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abstract: ABSTRACT Despite significant advancements in drug therapy, cardiovascular disease (CVD) is still the leading cause of death in the United States. Given this, research has begun to seek out alternative approaches to reduce CVD risk. One of these alternative approaches is Vitamin D supplementation. Current research has shown a link between Vitamin D status and CVD risk in both healthy and diseased populations. Among the possible mechanisms is a positive effect of Vitamin D on vascular endothelial function, which can be measured with noninvasive techniques such as flow-mediated dilation (FMD) of conduit vessels using high-resolution ultrasound. This dissertation is comprised of two studies. The first examines whether Vitamin D supplementation can improve FMD in older adults within a time period (two weeks) associated with peak increases in plasma Vitamin D concentrations after a single-dose supplementation. The second examines the effect of Vitamin D supplementation in people with Rheumatoid Arthritis (RA). The reason for looking at an RA population is that CVD is the leading cause of early mortality in people with RA. In the first study 29 Post-Menopausal Women received either 100,000 IU of Vitamin D3 or a Placebo. Their FMD was measured at baseline and 2 weeks after supplementation. After 2 weeks there was a significant increase in FMD in the Vitamin D group (6.19 + 4.87 % to 10.69 + 5.18 %) as compared to the Placebo group (p=.03). In the second study, 11 older adults with RA were given 100,000 IU of Vitamin D or a Placebo. At baseline and one month later their FMD was examined as well as plasma concentrations of Vitamin D and tumor necrosis factor-alpha; (TNF-alpha;). They also filled out a Quality of Life Questionnaire and underwent a submaximal exercise test on the treadmill for estimation of maximum oxygen uptake (VO2max). There was no significant change in FMD in Vitamin D group as compared to the Placebo group (p=.721). Additionally, there was no significant improvement in either plasma Vitamin D or TNF-alpha; in the Vitamin D group. There was however a significant improvement in predicted VO2max from the submaximal exercise test in the group receiving Vitamin D (p=.003). The results of these studies suggest that a single 100,000 IU dose of Vitamin D can enhance FMD within two week in older adults, but that a similar dose may not be sufficient to increase FMD or plasma Vitamin D levels in older adults with RA. A more aggressive supplementation regimen may be required in this patient population. / Dissertation/Thesis / Ph.D. Exercise and Wellness 2012

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / Objetivos: Avaliar a funÃÃo endotelial atravÃs da dilataÃÃo fluxo mediada em adolescentes e verificar se hà diferenÃa entre aquelas com antecedentes de gestaÃÃo normotensa ou com prÃ-eclÃmpsia (PE). Metodologia: Foram analisadas 99 adolescentes pÃs-parto (intervalo este que variou de dois meses a 11 meses pÃs-parto). Avaliou-se a dilataÃÃo fluxo mediada da artÃria braquial (DILA): apÃs repouso de cinco a dez minutos em decÃbito dorsal era verificada a pressÃo arterial no braÃo direito e realizada a medida da luz da artÃria braquial ao ultrassom. Essa medida era considerada a medida basal. Era, entÃo, realizada compressÃo do braÃo com o esfigmomanÃmetro por trÃs a cinco minutos com uma pressÃo que ultrapassasse em 30 mmHg a pressÃo sistÃlica. ApÃs a liberaÃÃo da compressÃo,era verificado o diÃmetro da luz arterial apÃs 30, 60, 90, 120 e 180 segundos em diÃstole no mesmo local da verificaÃÃo basal. Para cÃlculo da DILA, considerou-se a maior dilataÃÃo em porcentagem. Utilizou-se transdutor de alta frequÃncia (6 a 9 MHz). O ultrassonografista nÃo tinha conhecimento do resultado da gestaÃÃo no momento do exame. Verificou-se, retrospectivamente, o resultado da gestaÃÃo quanto a ausÃncia ou desenvolvimento de PE (leve ou grave). Considerou-se PE o aparecimento de pressÃo arterial maior ou igual a 140x90 mmHg apÃs 20 semanas de gestaÃÃo, associado à proteinÃria (uma cruz em duas verificaÃÃes ou duas cruzes em Ãnica verificaÃÃo, em amostra isolada ou 300 mg/dia em avaliaÃÃo de 24h). A normalidade da distribuiÃÃo dos dados foi avaliada pelos testes de Shapiro-Walk e Levene. Os grupos foram comparados pelos Testes de Kruskal-Wallis, T-Student e Mann-Whitney. Considerou-se p<0,05 como significante. Resultados: A idade variou de 13 a 18 anos (mÃdia 16,2  1,3). 