeira avaliação, a média sistólica em 24h, a média diastólica em 24h, o descenso sistólico, o descenso diastólico e o IARA (parâmetros da MAPA) o são. Este estudo encontrou que num grupo de transplantados de coração adultos, a hipertensão arterial sistêmica está independentemente associada com a rigidez arterial estimada pelo IARA, que é um novo método, não invasivo, de fácil execução e de baixo custo. A evidência demonstrada por este estudo pode auxiliar no direcionamento de tratamento dos pacientes transplantados, contribuindo com melhoria do prognóstico / Hypertension post cardiac transplant is frequent and is associated with increased cardiovascular morbidity and mortality and graft dysfunction, being reported because of the use of immunosuppressant, especially the calcineurin inhibitors. This study aims to evaluate the impact of hypertension on the arterial stiffness calculated using the IARA as surrogate outcome obtained by the Home Blood Pressure Monitoring in heart transplanted patients. This is an observational study, analytical, with the control group, in Heart and Lung Messejana´s Hospital, a public institution in the State of Ceará, which is specialized in cardiopulmonary diseases and especially in heart transplant, with adult patients cardiac transplanted, which underwent clinical and complementary exams, from which were obtained the IARA. Statistical significance tests and logistic regression to control for confounding were performed. The average age of transplanted was 55 years, against 48 of the non-transplanted. Hypertension was more frequent in prior not transplanted, but diabetes and coronary artery disease were more frequent in transplanted. The average diastolic of transplanted (82) is significantly higher than the non-transplanted (74) and decrease systolic is virtually nonexistent in transplant patients (-0.18) than in the control group (9.45). The condition of the transplanted patient is not determinant of arterial stiffness (p = 0.105), but are the systolic hypertension in the first evaluation, the average systolic, diastolic average in 12:0 am 12:0 am, systolic, diastolic descent and the IARA (parameters of the HBPM). This study showed that in a group of adult cardiac transplanted, hypertension is independently associated with arterial stiffness estimated by IARA, which is a new method, non-invasive, easy to perform and inexpensive. The evidence demonstrated by this study may assist in treatment of transplanted patients, contributing to improving the prognosis

While evidence suggests there is indeed a relationship between arterial stiffness and changes in brain structure and function cross-sectionally, the longitudinal relationship between arterial stiffness and changes in brain structure and function is unclear. Also unclear is whether a regional effect of arterial stiffness on brain structure exists, or if the effect is homogenous across brain regions. Using a healthy cohort of the UK Biobank study (N = 1858, meanSD: 61  7 years), we investigated the longitudinal association between changes in arterial stiffness index (ASI) and brain structure (grey matter cortical thickness, whole brain grey matter volume, white matter hyperintensity volume) and function (cognitive performance in 6 tests) over 2.5  1 years. We also examined the association between baseline ASI and all structural and functional brain outcomes 8-11 years post-baseline (N = 630). Prior to post-hoc correction, we observed a significant effect of changes in ASI over 2.5  1 years on grey matter cortical thickness in 11 brain regions contributing to reductions between 0.0004-0.0024mm annually, but none of the 11 regions remained significant post-correction. Following correction there was also no effect of changes in ASI on whole brain grey matter volume (p = 0.76), white matter hyperintensity volume (p = 0.84), or cognitive performance in the domains of interest. Baseline ASI was not associated with regional grey matter cortical thickness, white matter hyperintensity volume, or cognitive function, but did have a significant negative association with whole brain grey matter volume 8.5  1.05 (p = 0.015) years later and 11  1.02 (p = 0.03) years later. Our findings suggest that taken with the effect of age, elevations in ASI may have an additive effect to accelerate changes in brain structure beyond the range that is to be expected as a part of normal aging. Our findings also suggest the relationship between ASI and reductions in whole brain grey matter volume may require long-term exposure to elevations in arterial stiffness in otherwise healthy older adults. / Thesis / Master of Science in Kinesiology / Arterial stiffening both accompanies the normal aging process and can progress due to acquired health conditions. As arteries begin to stiffen the ability to buffer high pressure blood flow is impaired and can put