Cardiovascular disease (CVD) is the leading cause of death in the United States. Analysis of vascular reactivity (VR) in response to brachial artery occlusion is used to estimate arterial health and to determine the likelihood of future cardiovascular complications. Development of a sensitive technique to assess VR is fundamental to the field of preventive cardiology. The conventional technique to study VR is by monitoring arterial diameter changes during hyperemia following occlusion using ultrasound based methods. Such measurements require highly qualified technicians and expensive equipment; and are complicated by signal noise introduced by motion and posture among others. It is well known that tissue temperature changes are a direct response to variations in blood flow, and it has been observed in small clinical studies that variations in fingertip temperature during brachial artery occlusion and subsequent hyperemia is a simple surrogate for the measurement of vascular reactivity and endothelial dysfunction. Given the promising nature of thermal monitoring to study VR, this thesis focuses on the analysis of the underlying physics affecting fingertip temperature during vascular occlusion and subsequent hyperemia. I will quantify the contribution of hemodynamic, anatomical and environmental factors over digit temperature changes, which will serve to determine the sensitivity of the digital thermal monitoring (DTM) technique. I have quantified the effect of several contributing factors to fingertip temperature and DTM results. The aims of this thesis focus on: (1) creation of a mathematical model of heat transfer at baseline, during, and after a reactive hyperemia test; and (2) validation of the model and experimental analysis of thermal and flow parameters in healthy volunteers. The proposed project is an innovative study that intends to show and quantify the relationship between VR and digital thermal reactivity, translating mathematical models based on the physics of heat transfer and fluid mechanics to clinical application. The parametric studies performed with the zeroth order model served to separate the contribution of environment and blood flow over the temperature curves measured during brachial artery occlusion. The thermal models developed were able to reproduce the trend of the temperature response observed experimentally at the fingertip.

SAMMAMFATTNING Bakgrund: Reaktiv hyperemi definieras som ett övergående ökat blodflöde över det normala efter en tids ischemi. Det kan registreras med laserdopplerteknik. Att registrera reaktiv hyperemi är ett sätt att värdera mikrocirkulationen. Det finns många flödesvariabler att studera varav tid till maxflöde efter ocklusion är en. Det har gjorts studier som undersöker om det finns ett samband mellan reaktiv hyperemi och fysisk aktivitet/syreupptagningsförmåga. Det har inte gjorts någon studie som undersöker tid till maxflöde och fysisk aktivitet. Syftet var att undersöka om det finns ett samband mellan fysisk aktivitet och reaktiv hyperemi med avseende på tid till maxflöde. Material och metod: Testpersoner fick bära en accelerometer en vecka under dygnets alla vakna timmar samt göra en registrering av reaktiv hyperemi med laserdoppler. För statistiska beräkningar användes oparat T-test för att undersöka skillnad mellan olika grad av fysisk aktivitet och tid till maxflöde. Resultat: Ingen statistiskt signifikant skillnad mellan olika aktivitetsgrad och tid till maxflöde kunde observeras. Slutsats: Den här studien visade inte på statistiskt signifikant samband mellan blodflöde och fysisk aktivitet.

The purpose of this study was to define a lower standard cuff occlusion time to induce reactive hyperemia in assessing endothelial dysfunction. In this study, strong evidence was found by a novel technique that used oscillometric methods, which supported that 3 minute reactive hyperemia was sufficient to elicit a significant difference in arterial compliance from baseline. Twenty healthy Cal Poly students were assessed, (n=12 female, n=8 male) aged 22 years old with a standard deviation of 2.04 years. Arterial compliance was estimated by measuring the peak-to-peak oscillations for baseline, 3 minute reactive hyperemia, and 5 minute reactive hyperemia tests, with the result being statistical evidence of an increase in arterial compliance after 3 minutes of cuff occlusion compared to baseline. The peak-to-peak mean for the 3 minute reactive hyperemia test was significantly greater than the baseline peak-to-peak mean with p-values less than 0.0001. These results support that 3 minute reactive hyperemia is sufficient to assess endothelial dysfunction using oscillometry techniques. Endothelial dysfunction is the most significant predictor of a major adverse cardiovascular event, so this test can be used as an early detection tool for cardiovascular disease and allow patients to find treatment before irreversible damage is done to the body. Implementing this test into routine doctor checkups has the potential to have a significant effect on cardiovascular disease, which is the leading cause of death globally. The currently accepted clinical benchmark performed in hospitals uses high-frequency ultrasound with a standard cuff occlusion time of 5 minutes. Although noninvasive, 5 minutes of cuff occlusion causes slight discomfort to the patient and is not desirable. This test was improved and shortened by using a system based on the oscillometric method of blood pressure measurement. By reducing the duration of the test from 5 minute reactive hyperemia to 3 minute reactive hyperemia, this will make the procedure practical for an increased number of patients, providing a noninvasive option to regularly check for early symptoms of cardiovascular disease.

The overall aim of this thesis was to combine optical methods into a system with the ability to simultaneously measure blood flow changes at different tissue depths. The goal of such a system was to reveal vascular mechanisms relevant to pressure ulcer etiology under clinically relevant conditions and in relation to the evaluation of pressure-redistribution support surfaces. This thesis consists of four quantitative, cross-sectional studies measuring blood flow responses before, during, and after pressure exposure of the sacral tissue. Two optical methods – photoplethysmography and laser Doppler flowmetry – were combined in a newly developed system that has the ability to discriminate blood flows at different tissue depths. Studies I and II explored blood flow responses at different depths in 17 individuals. In Study I the blood flow was related to tissue thickness and tissue compression during pressure exposure of ≥ 220 mmHg. In Study II, the sacral tissue was loaded with 37.5 mmHg and 50.0 mmHg, and the variation in blood flow was measured. Studies III and IV included 42 healthy individuals < 65 years, 38 healthy individuals ≥ 65 years, and 35 patients ≥ 65 years. Study III included between-subject comparisons of blood flow and pressure between individuals in the three study groups lying in supine positions on a standard hospital mattress. Study IV added within-subject comparisons while the individual was lying on four different types of mattress. The studies explored the vascular phenomena pressure-induced vasodilation (PIV) and reactive hyperemia (RH). The most common blood flow response to tissue exposure in this thesis was PIV, although a decrease in blood flow (a lack of PIV) was observed in some individuals. The patients tended to have higher interface pressure during pressure exposure than the healthy groups but no differences in blood flow responses were seen. Our results showed that pressure levels that are normally considered to be harmless could have a significant effect on the microcirculation in different tissue structures. Differences in individual blood flow responses in terms of PIV and RH were seen, and a larger proportion of individuals lacked these responses in the deeper tissue structures compared to more superficial tissue structures. This thesis identified PIV and RH that are important vascular mechanisms for pressure ulcer development and revealed for the first time that PIV and RH are present at different depths under clinically relevant conditions. The thesis also identified a population of individuals not previously identified who lack both PIV and RH and seem to be particularly vulnerable to pressure exposure. Further, this thesis has added a new perspective to the microcirculation in pressure ulcer etiology in terms of blood flow regulation and endothelial function that are anchored in clinically relevant studies. Finally, the evaluation of pressureredistribution support surfaces in terms of mean blood flow during and after tissue exposure was shown to be unfeasible, but the assessment of PIV and RH could provide a new possibility for measuring individual physiological responses that are known to be related to pressure ulcer development.

L’atteinte de la fonction endothéliale représente une phase précoce de l’athérosclérose, un stade où les patients sont généralement asymptomatiques. Il existe donc un intérêt certain à détecter la dysfonction endothéliale. Nous avons développé une technique de mesure des variations de flot artériel au niveau des membres supérieurs, basée sur la spectroscopie proche infrarouge (NIRS). Cette approche permettrait d’étudier le niveau d’atteinte vasculaire et probablement de quantifier le degré de dysfonction endothéliale périphérique lors d’une hyperémie réactive. L'expérience a été exécutée sur deux cohortes de 13 et de 15 patients et a été comparée à la pléthysmographie par jauge de contrainte (SGP) qui est considérée comme une méthode de référence. Par la suite, nous avons caractérisé la réponse endothéliale par modélisation de la courbe hyperémique du flot artériel. Des études préliminaires avaient démontré que la réponse hyperémique adoptait majoritairement une forme bi-modale. Nous avons tenté de séparer les composantes endothéliales-dépendantes et endothéliales-indépendantes de l’hyperémie. La quantification des deux composantes de la réaction hyperémique permet de calculer un indice de la ‘santé’ du système endothélial local. Cet indice est nommé le ηfactor. Les résultats montrent une forte corrélation des mesures de flots entre la technique développée et la méthode de référence (r=0.91). Nous avons conclu que NIRS est une approche précise pour la mesure non-invasive du flot artériel. Nous avons obtenu une bonne répétabilité (ICC = 0.9313) pour le ηfactor indiquant sa robustesse. Cependant des études supplémentaires sont nécessaires pour valider la valeur de diagnostic du facteur défini. Mots clés: hyperémie réactive, réponse myogénique, oxyde nitrique, athérosclérose, spectroscopie proche infrarouge / Atherosclerotic diseases are mainly caused by coronary and peripheral blood vessel disorders. Endothelial dysfunction represents an early phase in these diseases, when patients are generally asymptomatic. We developed a technique, based on near infrared spectroscopy (NIRS), for measurement of arterial blood flow variations in limbs during reactive hyperemia. The technique allows the study of the level of vascular impairment and probably quantifying the level of endothelial dysfunction at peripheral arteries. The experiment was performed on two cohorts of 13 and 15 patients and was compared to strain gauge plethysmography (SGP) which is considered as gold standard. Afterward, we characterized endothelial reaction during reactive hyperemia through blood flow variations by modeling the hyperemic curve. Preliminary studies have shown that the hyperemic response generally adopts a bimodal form. The first peak was attributed to myogenic reaction that is endothelial independent and the second one to local endothelial cells reaction. The quantification of the two hyperemic response components makes it possible to calculate an index of ‘health’ for local endothelial cells, named ηfactor. The results showed a strong correlation (r = 0.91) of blood flow measurements between the developed method and the gold standard. We concluded that NIRS is a precise technique for non-invasive measurement of blood flow. Moreover, we found a high repeatability (ICC = 0.9313) of the ηfactor in repeated measurements indicating its robustness. Nonetheless, more studies are required to validate the diagnosis value of the defined factor. Key words: reactive hyperemia, myogenic response, endothelial dependent vasodilatation, nitric oxide, atherosclerosis, near infrared spectroscopy (NIRS)

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L’atteinte de la fonction endothéliale représente une phase précoce de l’athérosclérose, un stade où les patients sont généralement asymptomatiques. Il existe donc un intérêt certain à détecter la dysfonction endothéliale. Nous avons développé une technique de mesure des variations de flot artériel au niveau des membres supérieurs, basée sur la spectroscopie proche infrarouge (NIRS). Cette approche permettrait d’étudier le niveau d’atteinte vasculaire et probablement de quantifier le degré de dysfonction endothéliale périphérique lors d’une hyperémie réactive. L'expérience a été exécutée sur deux cohortes de 13 et de 15 patients et a été comparée à la pléthysmographie par jauge de contrainte (SGP) qui est considérée comme une méthode de référence. Par la suite, nous avons caractérisé la réponse endothéliale par modélisation de la courbe hyperémique du flot artériel. Des études préliminaires avaient démontré que la réponse hyperémique adoptait majoritairement une forme bi-modale. Nous avons tenté de séparer les composantes endothéliales-dépendantes et endothéliales-indépendantes de l’hyperémie. La quantification des deux composantes de la réaction hyperémique permet de calculer un indice de la ‘santé’ du système endothélial local. Cet indice est nommé le ηfactor. Les résultats montrent une forte corrélation des mesures de flots entre la technique développée et la méthode de référence (r=0.91). Nous avons conclu que NIRS est une approche précise pour la mesure non-invasive du flot artériel. Nous avons obtenu une bonne répétabilité (ICC = 0.9313) pour le ηfactor indiquant sa robustesse. Cependant des études supplémentaires sont nécessaires pour valider la valeur de diagnostic du facteur défini. Mots clés: hyperémie réactive, réponse myogénique, oxyde nitrique, athérosclérose, spectroscopie proche infrarouge / Atherosclerotic diseases are mainly caused by coronary and peripheral blood vessel disorders. Endothelial dysfunction represents an early phase in these diseases, when patients are generally asymptomatic. We developed a technique, based on near infrared spectroscopy (NIRS), for measurement of arterial blood flow variations in limbs during reactive hyperemia. The technique allows the study of the level of vascular impairment and probably quantifying the level of endothelial dysfunction at peripheral arteries. The experiment was performed on two cohorts of 13 and 15 patients and was compared to strain gauge plethysmography (SGP) which is considered as gold standard. Afterward, we characterized endothelial reaction during reactive hyperemia through blood flow variations by modeling the hyperemic curve. Preliminary studies have shown that the hyperemic response generally adopts a bimodal form. The first peak was attributed to myogenic reaction that is endothelial independent and the second one to local endothelial cells reaction. The quantification of the two hyperemic response components makes it possible to calculate an index of ‘health’ for local endothelial cells, named ηfactor. The results showed a strong correlation (r = 0.91) of blood flow measurements between the developed method and the gold standard. We concluded that NIRS is a precise technique for non-invasive measurement of blood flow. Moreover, we found a high repeatability (ICC = 0.9313) of the ηfactor in repeated measurements indicating its robustness. Nonetheless, more studies are required to validate the diagnosis value of the defined factor. Key words: reactive hyperemia, myogenic response, endothelial dependent vasodilatation, nitric oxide, atherosclerosis, near infrared spectroscopy (NIRS)

1 Cardiovascular risks in chronic airway disease in childhood The aim of this thesis was to evaluate cardiovascular risk by using a combined diagnostic approach by measuring RHI and specific biochemical markers in patients with chronic respiratory disease, where we could assume a possible risk of CVD. A total of 119 probands were examined, including 22 patients with cystic fibrosis (CF) and 52 asthma patients. We evaluated RHI using a new plethysmographic method that has a number of advantages over the ultrasonographic methods used in other studies, including non-invasiveness, high sensitivity, low biological variability and objectivity due to automatic processing. Of the biochemical parameters, we measured 4 biomarkers in relation to endothelial dysfunction (ED): hsCRP, ADMA, E-selectin, and VCAM-1. We compared RHI and biomarkers in CF and asthma patients with healthy controls and sought mutual correlations. We did not prove a statistically significant difference in RHI between the test groups with CF children but we confirmed the decreasing trend of RHI since adolescence and significantly lower RHI values in CF adults, confirming the progressive development of atherogenesis and worsening of ED with age. Biochemical parameters showed significantly higher levels of hsCRP, sVCAM-1 and E-selectin in CF...