76 gestaÃÃes foram consideradas normotensas, 23 prÃ-eclÃmpsias (11 PE leves e 12 graves). Verificou-se presenÃa de DILA > 10% em 75 pacientes e &#8804; 10% em 24 delas. Oito pacientes (8,1%) apresentaram DILA < 5%. Inicialmente, a populaÃÃo foi dividida em trÃs grupos: normotensa, PE leve e PE grave. NÃo houve diferenÃa estatÃstica entre os grupos quanto a idade (16,3 x 15,9 x 16,1, p = 0,615), tempo entre o parto e a avaliaÃÃo (6,8 x 6,2 x 6,7, p = 0,497), IMC (22,8 x 26,1 x 24,3 Kg/mÂ, p = 0,090) e pressÃo diastÃlica (70,3 x 73,6 x 73,4 mmHg, p = 0,181), ou DILA (16,8 x 16,5 x 11,4%, p = 0,085). A pressÃo sistÃlica foi estatisticamente diferente entre os grupos (108,8 x 117,2 x 110,8 mmHg, p = 0,005), [ a pressÃo arterial sistÃlica na PE leve foi maior do que nas normotensas (p = 0,003). NÃo houve diferenÃa entre PE leve e grave (p = 0,126) e entre PE grave e normotensa (p = 0,686)]. Quando foram comparadas somente os dois grupos PE x normotensas, o IMC apresentou-se estatisticamente diferente (p = 0,031). Nos antecedentes de prÃ-eclÃmpsia, o IMC foi maior ( 25,3 x 22,8 Kg/m ). ConclusÃes: NÃo hà diferenÃa na presenÃa de disfunÃÃo endotelial verificada pela dilataÃÃo fluxo mediada da artÃria braquial em adolescentes com antecedentes de gestaÃÃo normotensa ou prÃ-eclÃmpsia. As pacientes com antecedentes de PE apresentaram pressÃo arterial sistÃlica e IMC mais elevados do que as pacientes com gestaÃÃo previa normotens. / Aims : To evaluate the endothelial function by flow mediated dilation in adolescents and to observe if there is difference among those with a history of normotensive pregnancy or with prÃ-eclampsia ( PE ) . Methodology : A total of 99 adolescents after delivery ( this interval ranged from 2 to 11 months post partum ). It was evaluated the flow mediated dilation of brachial artery ( FMD), after resting from 5 to 10 minutes in a supine position, it was checked the blood pressure in the right arm and achieved the light measure of the brachial vessel to ultrasound. This measure was considered the baseline one. So, it was performed the compression of the arm with the sphygmomanometer about 3 to 5 minutes with a pressure that exceeded in 30 mmHg the systolic pressure. After the release of the compression, it was checked the diameter of the lumen after 30, 60, 90, 120, and 180 seconds in diastole in the same place of the basal verification . For FMD calculation, it was considered the biggest expansion in percentage. It was used a high-frequency transducer (6 to 9 MHz). The ultrasonographer did not know the result of the pregnancy at the moment of the exam. It was found retrospectively, the result of the pregnancy concerning to the absence or development of PE (mild or severe). PE was considered the appearing of arterial blood pressure greater or equal to 140 x 90 mmHg after 20 weeks of pregnancy associated with proteinuria (a cross in two checks or two crosses in only one in an isolated sample or 300 mg/day in 24-hour evaluation). The normal distribution of data was evaluated by Shapiro - Walk and Levene tests. The groups were compared through the test of Kruskal â Wallis, R- student and Mann â Whitney. It was considered p < 0, 05 as significant. Results: The age ranged from 13 to 18 years (mean 16,2  1,3 ). 76 pregnancies were considered normotensive, 23 preâeclampsia (11 mild and 12 severe PE). It was found the presence of FMD > 10 % in 75 patients and &#8804; 10% in just 24. Eight patients (8, 1%) presented FMD < 5%. First the population was divided in three groups: normotensive, mild and severe PE. There was no statistical difference between the groups in relation to age (16,3 x 15,9 x 16,1, p = 0,615), time between delivery and evaluation (6,8 x 6,2 x 6,7, p= 0, 497). IMC (22,8 x 26,1 x 24,3 Kg/mÂ, p = 0,090), diastolic blood pressure (70,3 x 73,6 x 73,4 mmHg, p = 0,181), or FMD (16,8 x 16,5 x 11,4%, p= 0,085). The systolic blood pressure was statistically different between the groups (108,8 x 117,2 x 110,8 mmHg, p = 0,005), systolic blood pressure in mild PE was higher than in normotensive (p = 0,003). There was no difference between mild and severe PE (p = 0,126) and between severe PE and normotensive (p = 0,686). When it was compared only two groups PE x normotensive, the Body Mass Index (BMI) was statistically different (p = 0,031). In the history of PE, the Body Mass Index (BMI) was higher (25,3 x 22,8 Kg /mÂ). Conclusion :There is no difference in the presence of endothelial disfunction observed by the flow mediated dilation of the brachial artery in adolescents with a history of normotensive pregnancy or PE. Patients with history of PE presented systolic blood pressure and BMI higher than women with prior gestational normotensive.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2008. / Härtill 4 uppsatser.

No description available.

Until recently, tests of vascular structure, function and compliance have been used predominantly for assessing the efficacy of treatment – for example, aggressive medical therapy may yield improvements in vascular structure and function with a concomitant decrease in cardiac events. However, the role of abnormal vessel function in the development of atherosclerosis, and the relationship of structural changes in peripheral vessels with coronary disease might suggest that these tests could be used as a screening test for patients with subclinical coronary disease. At present, there is insufficient evidence to support the theory that normal vascular structure and function can rule out significant coronary disease, and indeed, such an association may be confounded by the presence of risk factors that alter these test results in the absence of significant coronary artery disease (CAD). The overall hypothesis of the studies undertaken in this thesis was that utilizing contemporary technology during ultrasonic and tonometric assessment of arterial structure, function and compliance, it is possible to non-invasively characterise both early and advanced arterial dysfunction and identify patients both at risk and with cardiovascular disease. The aim of these studies was to determine whether these tests can be used to guide intervention when arterial dysfunction is diagnosed and whether they are robust enough as a follow-up tool. The thesis initially reviews arterial structure, function and compliance and their relationship to cardiovascular risk and in particular, CAD. This review provides a rationale for the studies undertaken here to resolve clinical and technical issues as well as provide an insight into the tests chosen to assess arterial function. The second chapter discusses the methodology used in these studies to assess arterial structure, function and compliance, diagnose coronary artery disease and determine cardiovascular risk. They range from stress echocardiography for the diagnosis of CAD to tests for arterial structure (carotid intima-media thickness [IMT]), endothelial function (brachial artery reactivity [BAR]), local arterial distensibility (distensibility coefficient [DC]) and systemic or total arterial compliance (TAC). In addition, several methods will be discussed for assessing local arterial elasticity with a novel imaging technique. The rationale for using tests for arterial structure, function and compliance in patients with CAD as well as cardiovascular risk is examined in chapter 3. Chapter 3 examines the use of TAC, IMT and BAR in patients undergoing dobutamine stress echocardiography (DSE) in a group of patients with and without disease. TAC was neither an independent predictor of CAD risk or patients having CAD in this study. BAR was a predictor of risk status but not of patients having CAD. Only IMT was an independent predictor of both patients at risk for CAD and those with CAD. In chapter 3 both pulse pressure and total arterial compliance were only univariate predictors of risk for CAD. Chapter 4 examines three different methods of estimating TAC, all based on the two-element Windkessel model in 320 patients with and without cardiovascular risk. The pulse-pressure method (PPM) is based on a combination of pressure, obtained using applanation tonometry of the radial artery, and an estimate of stroke volume obtained by Doppler echocardiography of the left ventricular outflow and by 2D echocardiographic dimension of the left ventricular outflow tract. The area method (AM) is an integral variation of the Windkessel equations and is based on the derived central pressure waveform. The stroke volume-pulse pressure method (SVPP) is a simple ratio of stoke volume and pulse pressure. We conclude that they correlate well and show similar differences between groups with and without risk. The PPM had the smallest difference from the mean and standard deviation in Bland Altman analysis and we therefore used the PPM for most future studies. Chapter 5 discusses the use of tissue Doppler for the derivation of central pressure and determination of distensibility coefficient, a marker of local arterial elasticity. Tissue Doppler can be used to evaluate the low frequency, high amplitude signals which come from tissue by changing filtering settings on an ultrasound machine. Using off-line software, the tissue velocities can be extracted and with a processing algorithm, vessel wall displacement values over time can be generated. These vessel wall displacement values which are in microns (µm) can then be used to calculated distensibility coefficient which is calculated as 2*((net displacement/minD)/PP). We studied a large group of patients with and without cardiovascular risk and conclude that DC using tissue Doppler correlates highly with DC by B-mode and M-mode imaging and is also very reproducible. In a subgroup, the vessel displacement values were “calibrated” using mean and diastolic pressure and with specialised software and a transfer function, central pressure wave forms were reconstructed. In this study we conclude that the central pressure obtained using tissue Doppler displacement of the carotid artery correlates highly with that obtained using applanation tonometry although there are technical challenges involved. With the known prognostic value of pulse pressure, chapter 6 explores whether there is added benefit to measuring total arterial compliance over pulse pressure alone. Once again patients with and without disease were studied and we conclude that brachial pulse pressure correlates well with TAC in men with normal cardiac function. However, in women and in patients at the low and high extremes of function, and in patients with preclinical and overt cardiovascular disease, there appears to be incremental value in measuring TAC. The role of cardiovascular risk factors in association with TAC is examined in chapter 7. Several studies have shown that TAC is lower in certain groups due to age, height, hypertension, hyperlipidaemia or other factors. We studied 720 patients with and without cardiovascular risk factors and did several multiple linear regression models based on anthropomorphic variables. Age was an independent correlate of TAC in most of the regression models and we conclude that TAC is associated with multiple risk factors, but age is a major determinant. The influence of age and other correlates may dwarf the contribution of individual risk factors and therefore their alteration with therapy. Chapter 8 examines the correlates of preclinical cardiovascular disease in both indigenous and non-indigenous Australians with and without diabetes mellitus (DM). DM is a major health problem in the Indigenous population in Australia and CVD occurs earlier in this group than in caucasians and is responsible for 1/3 of all deaths. We studied a large group of indigenous Australians with and without DM and matched them to a caucasian population. There were no differences in BAR between the groups probably due to large standard deviations in the measurements. In assessing DC, both DM groups had significantly lower DC than the non-DM groups. However, in the IMT analysis both of the indigenous groups had significantly higher IMT than their caucasian counterparts and even after IMT was corrected for age, Indigenous patients even at an early age had significantly higher IMT. We conclude that despite a high incidence of risk factors in indigenous Australians both with and without DM, ethnicity (and various other risk factors for which it is a marker) appears to be an independent predictor of preclinical cardiovascular disease. In chapter 3 we determined that TAC was not an independent correlate of patients either at risk of CAD or with CAD. Chapter 9 discusses the results of a study of patients presenting for stress echocardiography for either detection of CAD or risk stratification. