The inclusion of a new device in clinical practice requires an adequate validation. The original publication which introduced multichannel bioimpedance monitor MBM was focused on discribing its technical parameters and demonstration measurements. Further evaluation desires comparision with other standard measuring device. This thesis describes pulse wave measurement by MBM and by other medical devices used for establishing cardiovascular risk. It proposes the validation experiment with synchronized vascular ultrasonography as a reference method. The process of the experimental measurement, aquired data and following data analysis are described in detail. The outputs of the experiment are statistically evaluated. The MBM’s performance and design of the experiment are discussed.

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.

Elle peut être estimée par deux indices : la distensibilité de la paroi aortique et la vitessede propagation de l'onde de pouls (VOP) le long de l'artère. Ces marqueurs peuvent êtreobtenus dans l'aorte proximale grâce à l'imagerie de résonance magnétique (IRM) et sontreliés entre eux par le modèle de Bramwell-Hill. L'objectif de cette thèse est, d'une part, deproposer et de valider cliniquement des méthodes d'estimation de la distensibilité et de laVOP aortique, et, d'autre part, d'étudier le modèle théorique de Bramwell-Hill, au regarddes données cliniques. Nous avons dans un premier temps comparé différentes méthodesd'estimation de la distensibilité de l'aorte. Cette étude a permis d'identifier l'approche quifournit la meilleure description physiologique de l'aorte ascendante et descendante. Ensuite,nous avons proposé une nouvelle méthode de mesure de la VOP proximale. Celle-cia été validée par comparaison avec les méthodes proposées dans la littérature en termesde reproductibilité et de corrélations des mesures avec : 1) l'âge : facteur de risque "naturel " de la rigidité aortique chez des sujets sains, et 2) la VOP carotido-fémoralemesurée par tonométrie, méthode de référence utilisée en routine clinique pour estimer larigidité globale de l'aorte. Enfin, nous avons validé le modèle théorique de Bramwell-Hillau niveau des sections de l'aorte ascendante et descendante. En conclusion, nous avonsproposé des approches locale et régionale d'évaluation de la rigidité de l'aorte proximaleet nous en avons validé la robustesse, notamment dans le cadre du vieillissement artériel. / The aortic stiffness is recognized as a major factor of cardiovascular risk, and is characterizedby distensibility and pulse wave velocity (PWV) measurements. These aorticindices are related according to the Bramwell-Hill model and can be assessed in the proximalaorta with magnetic resonance imaging (MRI). The aims of this thesis were : 1) topropose and validate clinical methods for estimating the distensibility and aortic PWVfrom MRI data, and 2) to study the theoretical model of Bramwell-Hill in the light ofclinical data. First, we compared different methods for estimating the distensibility ofthe aorta. This study permitted to identify the approach which provides the best physiologicaldescription of the ascending and descending aorta. Then we proposed a newmethod for estimating the PWV in the proximal aorta, which was validated by comparisonwith previously described methods in terms of reproducibility and correlation ofaortic PWV with : 1) age : major risk factor of aortic stiffness in healthy subjects, and 2)carotid-femoral PWV measured by tonometry, gold standard method in clinical routinefor estimating the overall stiffness of the aorta. Finally, we validated the theoretical modelof Bramwell-Hill at the sections of the ascending and descending aorta. In conclusion, weproposed local and regional approaches to assess the stiffness of the proximal aorta, andwe validated its robustness, particularly in the context of aging.

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.

Arterial stiffness represented by carotid-femoral pulse wave velocity (PWV) is considered to be an independent cardiovascular risk factor. This study was focused on large artery properties investigation in specific forms of hypertension using applanation tonometer Sphygmocor (Atcor Medical). PWV was significantly higher in resistant hypertension patients when compared to moderate essential hypertension (EH) patients. This difference appears to be independent of clinical blood pressure (BP). Night-time BP appears to be a more accurate predictor of PWV in EH. In another study we demonstrated that primary hyperparathyroidism (PH) (both hypertensive or non-hypertensive forms) might be associated with higher PWV when compared to EH patients or to normotensive controls and that this difference is independent of age and clinical BP. Neither calcium serum level, nor parathyroid hormone has been associated with PWV. Specific treatment by parathyroidectomy (PTX) seems to be beneficial for PWV decrease, which might be mainly determined by improved BP control after surgery. Since PTX indications for asymptomatic forms of PH have been discussed, our data suggest the potential benefit to the extent of subclinical organ damage after surgical treatment in these patients. Similarly, we prooved higher PWV in...

Arterial system is a system of vessels distributing blood. Ageing of arterial system leads to two distinct pathologies: atherosclerosis and arteriosclerosis - stiffening of arterial wall. These pathologies can coexist and interfere; however, they differ in their pathogenesis, location, scope and consequences. Progressive loss of elastic properties of large arteries is natural part of vascular ageing. It is directly responsible for several age dependent consequences, such as increase of central systolic pressure or prevalence of isolated systolic hypertension in the elderly. Clinically, central arteries stiffness manifests as aortic pulse wave velocity, which can be quantified, among other methods, using applanation tonometry. There is abundant evidence that aortic pulse wave velocity represents an independent predictor of cardiovascular mortality and morbidity. The most important mechanism in arterial stiffening is repeated mechanical damage which leads to fractures, fragmentation and thinning of elastin. Stiffening of large arteries can be accelerated by several other mechanisms, e.g. deposition of several substances (calcium, advanced glycation end-products, etc.), metabolic turnover of key elements of vascular extracellular matrix (collagen and elastin) or individual genetic susceptibility. In...

This diploma thesis deals with the variability of pulse wave velocity. It studies the variability of cardiovascular signals. It presents the research of measurement of pulse wave velocity and its analysis in physiology and pathological physiology. Applies spectral analysis in Matlab to a data set. It evaluates and reviews the results of this analysis

Arterial stiffness represented by carotid-femoral pulse wave velocity (PWV) is considered to be an independent cardiovascular risk factor. This study was focused on large artery properties investigation in specific forms of hypertension using applanation tonometer Sphygmocor (Atcor Medical). PWV was significantly higher in resistant hypertension patients when compared to moderate essential hypertension (EH) patients. This difference appears to be independent of clinical blood pressure (BP). Night-time BP appears to be a more accurate predictor of PWV in EH. In another study we demonstrated that primary hyperparathyroidism (PH) (both hypertensive or non-hypertensive forms) might be associated with higher PWV when compared to EH patients or to normotensive controls and that this difference is independent of age and clinical BP. Neither calcium serum level, nor parathyroid hormone has been associated with PWV. Specific treatment by parathyroidectomy (PTX) seems to be beneficial for PWV decrease, which might be mainly determined by improved BP control after surgery. Since PTX indications for asymptomatic forms of PH have been discussed, our data suggest the potential benefit to the extent of subclinical organ damage after surgical treatment in these patients. Similarly, we prooved higher PWV in...