microvasculature at risk of damage. Microvascular damage in the brain can disrupt blood and subsequent oxygen delivery to the brain. When delivery to the brain does not meet the metabolic demand, changes in brain structure brain can occur. Changes in brain structure are associated with impaired brain function, as well as potentially accelerating the progression of neurological diseases. What remains unclear is whether arterial stiffness impacts brain structure differently across regions or all regions homogenously. The purpose of this thesis was to examine the relationship between arterial stiffness and structural and functional changes in the brain over time (objective 1: 2-5 years; objective 2: 8-11 years). Our observations suggest that the progression of arterial stiffness had an effect that was equivalent to approximately 30% of the rate of grey matter tissue loss associated with normal healthy aging (~0.25% reduction in grey matter per year). We found no effect of changes in arterial stiffness on the progression of total grey matter volume, white matter lesions or brain function. We did observe a significant negative relationship between arterial stiffness at baseline and total grey matter volume 8-11 years later. We found no relationship between baseline arterial stiffness and brain structure or function 8–11-years post-baseline. Taken with the effects of normal aging, the loss of tissue in select brain regions associated with changes in arterial stiffness may result in grey matter reductions beyond the range associated with what is considered healthy or normal aging. The association of arterial stiffness and total grey matter volume 8-11 years later suggests that changes in whole brain structure are the product of long-term exposure to arterial stiffness.

<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)

The electro-optic technique of measuring the cardiovascular pulse wave known as photoplethysmography (PPG) is clinically utilised for noninvasive characterisation of physiological components by dynamic monitoring of tissue optical absorption. There has been a resurgence of interest in this technique in recent years, driven by the demand for a low cost, compact, simple and portable technology for primary care and community-based clinical settings, and the advancement of computer-based pulse wave analysis techniques. PPG signal provides a means of determining cardiovascular properties during the cardiac cycle and changes with ageing and disease. This thesis focuses on the photoplethysmographic signal for cardiovascular assessment. The contour of the PPG pulse wave is influenced by vascular ageing. Contour analysis of the PPG pulse wave provides a rapid means of assessing vascular tone and arterial stiffness. In this thesis, the parameters extracted from the PPG pulse wave are examined in young adults. The results indicate that the contour parameters of the PPG pulse wave could provide a simple and noninvasive means to study the characteristic change relating to arterial stiffness. The pulsatile component of the PPG signal is due to the pumping action of the heart, and thus could reveal the circulation changes of a specific vascular bed. Heart rate variability (HRV) represents one of the most promising quantitative markers of cardiovascular control. Calculation of HRV from the peripheral pulse wave using PPG, called pulse rate variability (PRV), is investigated. The current work has confirmed that the PPG signal could provide basic information about heart rate (HR) and its variability, and highly suggests a good alternative to understanding dynamics pertaining to the autonomic nervous system (ANS) without the use of an electrocardiogram (ECG) device. Hence, PPG measurement has the potential to be readily accepted in ambulatory cardiac monitoring due to its simplicity and comfort. Noncontact PPG (NPPG) is introduced to overcome the current limitations of contact PPG. As a contactless device, NPPG is especially attractive for physiological monitoring in ambulatory units, NICUs, or trauma centres, where attaching electrodes is either inconvenient or unfeasible. In this research, a prototype for noncontact reflection PPG (NRPPG) with a vertical cavity surface emitting laser (VCSEL) as a light source and a high-speed PiN photodiode as a photodetector is developed. The results from physiological experiments suggest that NRPPG is reliable to extract clinically useful information about cardiac condition and function. In summary, recent evidence demonstrates that PPG as a simple noninvasive measurement offers a fruitful avenue for noninvasive cardiovascular monitoring. Key words: Photoplethysmography (PPG), Cardiovascular assessment, Pulse wave contour analysis, Arterial stiffness, Heart rate (HR), Heart rate variability (HRV), Pulse rate variability (PRV), Autonomic nervous system (ANS), Electrocardiogram (ECG).

L'hypertension systolique isolée (HSI), amenée par une augmentation de la rigidité vasculaire, est la forme d'hypertension la plus fréquente chez les personnes âgées de plus de 60 ans. L'augmentation de la rigidité vasculaire, causée en partie par la calcification aortique médiale, est accélérée de 15 ans chez les diabétiques. Il est suggéré que la calcification aortique serait responsable de la résistance aux agents antihypertenseurs chez les patients souffrant d'HSI, d'où la nécessité de développer de nouvelles stratégies thérapeutiques ciblant la calcification artérielle. La protéine Gla de la matrice (MGP) est une protéine anti-calcifiante dépendante de la vitamine K, qui doit être γ-carboxylée pour être active. Deux enzymes sont responsables de la γ-carboxylation, soit la γ-glutamyl-carboxylase et la vitamine K époxyde réductase (VKOR). Plusieurs études récentes ont indiqué que la calcification vasculaire semblait être associée à une réduction de la γ-carboxylation de la MGP, et à un déficit en vitamine K. La modulation de l'expression et/ou de l'activité de la γ-carboxylase et de la VKOR et l'impact de cette modulation sur la γ-carboxylation de la MGP en présence de diabète n'est pas connue. L'objectif principal de cette thèse était de déterminer les mécanismes impliqués dans l'accélération de la rigidité artérielle causée par la calcification des gros troncs artériels dans le diabète. Nous avons ainsi confirmé, dans un modèle animal de rigidité artérielle en présence de diabète de type 1, que la γ-carboxylation de la MGP était bel et bien altérée au niveau aortique. En fait, nous avons démontré que la quantité de MGP active (i.e. MGP γ-carboxylée, cMGP) au sein de la paroi vasculaire est diminuée significativement. Parallèlement, l'expression de la γ-carboxylase était diminuée de façon importante, alors que ni l'expression ni l'activité de la VKOR n'étaient modifiées. La diminution de l'expression de la γ-carboxylase a pu être reproduite dans un modèle ex vivo d'hyperglycémie. À l'aide de ce modèle, nous avons démontré que la supplémentation en vitamine K dans le milieu de culture prévenait la diminution de l'expression de la γ-carboxylase, alors que les animaux diabétiques de notre modèle in vivo avaient des concentrations plasmatiques de vitamine K pratiquement triplées. D'autre part, l'étude des voies de signalisation impliquées a révélé que la voie PKCβ pourrait être responsable de l'altération de la γ-carboxylase. Ces résultats génèrent de nouvelles pistes de réflexion et de nouvelles idées de recherche. Par exemple, il serait important de vérifier l'effet de la supplémentation en vitamine K dans le modèle animal de rigidité artérielle en présence de diabète pour évaluer l'effet sur la γ-carboxylation de la MGP et par le fait même, sur la calcification vasculaire. De plus, l'évaluation de l'effet de l'administration de molécules ciblant la voie PKC chez ce même modèle animal permettrait de déterminer leur impact sur le développement de la calcification vasculaire et d'évaluer leur potentiel thérapeutique. Selon les résultats de ces études, de nouvelles options pourraient alors être à notre disposition pour prévenir ou traiter la calcification artérielle médiale associée au diabète, ce qui aurait pour effet de ralentir le développement de la rigidité artérielle et d'ainsi diminuer le risque cardiovasculaire associé à l'HSI. / Arterial stiffness contributes to the development of isolated systolic hypertension (ISH), the most prevalent form of hypertension in the elderly. Arterial stiffness, due in part to the calcification of large arteries, is accelerated by 15 years in diabetic patients. It is suggested that vascular calcification could be responsible for the resistance to anti-hypertensive agents in patients suffering from ISH, emphasizing the need of developing new therapies directly targeting vascular calcification. The matrix Gla protein (MGP) is a vitamin K-dependent secretory protein post-transtionnaly modified by the enzyme γ-glutamyl-carboxylase. This post-translational modification renders MGP active, i.e. able to inhibit vascular calcification (cMGP). Another enzyme, the vitamin K oxidoreductase (VKOR) is necessary to ensure the recycling of vitamin K from the epoxide to hydroquinone, the form used by the γ-carboxylase. Recent studies have shown that vascular calcification is associated with increased levels of under-carboxylated MGP (ucMGP), and vitamin K deficiency. However, the modulation of the expression or the activity of the enzymes involved in γ-carboxylation, as well as the impact of this modulation is currently unknown. The goal of this research project was to study the mechanisms involved