Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Patients at risk of evolving CVDs are assessed by evaluating a risk factor-based score that incorporates different bio-markers ranging from age and sex to arterial stiffness (AS). AS depicts the rigidity of the arterial vessels and leads to an increase in the arterial pulse pressure, affecting the heart and vascular physiology. These facts have encouraged researchers to propose surrogate markers of cardiovascular risks and develop simple and non-invasive models to better understand cardiovascular system operations. This work thus fundamentally capitalizes on developing a novel class of low-dimensional physics-based fractional-order models of systemic arteries and exploring the feasibility of fractional differentiation order to portray the vascular stiffness. Fractional-order modeling is a successful paradigm to integrate multiscale and interconnected mechanisms of the complex arterial system. However, this type of modeling alone often fails to efficiently integrate altered variabilities in vascular physiology from various sources of large datasets, multi-modalities, and levels. In this regard, combining fractional-order-based approaches with machine learning techniques presents a unique opportunity to develop a powerful prediction framework that reveals the correlation between intertwined vascular events. This work is divided into three parts. The first part contributes to developing the fractional-order lumped parametric model of the arterial system. First, we propose fractional-order representations to model and characterize the complex and frequency-dependent apparent arterial compliance. Second, we propose fractional-order arterial Windkessel modeling the aortic input impedance and hemodynamic. Subsequently, the proposed models have been applied and validated using both human in-silico healthy datasets and real vascular aging and hypertension. The second part addresses the non-zero initial value problem for fractional differential equations (FDEs) and proposes an estimation technique for joint estimation of the input, parameters, and fractional differentiation order of non-commensurate FDEs. The performance of the proposed estimation techniques is illustrated on arterial and neurovascular hemodynamic response models. The third part explores the feasibility of using machine learning algorithms to estimate the gold-standard measurement of AS, carotid-to-femoral pulse wave velocity. Different modalities have been investigated to generate informative input features and reduce the dimensionality of the time series pulse waves.

Perivascular adipose (PVAT) has been hypothesized to influence arterial health, where an excess can lead to pathogenesis of atherosclerosis and other arterial pathologies. A novel assessment of carotid PVAT is the use of carotid extra media thickness (EMT) ultrasonography. Currently, there is a lack of research to demonstrate the relationship between carotid EMT and existing measures of arterial health, notably, central pulse wave velocity, and carotid distensibility and intimal media thickness. In the current cross sectional study, 81 participants of younger recreationally active (ages 23.2 ± 2.5 years), younger sedentary (ages 26.4 ± 7.2 years), older healthy (ages 70.3 ± 5.4 years) and older adults with coronary artery disease (CAD) (ages 67.9 ± 8.7 years) were recruited. Resting measures of central arterial stiffness was examined through the assessment of aPWV, while measures of local carotid stiffness were examined through carotid distensibility. Aortic PWV was calculated using an accepted direct distance method (80% of carotid to femoral direct distance) and time difference between the feet of the carotid and femoral waveforms. Carotid intima-media thickness (IMT), a measure of the inner arterial walls, and carotid extra media thickness (EMT), a measure of carotid PVAT, were assessed through B-mode ultrasound images and a semi-automated edge tracking software. Carotid EMT, IMT, and aPWV were significantly greater in older adults than in younger adults (p < 0.05). No difference in carotid EMT was found between younger recreationally active (0.47 ± .08 mm) and sedentary adults (0.46 ± .06 mm). There were also no differences in carotid EMT between the older healthy (0.58 ± .06 mm) and older adults with CAD (0.54 ± 0.08 mm). Carotid EMT was also significantly correlated with age (r =0 .500), waist circumference (r = 0.521), aPWV (r =0.431), carotid distensibility (r = -0.364 and IMT (r = 0.404). Despite significant correlations, carotid EMT was not an independent predictor of aPWV, carotid distensibility and IMT. Because of the lack of predictive power in measures of arterial stiffness and carotid IMT, there is a potential that carotid EMT may be an independent vascular disease marker. Future investigations should involve carotid EMT in longitudinal studies to evaluate the potential marker for a more comprehensive cardiovascular risk assessment. / Thesis / Master of Science (MSc)

BACKGROUND: Electronic cigarettes (e-cigarettes) are nicotine delivery systems that generate an aerosol that can be inhaled and come in a variety of attractive designs and e- liquid flavorings. E-cigarettes are the second most commonly used tobacco product in the United States and are predominantly used by youth and young adults. The cardiovascular health risk of combustible cigarette use is well-established, but whether e-cigarettes increase the risk of cardiovascular events is less clear. Evaluating the short-term vascular effects of e-cigarette use is an approach to gain insight into the cardiovascular health impact. Limited studies have shown that acute e-cigarette use in combustible cigarette users was associated with increased central hemodynamic values and arterial stiffness. Few studies have assessed the effects of chronic e-cigarette use on arterial stiffness, particularly in young adults. OBJECTIVE: To assess the effects of e-cigarette use on central hemodynamics and arterial stiffness in regular e-cigarette users in comparison to combustible cigarette users and non-users. METHODS: Combustible cigarette users, e-cigarette users, and non-users without known cardiovascular disease (CVD) or CVD risk factors between the ages of 18 and 45 were enrolled in the ongoing Cardiovascular Injury due to Tobacco Products 2.0 (CITU 2.0) study at the Boston University School of Medicine and the University of Louisville School of Medicine starting from 2019. Non-invasive arterial tonometry, using the SphygmoCor system, was performed to measure peripheral artery waveforms to obtain central hemodynamic values and arterial stiffness parameters: augmentation index (AIx), carotid-radial (CR) and carotid-femoral pulse wave velocities (CFPWV). RESULTS: We had available arterial stiffness measures in 209 study participants (mean age 26±7, 48% female) across 3 tobacco product use groups: combustible cigarette users (N=51), e-cigarette users (N=97), and non-users (N=61). Amongst the e-cigarette users, 41 were dual users (use of both e-cigarettes and combustible cigarettes), 25 were exclusive e-cigarette users who were former combustible cigarette users, and 31 were exclusive e-cigarette users who were never combustible cigarette users. The majority (87%) of e-cigarette users used a pod-based product with fruit and mint/wintergreen or menthol as the most popular e-liquid flavors. In unadjusted analyses, central systolic blood pressure, AIx, CRPWV, and CFPWV differed across the three tobacco product use categories. In multivariable regression models adjusting for age, sex, race and study site, e-cigarette users and combustible cigarette users had higher central systolic blood pressure (β=3.9±2.0, p=0.048 and β=4.8±2.4, p=0.04, respectively) whereas combustible cigarette smokers also had higher central AIx, and CRPWV compared to non-users (β=6.9±3.3, p=0.04 and β=0.97±0.31, p=0.002, respectively). In unadjusted analyses across the five groups, we found similar patterns of differences in vascular measures. In multivariable regression models comparing to combustible cigarette users, dual product users had similar measures of vascular function whereas exclusive e-cigarette users who were former smokers had lower CRPWV (β=-0.95±0.36, p=0.009), and exclusive e- cigarette users who were never combustible cigarette users had lower AIx (β=-9.0±4.2, 0.04). CONCLUSIONS: Our findings suggest that in young adults, combustible cigarette use is associated with measures of arterial stiffness. Dual e-cigarette use was largely similar to combustible cigarette use whereas exclusive e-cigarette use had a lesser degree of vascular stiffening. Further studies are needed to evaluate the long-term impact of e- cigarette use on cardiovascular health.

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Cardiovascular disease is the leading cause of mortality in diabetic patients, and diabetes is one of the main causes of cardiovascular disease. Risk factors for cardiovascular disease result in structural and functional changes in the vascular wall. Arterial stiffness is a prominent structural change observed in the arterial wall that can be measured in clinical settings. The purpose of this thesis was to create a static model of the changes in arterial stiffness seen in diabetes. Elastic tubes with varying wall thicknesses were used to create artificial arteries for this purpose. Compliance (inverse of stiffness) of the arteries was determined using a pressurevolume model and a mathematical model. The compliance curves generated using the pressurevolume model exhibited trends predicted by the mathematical model. These trends were comparable to arterial stiffness changes seen in diabetes. Compliance obtained from pressurevolume measurements of elastic tubes with varying wall thickness can therefore be used to model the general trends of arterial stiffness in diabetes.

<p>Arterial stiffness is a natural and inevitable process for an ageing artery. In adults and school-aged children, increased stiffness of the central arteries is associated with cardiovascular disease (CVD) and CVD risk factors. Arterial stiffness, and its relationship with adiposity and physical activity (PA), has not been studied in preschool-aged children (3-5 years) despite the high prevalence of obesity and inactivity in this age group. Ninety-eight healthy preschoolers (4.4 ± 0.9 years; 50% boys) participated in this thesis, completing baseline and follow up assessments 12.5 ± 1.1 months apart. Whole-body PWV (carotid to dorsalis pedis; m/s) was used to assess arterial stiffness, body mass index percentile (BMI%ile) was a surrogate measure of adiposity, and PA levels (total, TPA; moderate-to-vigorous, MVPA) were quantified objectively with accelerometers and expressed as a percent of wear time. In our cohort, PWV increased significantly from baseline (4.3 m/s) to follow up (4.8 m/s; p< .001). PWV also tracked fair-to-moderately well (κ=0.25, r=0.37) with no sex differences (χ²=.485, p=.785). Girls had a higher BMI%ile than boys, and the prevalence of overweight/obese preschoolers increased from 18.8% to 21.3% over the 1-year period. Boys were more active than girls and engaged in more MVPA. 75% of preschoolers at baseline, and 70% at follow up, met the current PA guidelines (3-hrs of TPA/day). PWV was not related to BMI%ile or PA at baseline; however, it was weakly related to TPA (r=-0.28, p=.013) and MVPA (r=-0.25, p=.024) at follow up. Furthermore, longitudinal and cross-sectional regression models of sex, age, BMI%ile and TPA or MVPA could not predict PWV. Our findings indicate that adiposity and PA do not influence arterial stiffness in healthy 3 to 5 year old children. Nevertheless, maintaining a healthy body composition and engaging in regular PA has other health benefits and should be encouraged.</p> / Master of Science (MSc)

<p>A comprehensive understanding of the mechanisms regulating vascular structure and function may assist in designing effective strategies to decrease cardiovascular disease risk. The current studies were designed to investigate a) relationships between collagen markers and arterial stiffness and markers of vasoconstriction and inflammation and endothelial function in humans with a wide range of vascular health, including overweight women, elderly healthy men, individuals with coronary artery disease, individuals with spinal cord injury and young healthy men and b) changes in arterial structure and function and circulating serum markers of type I collagen synthesis and degradation, vasoconstriction and inflammation in overweight pre-menopausal women before and after a 16- week diet and exercise intervention. Resting brachial artery flow mediated dilation (FMD), upper limb and/or central pulse wave velocity (PWV_c-r and PWV_c-f) and carotid artery distensibility were assessed at baseline in all groups and, in the overweight population, after the 16-week intervention. Pro-collagen type I C-peptide (PIP), C-telopeptide of type I collagen (CTX), markers of collagen synthesis and degradation respectively, endothelin-1 (ET-1) a vasoconstrictor and interleukin-6 (IL-6) an inflammatory marker were measured. In the spectrum of vascular health, a negative relationship exists between collagen markers and central PWV (CTX–PWV_c-f: r = -0.41, p = 0.001 and PIP – PWV_c-f: r = -0.32, p = 0.01) and a positive relationship between markers and carotid distensibility (CTX: r = 0.59, pc-r increased over time in the overweight population (FMD pre: 4.1 ± 0.5 % vs. post: 6.9 ± 0.7 %, pc-r pre: 8.1 ± 0.3 m/s vs. post: 8.9 ± 0.3 m/s, p</p> / Doctor of Philosophy (PhD)

<p> Supervised isometric handgrip training (IHG) has been shown to lower blood pressure (BP) and therefore, may be an effective non-pharmacological treatment for hypertension. The present investigation examined the efficacy of unsupervised IHG to lower BP in patients who were recently diagnosed as hypertensive. Since the mechanisms responsible for attenuating BP remain unclear, this study also investigated the concurrent effects of IHG training on the autonomic nervous system (ANS) and arterial stiffness.</p> <p>Eight participants were randomized to the experimental group and the remaining six served as controls. Lifestyle modifications to lower BP were recommended for both groups. In addition, the experimental group completed IHG three times per week for six weeks. IHG consisted of four two-minute isometric contractions at 30% maximal voluntary contraction using alternate hands, each separated by a one-minute rest period. Pre- (PRE) and post-intervention (POST), BP was measured and the ANS was assessed by baroreceptor sensitivity (BRS) and both systolic and diastolic blood pressure variability (SBPV and DBPV) and arterial stiffness was evaluated by carotid-finger pulse wave velocity (PWV). All measures were assessed during a period of supine rest and during a 60° passive tilt.</p> <p> There were no significant changes in any BP measure from PRE to POST for either the experimental or control groups. There was a non-significant trend toward decreased heart rate (p = 0.065). BRS decreased from PRE to POST in both the experimental (10.7 ± 2.4 mm Hg to 9.7 ± 2.3 mm Hg) and control groups (8.6 ± 2.1 mm Hg to 7.6 ± 1.5 mm Hg), but there was no difference between groups. SBPV LF:HF was lower at POST than PRE in both experimental (6.8 ± 1.5 to 4.6 ± 1.1) and control (3.4 ± 1.9 to 2.3 ± 0.9), but there were no other differences in any other BPV variable. There were no significant changes in PWV.</p> <p> In conclusion, unsupervised IHG did not lower resting BP in newly diagnosed hypertensive patients, so there were no improvements in autonomic indices. There was a decrease in SBPV LF:HF indicating improved sympathovagal balance, but this was likely a result of lifestyle modification rather than IHG. Future studies are necessary to determine appropriate use of IHG as a treatment for hypertension and to verify the mechanisms responsible for BP attenuation with IHG.</p> / Thesis / Master of Science (MSc)

Les conséquences cardiovasculaires du vieillissement sont l'une des principales causes de mortalité. En plus de l'âge chronologique, plusieurs autres facteurs peuvent influencer l'apparition des modifications liées au vieillissement. L'étude des déterminants génétiques et environnementaux accélérateurs du vieillissement cardiovasculaire pourrait améliorer la prévention de ces pathologies. Nous avons démontré chez le rat Zucker (modèle de syndrome métabolique) en fin de vie (80 semaines) que l'obésité et les troubles métaboliques associés et le vieillissement agissent de façon synergique pour modifier la structure et la fonction vasculaire, en ciblant les propriétés endothéliales. L'augmentation précoce des acides gras libres (AGL) plasmatiques et les altérations de réactivité carotidienne qu'ils induisent sont des mécanismes clés du développement de la rigidité artérielle dans ce modèle. La souris déficiente pour le gène Klotho (Kl) possède une faible espérance de vie, un vieillissement accéléré et des pathologies semblables à celles de l'homme âgé. Nous avons caractérisé le phénotype artériel (peu connu) des souris Kl+/- à 6 et 12 mois, en comparaison de leurs contrôles Kl+/+ aux mêmes âges. Nous avons démontré dans ce modèle que dans des conditions basales, les souris Kl+/- ne présentent pas de phénotype de vieillissement accéléré de la paroi artérielle à l'âge de 12 mois. Néanmoins, à l'âge de 6 mois, les souris Kl+/- présentent une augmentation de leur rigidité carotidienne, en faveur d'une altération de la fonction vasculaire. L'étude de ces deux modèles nous a ainsi permis d'évaluer l'implication de l'obésité et de la protéine Klotho dans le vieillissement artériel / The cardiovascular consequences of aging are a leading cause of death. In addition to chronological age, several other factors may influence the onset of changes associated with aging. The study of genetic and environmental determinants of cardiovascular aging accelerators could improve prevention of these diseases. We have demonstrated in very old (80 weeks) Zucker rats (model of metabolic syndrome) that obesity and associated metabolic disorders act synergistically with aging to alter the vascular structure and function by targeting endothelial properties. The early increase in plasma free fatty acids (FFA) and alterations in carotid responsiveness induced by AGL are key mechanisms of development of arterial stiffness in this model. Mouse deficient for the gene Klotho (Kl) has a short life expectancy, accelerated aging and diseases similar to an old man. We characterized the arterial phenotype (unknown) mice Kl +/- at 6 and 12 months, compared to their controls K +/+ at the same ages. We have demonstrated in this model that in basal conditions, Kl +/- mice show no phenotype of an accelerated aging of the arterial wall at the age of 12 months. However, at the age of 6 months, mice Kl +/- show an increase in carotid stiffness in favor of an alteration of vascular function. The study of these two models has allowed us to assess the implication of obesity and Klotho protein in aging arteries