For more than half a century cardiovascular disease has been the leading cause of death in the United States.  Aging, hypertension, and obesity are major risk factors for cardiovascular disease and clearly associated with arterial stiffness.  Arterial stiffness generates higher afterloads and diminishes coronary perfusion thereby causing ventricular hypertrophy and ischemia.  Importantly, arterial stiffness is an independent predictor of cardiovascular disease risk and all-cause mortality.   Current strategies such as inhibition of angiotensin II or angiotensin converting enzyme, reduction of smooth muscle tone, blood volume, or inflammatory mediators, and improving glucose homeostasis are effective destiffening options.  Nebivolol, a third generation beta-blocker, has unique vasodilatory characteristics and may be particularly efficacious as a destiffening agent.  Only a few studies have addressed this issue while relying on indirect, blood pressure-dependent stiffness indices precluding clear understanding of study outcomes.  There remains a need to determine the potential utility of nebivolol therapy as an arterial destiffening strategy.   Thus, we hypothesized that the combination of nebivolol and lifestyle modification would reduce central arterial stiffness in middle-aged and older hypertensive adults more than either intervention alone.  To test this hypothesis, we randomized 45 hypertensive adults to receive lifestyle modification, nebivolol, or combination for 12 weeks.  β-stiffness index, pulse wave analysis, and arterial compliance were measured at baseline and following the intervention.  No baseline differences in variables of  interest were observed between groups.  In contrast to our hypothesis, lifestyle modification, nebivolol, and combination groups had similar (P>0.05) reductions in beta-stiffness index (-1.87±0.83; -2.03±0.60; and -2.51±0.90 U), respectively, while carotid-femoral pulse wave velocity declined only in the nebivolol and combination groups.   Our findings suggest combination of nebivolol and lifestyle modification reduces arterial stiffness to a similar degree as either intervention alone in middle-aged and older hypertensive adults.  Further studies are needed to determine if the changes in arterial stiffness continue to occur or remain clinically significant over longer durations. / Ph. D.

Cardiovascular diseases (CVD) are the leading cause of mortality in the United States. Aging is the major risk factor for CVD development, which is independently predicted by arterial stiffness (AS). Arterial stiffening is closely related to age-related arterial structural/functional changes and obesity. Therefore, obese middle-aged and older adults are considered a high CVD risk population. In light of the current obesity epidemic and the projected growth of the older population, there is an overwhelming need to determine if weight loss (WL) may reduce AS (CVD risk) in this population. Thus, we hypothesized that WL via a hypocaloric diet-alone would reduce AS in overweight and obese middle-aged and older adults. To test our hypothesis, baseline assessment of anthropometrics, blood pressure and AS was conducted, and subjects were randomized to a 12-week WL intervention or a control group. Arterial stiffness was measured using applanation tonometry to estimate carotid-femoral artery pulse wave velocity (C-F PWV), and with high-resolution ultrasonography of the carotid artery (β-SI). There were no baseline differences between groups in our variables of interest. Consistent with our hypothesis, both measures of AS were significantly reduced (C-F PWV= -16% and β-SI= -12%, P<0.05) with WL (-8%, P<0.05). Weight loss also resulted in significantly decreased blood pressure, total body and abdominal fat. No such changes were observed in the control group. Pooled correlation analysis suggests that the magnitude of change in C-F PWV was not associated with changes in systolic, diastolic or mean blood pressure. We further hypothesized that reductions in AS, if observed, would be associated with the magnitude of reduction in total body or abdominal adiposity. Concordant with our hypothesis, the reductions in C-F PWV were significantly associated with total and abdominal fat. However, linear regression analysis indicate that neither total body nor abdominal body fat were capable of independently predicting reductions in C-F PWV. Our findings suggest that moderate WL in overweight and obese middle-aged and older adults is an efficacious treatment strategy for reducing AS. Further studies are needed to determine if the improvements in arterial compliance would be sustained with long-term WL maintenance. / Ph. D.

Arterial stiffness is one of the major risk factors and markers of cardiovascular disease (CVD). An increase in the arterial stiffness is influenced by various factors such as age, lifestyle, genetics and the presence of other cardiovascular risks such as obesity and diabetes. Arterial stiffness is a consistent thread in this thesis. This thesis investigates the effects of exercise-based management programmes for CVD and risk factors with a focus on carotid-radial applanation tonometry which is a specific non-invasive technique for measuring arterial stiffness. Erectile dysfunction is a marker of CVD and is associated with endothelial dysfunction that leads to arterial stiffness. The effects of centrebased, supervised and exercise-based cardiac rehabilitation (CR) programmes were studied on the changes in arterial stiffness, erectile dysfunction and quality of life of patients with CVD. Despite the effectiveness of CR programmes, there is poor attendance at these programmes and unsupervised home-based, IT (information technology)-supported programmes could improve patient participation and cost effectiveness. Moreover, earlier identification of risks and appropriate management can reduce the incidence of CVD. There are no such programmes for early stages of CVD in practice, especially in developing countries such as India. A 12-week, IT-supported home-based exercise programme in India, for patients with metabolic syndrome was developed and studied. In general, arterial stiffness was improved in both centre-based and home-based exercise programmes. There were acute increases in arterial stiffness following exercise in healthy Caucasians and South Asians as well as people with metabolic syndrome. Carotid-radial pulse wave analysis could be a simple and reliable prognostic tool in exercise based rehabilitation programmes.

Age-related increases in arterial stiffness are mediated in part by mitochondrial dysfunction. Sirtuin 3 (SIRT3) is a mitochondrial NAD+-dependent deacetylase that regulates mitochondrial function. SIRT3 deficiency contributes to physiological dysfunction in a variety of pathological conditions. Here, we tested the hypothesis that age-associated arterial stiffness, assessed by aortic pulse wave velocity (PWV), would be accompanied with decreased renal and aortic SIRT3 expression and activity due to decreased NAD+ levels. We further tested whether boosting NAD+ concentration with nicotinamide riboside (NR), a NAD+ precursor, for 6 months would reverse the effects of aging. Old (~26 mo, n = 9) C57BL/6 male mice had higher PWV vs. young (6 mo, n = 10) (448 ± 14 vs 382 ± 13, p < 0.005), which was associated with reduced arterial SIRT3 protein (0.365 ± 0.088 AU’s vs 1.000 ± 0.000); p < 0.05). Furthermore, SIRT3 deficient male mice demonstrated higher PWV compared to age-matched control mice (480 ± 21 n = 6 vs. 391 ±12 n = 7, p < 0.005). Aortic SIRT3 protein was negatively correlated with PWV (r=-0.7798, p < 0.005). Old mice also exhibited reduced kidney SIRT3 protein (0.73 ± 0.10 AU’s) compared to young controls (1.00 ± 0.00; p = 0.0192) and reduced NAD+ (918.6 ± 50.5 pmol/mg vs. young 1302.0 ± 56.6 pmol/mg, p = 0.0036). Old mice supplemented with NR had increased NAD+ concentration in kidney tissue (1303.0 ± 90.2 pmol/mg) however, had no effect on normalizing age-associated arterial stiffness (402 ± 18 old with NR vs 418 ± 15 old; p = 0.78). Here we show for that SIRT3 protein correlates with aortic stiffness and may be required for the maintenance of healthy arteries and for the first time that supplementation with NR, a commercially available supplement, ameliorates age-associated decreases in renal NAD+ demonstrating therapeutic potential in kidney disease.

The primary purpose of the present study was to determine the acute hemodynamic responses to twenty-three select yoga postures in advanced and novice yoga practitioners. Additionally, we sought to determine if trunk flexibility is related to arterial stiffness. Using a cross-sectional study design, 37 apparently healthy adults (26 females and 11 males; 22-71 years old) were divided into two groups according to level of yoga experience. Beat-to-beat measures of blood pressure, stroke volume, cardiac work-load, cardiac output, and total peripheral resistance were measured using a finger plethysmograph during the yoga routine. Baseline measures of trunk flexibility (sit-and-reach scores and inclinometer measurements) and arterial stiffness (carotid-femoral pulse wave velocity) were also compared. Yoga postures elicited significant increases in heart rate, blood pressure and cardiac output (P<0.05) for both groups. There was no difference in blood pressure responses between the two groups throughout the yoga testing session. Lumbar flexion, as measured by an inclinometer, was significantly (P<0.01) and inversely associated with cfPWV (r=-0.52). / text

BACKGROUND: Arterial stiffness (AS), or loss of elastic compliance of large arteries, is an independent risk factor for cardiovascular events1. A recent study demonstrated that single nucleotide polymorphisms (SNPs) in a genetic locus downstream of the gene Bcl11b are associated with AS2. However, how this genetic locus and Bcl11b regulate AS is unknown. OBJECTIVES: To determine the molecular mechanisms by which Bcl11b effects the aortic wall and AS. METHODS: Vascular smooth muscle (VSM) cells were isolated from aortas of wildtype (WT) mice and mice with VSM-specific Bcl11b deletion (BKO). mRNA levels of Bcl11b, vascular contractile markers (myosin heavy chain 11 (MYH11), smooth muscle -actin (ACTA2), and myocardin (MYOCD)) and a cell proliferation marker (Ki67) were measured in WT and BKO VSM cells isolated from murine aortas. VSM cell contractility in response to angiotensin II (angII), a contractile stimulus, was measured in WT and BKO VSM cells using an optimized collagen gel contractility assay. RESULTS: BKO VSM cells had decreased expression of contractile markers compared to WT cells, which resulted in impaired collagen gel contraction in response to angII. CONCLUSIONS: Bc111b is expressed in aortic smooth muscle cells and it regulates the expression of VSM contractile proteins. Our data strongly supports the hypothesis that Bcl11b regulates AS by regulating the contractile function of VSM cells in the aortic wall. / 2019-07-11T00:00:00Z

Orientador: Marilza Vieira Cunha Rudge / Banca: José Carlos Peraçoli / Banca: Nelson Lourenço Maia / Banca: Geraldo Duarte / Banca: Nelson Sass / Resumo: A hipertensão gestacional está presente em cerca de 10% das gravidezes e ainda é a primeira causa de mortalidade materna no Brasil. O diabetes gestacional complica 7,6% das gestações no Brasil e está associado a esultados perinatais insatisfatórios. Estas complicações cursam com disfunção endotelial e alteração da elasticidade da parede -.vascular. A onometria de aplanação é um método não invasivo, portátil e de fácil aprendizagem que avalia a função endotelial através do estudo da rigidez arterial (perda da elasticidade arterial). Além de avaliar a função endotelial este método oferece estudo indireto de vários parâmentros cardiovasculares centrais. O grande número de informações que este método obtém de maneira não invasiva, faz deste, um instrumento valoroso em pesquisa. Apresenta grande potencial, especialmente, na compreensão dos mecanismos fisiopatológicos que cursam com comprometimento vascular na gravidez. / Abstract: Gestational hypertension affects 10% of pregnancies and is still the first :ause of maternal mortality in Brazil. Gestational diabetes affects 7,6% of gnancies in Brazil and is associated with an unsatisfactory peri-natal come. These complications are associated to endothelial dysfunction and abnormal elasticity of the arterial wall. Applanation tonometry is a nonvasive, portable and easy learning method that evaluates endothelial nction by the study of arterial stiffness (Iost of arterial elasticity). Beyond e endothelial function evaluation, this method gives, indirectly, several central cardiovascular parameters. The great number of information btained non invasively by this method, makes of this, a valuable instrument in research. It has special potential to help in the comprehension of the mechanisms of those diseases that presents with vascular commitment in pregnancy. / Doutor

Increased arterial stiffness is a predictor of cardiovascular events and mortality across a diverse range of populations. Although gross-mechanical stiffness can be measured in vivo, in order to understand the pathological mechanisms it will be necessary to identify which local micro-structural remodelling events are the prime drivers of altered macro-mechanical function. However, characterisation of arterial structure by conventional histological approaches: i) commonly induces artefacts as a consequence of the sectioning process, ii) provides no insight into the three dimensional structure of the tissue and iii) is performed on unpressurised tissue. This project has set out to address these limitations by developing new micro computed x-ray tomography (micro-CT) methodologies which are capable of visualising the three dimensional structure of rat arteries. This new methodology was then been applied in combination with gross-and micro-mechanical testing and atomic force microscopy imaging to characterise the effects of both intra-luminal pressure and age on arterial structure and function. From these investigations it was clear that micro-CT could readily distinguish discrete tissue sub-structures in paraffin embedded tissues, including skin and arteries and that this imaging approach was compatible with complimentary histological and immunohistochemical analyses. Characterisation of the structure and mechanical function of carotid arteries in aged rats demonstrated localised stiffening in the adventitial layer and a change in the molecular structure of adventitial collagen. The effects of intra-luminal pressure on structure using micro-CT revealed changes in artery cross-sectional area, which suggest the artery wall may be compressible. Investigations into the effects of pressure on the molecular structure of adventitial collagen revealed an increase in periodicity at mean pressure. These findings together demonstrate that the adventitial layer has an important role in the development of arterial stiffness. Micro-CT can reveal novel information that improves our understating of artery structure and how artery structure changes during ageing.

Heat therapy may be an alternative or adjunct intervention to exercise training for improving cardiovascular function and health. However, its prescription must be refined in order to overcome the feasibility and tolerability issues associated with current whole-body heating modes. There is substantial evidence to support the beneficial effects of high doses (e.g., frequency, duration, and intensity) of heating typically achieved using whole-body modes, but there is limited knowledge on whether lower doses of heating administered through local hot water immersion of the limbs can still have an impact on vascular function. All studies were conducted in heathy young men and women. In the first study, we found that regardless of whether local heating was applied to the lower limbs up to the ankles or knees, upper limb endothelial function and lower limb arterial stiffness improved acutely. In the second study, we proceeded to prescribe ankle-level heating in a chronic intervention and compared its effects to that of moderate-intensity cycling exercise training. We observed no changes in endothelial function, but decreases in central arterial stiffness and increases in cardiorespiratory fitness in those who performed heat therapy and exercise training combined with heat therapy. In the third study, we evaluated the ability of acute vascular function responses to predict chronic vascular function responses with heating and exercise interventions, and found significant positive associations between the acute and chronic responses for absolute and relative brachial artery flow-mediated dilation and femoral-foot pulse wave velocity. These findings suggest that, in healthy young men and women, local heating through ankle-level hot water immersion can improve indices of cardiovascular function both acutely and chronically, alone or combined with exercise training. Further, acute responses may be used to determine an individual’s chronic responsiveness to a heat therapy and/or exercise training intervention. More research in larger, more diverse samples and with a longer duration of therapy and/or training should be conducted to determine if the results are replicable. / Dissertation / Doctor of Philosophy (PhD) / Regular participation in whole-body heat therapy can extend health and life span, but it is used infrequently because of a lack of feasibility from a cost, accessibility, and tolerability standpoint. This thesis explored whether local heat therapy in young healthy men and women would be effective for improving blood vessel health defined as endothelial function and arterial stiffness, both of which are linked to the risk of developing many chronic diseases. Furthermore, the effects of local heat therapy were compared to that of exercise training. We found that there were beneficial short- and long-term effects of lower limb hot water immersion that manifested in different areas of the body. Local heat therapy improved upper limb endothelial function and lower limb arterial stiffness immediately after a session, whereas with repeated exposure, it may have improved central arterial stiffness and cardiorespiratory fitness. Exercise training only had beneficial effects on the blood vessels when combined with heat therapy. Finally, short-term vascular responses can predict long-term vascular responses to both heat therapy and/or exercise training. Overall, our findings suggest that there may be some utility for local heat therapy to promote healthy blood vessels, but more work must be done to replicate our findings and explore its effects on other populations.

No description available.