in the accelerated development of arterial stiffness in diabetes due to increased vascular calcification of large arteries. In a rat model of type 1 diabetes with increased arterial stiffness, we demonstrated that aortic MGP γ-carboxylation was altered. In fact, the amount of active MGP was reduced in the arterial wall, coupled with a marked reduction of γ-carboxylase expression. However, neither VKOR expression nor activity was modified. This alteration of the γ-carboxylase was reproduced in an ex vivo model of hyperglycemia. In this model, vitamin K supplementation prevented the reduction of γ-carboxylase expression, whereas surprisingly, plasma levels of vitamin K were increased in diabetic rats compared to controls. The PKC signaling pathway has been identified as the pathway involved in the γ-carboxylase alteration. Our results provide multiple new research ideas. For instance, it would be important to study the effect of vitamin K supplementation in an animal model of diabetes-associated arterial stiffness, to gain insight into its impact on γ-carboxylase and MGP γ-carboxylation, and ultimately on vascular calcification. Moreover, it would be very interesting to determine the effect of molecules affecting the PKC pathway on vascular calcification in this model, which would allow for a better understanding of their therapeutic potential. Depending on the results of these experiments, we could have at our disposition new therapeutic options to prevent and treat vascular calcification, which would have the potential to slow down the acceleration of arterial stiffness in diabetic patients and reduce the cardiovascular risk associated with ISH.

La rigidité artérielle est considérée comme un facteur de risque important pour le développement du déclin cognitif. Toutefois, les effets précis de la rigidité artérielle sur le cerveau sont peu connus et, à ce jour, aucun modèle animal ne permet d’étudier l’effet isolé de ce facteur sur l’homéostasie cérébrale. Dans cette étude, nous avons développé un nouveau modèle de rigidité artérielle qui se base sur la calcification de l’artère carotide chez la souris. Au niveau artériel, ce modèle présente une fragmentation de l’élastine, une augmentation de la distribution du collagène et de l’épaisseur intima-média ainsi qu’une diminution de la compliance et de la distensibilité artérielles démontrant la rigidité artérielle. De plus, le modèle ne présente pas d’augmentation de pression artérielle ni de changement de rayon du lumen indiquant une absence d’hypoperfusion globale et d’anévrisme. Au niveau cérébral, les résultats montrent que la rigidité artérielle induit une augmentation de la pulsatilité du flux sanguin cérébral menant ainsi à une augmentation du stress oxydatif. Ce dernier induit une inflammation cérébrale, détectée par l’activation de la microglie et des astrocytes, induisant ultimement une neurodégénérescence. Ces effets sont surtout observés au niveau de l’hippocampe, la région cruciale pour la mémoire et la cognition. Ainsi, cette étude montre que la rigidité artérielle altère l’homéostasie cérébrale et mérite d’être considérée comme une cible potentielle dans la prévention et le traitement des dysfonctions cognitives chez les personnes âgées. / Arterial stiffness is considered as an important risk factor for the development of cognitive decline in the elderly population. However, its precise effects on the brain are unknown and, to date, no animal model allows to study the precise outcome of arterial stiffness on the brain homeostasis. In this study, we developed a new animal model of arterial stiffness based on the calcification of the carotid artery in mice. On the arterial level, this model shows a fragmentation of elastin, increased collagen distribution and intima-media thickness as well as decreased arterial compliance and distensibility, thus fulfilling the major arterial stiffness properties. In addition, this model does not a show an increase in blood pressure or change in arterial lumen radius indicating a lack of global hypoperfusion and aneurysm. Regarding the brain, the results show that arterial stiffness induces an increase in cerebral blood flow pulsatility leading to increased oxidative stress. Oxidative stress induces brain inflammation, detected by the activation of microglia and astrocytes, ultimately leading to neurodegeneration. These effects are particularly observed in the hippocampus, a crucial area for memory and cognition. Thus, this study shows that arterial stiffness alters brain homeostasis and therefore should be considered as a potential therapeutical target for the prevention and treatment of cognitive dysfunction in the elderly.

Réalisé en cotutelle avec l'Université de Lorraine (France) / Ce projet traite de la programmation développementale de l’hypertension artérielle (HTA) à travers des influences néonatales précoces pouvant moduler le développement vasculaire. Les bébés prématurés présentent des défenses antioxydantes diminuées comparés aux nouveau-nés à terme et sont exposés à la naissance à des concentrations élevées en oxygène (O2) engendrant la production d’espèces réactives de l’O2 (ERO). Les conséquences vasculaires à long terme de dommages liés aux ERO en période néonatale et les mécanismes impliqués sont très partiellement compris. Les précédents résultats du laboratoire ont montré qu’un stress hyperoxique néonatal conduit chez le rat adulte à de l’HTA, une dysfonction endothéliale et une rigidité artérielle, éléments de vieillissement vasculaire. Nous émettons l'hypothèse qu'un stress hyperoxique néonatale conduit à long terme à l'altération de la structure vasculaire et à un vieillissement vasculaire précoce. Nous avons démontré une diminution de la prolifération cellulaire, une capacité angiogénique altérée, des dommages à l’ADN et une augmentation de l’expression de protéines de sénescences (des indices de sénescence cellulaire) au-delà de la période néonatale suite à une exposition brève à l’O2 au niveau vasculaire dans un modèle animal (ratons Sprague-Dawley exposés à 80 % d’O2 du 3ème au 10ème jour de vie comparés à des ratons restés à l’air ambiant) et cellulaire (cellules musculaires lisses d'aortes thoraciques d'embryon de rat exposées à 40% O2 pendant 24h ou 48h, puis remises en normoxie pendant 96h). De plus, des altérations des composants de la structure vasculaire indiquant un remodelage vasculaire aortique ont été mises en évidence. Ces changements précèdent tous l’HTA et la dysfonction vasculaire observées dans le modèle animal à l’âge adulte et pourraient y contribuer. L’étude de jeunes adultes nés < 29 semaines comparés à des jeunes adultes nés à terme indique une augmentation de marqueurs de rigidité artérielle (indices d’un vieillissement vasculaire précoce) chez la population prématurée. L’ensemble des résultats démontre un vieillissement vasculaire précoce après une exposition néonatale transitoire à un stress hyperoxique permettant une meilleure compréhension des mécanismes physiopathologiques impliqués dans la survenue des troubles vasculaires retrouvés chez l’adulte et contribue à la mise en place de moyens de prévention chez des patients prématurés. / The scope of this thesis is developmental programming of arterial high blood pressure (HBP) hypertension through early neonatal stimuli that may alter vascular development. Premature newborns have decreased antioxidant defenses compared to term babies and are exposed upon birth to high oxygen (O2) concentration, causing reactive oxygen species (ROS) production. Long term vascular consequences of ROS related damage during the neonatal period and the mechanisms involved remain unknown. Recent data from the laboratory show that neonatal hyperoxic stress leads in adult rat to HBP, endothelial dysfunction and arterial rigidity, characteristic features of vascular aging. We hypothesize that a neonatal hyperoxic stress leads to long term vascular structure alteration explained by an early aging of the vascular system. We showed a decreased proliferation rate, an altered angiogenic capacity, as well as long term DNA damage and increased expression of senescence proteins at a vascular level following O2 exposure in the animal (male Sprague-Dawley pups kept at 80% O2 from postnatal days 3 to 10 vs. rats remained in room air) and cellular models (embryonic vascular smooth muscle cells from rat thoracic aorta exposed to 40% O2 for 24h or 48h followed by 96h recovery in control conditions). In addition, alterations of vascular structure components indicating vascular remodeling was shown before the onset of the HBP at adult age. Those changes precede the HBP and vascular dysfunction observed in our animal model at adult age and could contribute to them. Study of young adults born before 29 weeks vs. young adults born at term showed that young adults born preterm present indices of arterial stiffness vs. term controls. Results of the present thesis demonstrate a major role of premature vascular aging in the surge of vascular diseases in adulthood and contribute to a better understanding of the patho-physiological mechanisms involved and could put into practice new prevention strategies among preterm patients.

A Arterite de Takayasu (AT) é uma vasculite granulomatosa de aorta e grandes vasos associada a elevado risco cardiovascular. A velocidade de onda de pulso (VOP) é um método de avaliação indireta de diminuição da distensibilidade arterial, e valores elevados de VOP correlacionam-se com maior morbimortalidade cardiovascular. A avaliação da VOP em pacientes com arterite de Takayasu é complexa devido a muitos fatores de confusão. O objetivo do presente estudo foi avaliar a rigidez arterial, por meio da velocidade de onda de pulso carótido-femoral (VOP-CF) em pacientes do sexo feminino com arterite de Takayasu e controles saudáveis com variáveis clínicas e antropométricas comparáveis, e sua possível associação com os parâmetros da doença. Método: Pacientes com arterite de Takayasu (n = 27) foram avaliados consecutivamente e foram selecionados controles saudáveis com idade, pressão arterial, peso e altura comparáveis (n = 27). Os critérios de exclusão foram menopausa, tabagismo, diabetes, insuficiência renal, hipertensão mal controlada, arritmias cardíacas, obesidade, comorbidades inflamatórias, gravidez e história de procedimentos cirúrgicos que envolvessem a aorta. A atividade da doença foi determinada por parâmetros clínicos e laboratoriais. As medições de VOP-CF foram obtidas pelo Sistema Complior. Resultados: A média de VOP-CF foi maior em pacientes com arterite de Takayasu do que em controles (9,77 ± 3,49 vs. 7,83 ± 1.06 m/s, p = 0,009). Apesar dos rigorosos xv critérios de seleção, os pacientes com arterite de Takayasu ainda apresentavam, em média, pressão arterial sistólica de 8 mmHg maior do que os controles (p > 0,05), e os valores de pressão de pulso significativamente mais elevados. O modelo de regressão linear múltipla mostra que 93,8% da variabilidade da VOP é explicada pelas variáveis idade, pressão arterial média (PAM) e pela própria doença (R2 ajustado = 0,938). A análise logística stepwise usando como variável dependente o valor de corte de VOP estabelecido pela curva ROC (> 8,34 m/s) e, como variáveis independentes, os parâmetros com significância na análise univariada, revelou que arterite de Takayasu (OR: 4,69, IC 95% 1,31 - 16,72; p = 0,017) e PAM (OR: 1,06, IC 95% 1,00 - 1,12, p = 0,048) foram independentemente associados a maior VOP. Uma análise mais aprofundada dos parâmetros de doença revelou que os valores de VOP não foram correlacionados com velocidade de hemossedimentação, proteína C-reativa, dose cumulativa de glicocorticoides e fração de ejeção (p > 0,05). Conclusão: Nesta coorte de pacientes do sexo feminino com arterite de Takayasu, a própria doença e a pressão arterial média foram os determinantes mais fortemente associados com elevada rigidez arterial e não houve correlação dos valores de VOP com parâmetros de atividade da doença / Takayasu arteritis (TA) is a granulomatous vasculitis that affects the aorta and large vessels and is associated with higher cardiovascular risk. Pulse wave velocity (PWV) is a method of indirect evaluation of decreased arterial distensibility, and elevated PWV correlates with increased cardiovascular morbidity and mortality. The assessment of PWV in patients with Takayasu arteritis is complex due to many confounding factors. The aim of this study was to evaluate arterial stiffness, assessed by carotid-femoral pulse wave velocity (CF-PWV) in female patients with TA and healthy controls with comparable anthropometric and clinical variables, and the possible association with parameters of the disease. Method: Patients with TA (n = 27) were consecutively evaluated and healthy controls were selected with comparable age, blood pressure, weight and height (n = 27). Exclusion criteria were menopause, smoking, diabetes, renal insufficiency, poorly controlled hypertension, cardiac arrhythmias, obesity, inflammatory comorbidities, pregnancy and history of surgical procedures involving the aorta. Disease activity was determined by clinical and laboratory parameters. The CF-PWV measurements were obtained by the Complior System. Results: The mean CF-PWV was higher in patients with TA than in controls (9.77 ± 3.49 vs. 7.83 ± 6.1 m / s, p = 0.009). Despite the strict selection criteria, TA patients still had, on average, systolic blood pressure of 8 mmHg greater than controls (p > 0.05), and pulse pressure values significantly higher. The multiple linear regression model showed that 93.8% of the variability in PWV is explained by the variables age, mean arterial pressure (MAP) and the disease itself (adjusted R2 = 0.938). A stepwise logistic analysis using as the dependent variable the cutoff value of VOP established by the ROC curve (> 8.34 m/s) and, as independent variables, parameters with significance in the univariate analysis, revealed that Takayasu arteritis (OR: 4.69 95% CI 1.31 - 16.72, p = 0.017) and MAP (OR: 1.06, 95% CI 1.00 - 1.12, p = 0.048) were independently associated with increased PWV. Further analysis of disease parameters revealed that PWV values were not correlated with erythrocyte sedimentation rate, C-reactive protein, cumulative dose of glucocorticoids or ejection fraction (p > 0.05). Conclusion: In this cohort of female patients with Takayasu arteritis, the disease itself and mean arterial pressure were determinants most strongly associated with elevated arterial stiffness and no correlation of PWV values and parameters of disease activity was found

Rationnel : La vitesse d'onde de pouls (VOP) est une méthode non invasive d'estimation de la rigidité artérielle. Les recommandations internationales établissent que la VOP est un marqueur puissant du risque cardiovasculaire (CV). La corrélation entre la pression artérielle périphérique et la VOP et leurs influences respectives sur la mortalité ont été peu étudiés chez les sujets âgés. Notre objectif était d'analyser cette corrélation chez les sujets institutionnalisés de plus de 80 ans. Méthodes : PARTAGE (valeur prédictive de la pression artérielle et de la rigidité artérielle chez institutionnalisé la population très âgée) est une étude de cohorte suivant pendant 2 ans 1130 sujets de plus de 80 ans institutionnalisés dans 72 centres en France et en Italie. La corrélation entre pression artérielle systolique et diastolique (PAS et la PAD) et la VOP (mesuré avec un tonomètre PulsePen ®) a été étudié chez 1071 sujets ayant des données de VOP. Résultats : La corrélation entre la PA et la VOP dans notre étude est significative mais faible. Les coefficients de corrélation sont de 0,24 pour la corrélation PAS clinique-VOP, 0,26 pour la corrélation PP-VOP, et 0,30 pour la corrélation PA automesure-VOP. La corrélation est systématiquement plus élevée chez les femmes mais sans atteindre la significativité. Le niveau de corrélation est inversement proportionnel à l'âge : les corrélations les plus fortes sont retrouvées dans la population la plus jeune. Le traitement antihypertenseur n'a pas d'impact sur la corrélation. Conclusion : La faiblesse de la corrélation montre que la PA et la VOP expriment différents phénomènes physiopathologiques de la rigidité artérielle. L'analyse longitudinale de l'étude PARTAGE, mise en perspective avec ceux trouvés dans nos travaux, pourraient permettre de proposer la VOP comme une méthode complémentaire, voire alternative, à la mesure de la PA dans l'évaluation du risque CV dans la population des sujets très âgés / Background: Carotid-femoral pulse wave velocity (PWV) provides a comprehensive non-invasive assessment of arterial stiffness. PWV is now established as a strong marker of cardiovascular disease. The correlation between peripheral blood pressure and PWV and their respective influences on mortality have been poorly studied in the elderly. Our objective was to analyze this correlation in nursing home residents over 80 years of age. Results could ultimately be helpful in implementing strategies for diagnosis and long-term follow-up of the very elderly population. Methods: The PARTAGE (Predictive value of blood pressure and ARTerial stiffness in institutionalized very AGEd population) study is a 2-year cohort study of 1130 subjects living in 72 nursing homes in France and Italy. The correlation between baseline systolic and diastolic blood pressure (SBP and DBP) and baseline PWV (measured with a PulsePen® tonometer) was studied in 1071 subjects with available PWV measurements. Results: Correlations between peripheral blood pressure and PWV were significant but weak: r=0.24 for self-measured SBP, r=0.30 for casual SBP, r=0.11 for self measured DBP, r=0.14 for casual DBP and r=0.26 for casual pulse pressure (PP). A trend for a weaker correlation was observed in the higher age group for self measured SBP and in the lower ADL group for self measured SBP and DBP. The correlations were systematically higher in women compared to men (but did not reach statistical significance) and lower with advanced age group. The correlation was not impacted by antihypertensive. Conclusion: These findings suggest that SBP, DBP and PWV provide different information in the very elderly. The prospective, longitudinal, long term PARTAGE study results will allow further insight; provide additional in-depth information regarding the respective prognostic value of these two measurement methods. NCT00901355

La rigidité artérielle et la fibrose ont une valeur prédictive dans le développement des maladies cardiovasculaires (CV). Ces 2 phénotypes impliquent les cellules musculaires lisses vasculaires (CMLVs) notamment des récepteurs membranaires et les protéines du cytosquelette. Les objectifs ont été d’étudier : (i) l’influence du récepteur minéralocorticoïde (MR) sur la réactivité vasculaire, (ii) le rôle de l’intégrine αvβ3 dans le développement de la rigidité artérielle et la fibrose vasculaire, et (iii) l’impact de la vimentine et la synémine sur la structure et la fonction artérielle. Ces trois études ont utilisées des souris avec invalidation génétiques des protéines d’intérêt. Résultats : l’absence du MR diminue la réactivité vasculaire en altérant le couplage contraction/relaxation des CMLVs via des mécanismes Ca2+- et NO-dépendants (une diminution de la vasoconstriction en réponse au Ca2+ extracellulaire et une altération de la vasorelaxation endothélium-dépendante en réponse à l’acétylcholine). L’invalidation de la sous-unité αv prévient la fibrose en réponse à l’administration d’angiotensine II. L’absence de la vimentine et non celle de la synémine augmente la rigidité artérielle via des changements des adhésions focales des CMLVs mais aussi des cellules endothéliales. En conclusion, les récepteurs membranaires et protéines intracellulaires étudiées influencent la fonction et la structure des artères grâce à des actions spécifiques sur le tonus musculaire, la mécanotransduction et l’organisation ultra-structurale des CMLVs. Ces études montrent au niveau cellulaire et moléculaire le déterminisme plurifactoriel des phénotypes de rigidité-fibrose de la paroi artérielle. Ces résultats nécessitent des travaux plus mécanistiques pour affirmer l’implication de ces protéines dans les maladies CV liées au vieillissement / Arterial stiffness and fibrosis have a predictive value in the development of cardiovascular diseases (CV). These two phenotypes involve vascular smooth muscle cells (VSMCs) including membrane receptors and cytoskeletal proteins. The objectives were to examine: (i) the influence of the mineralocorticoid receptor (MR) on vascular reactivity, (ii) the role of avb3 integrin in the development of arterial stiffness and vascular fibrosis, and (iii) the impact of vimentin and synemin on arterial structure and function. The mice with genetic invalidation of the proteins of interest were used in these three studies. Results: the absence of MR decreased vascular reactivity by altering the contraction/relaxation coupling of VSMC through Ca2+- and NO-dependent mechanisms (a decrease of vasoconstriction in response to extracellular Ca2+ and impaired endothelium-dependent vasorelaxation in response to acetylcholine). The invalidation of the αv subunit prevented fibrosis in response to the administration of angiotensin II. The absence of vimentin, and not that of the synemin, increased arterial stiffness via changes in focal adhesions of VSMCs as well as endothelial cells. In conclusion, the studied membrane receptors and intracellular proteins that influenced the structure and function of arteries through specific actions on muscle tone, the mechanotransduction and the ultra-structural organization of VSMCs. These studies show the multifactorial dependency of the stiffness-fibrosis phenotypes of the arterial wall at the cellular and molecular levels. These results require more mechanistic work to determine the role of these proteins in CV diseases related to aging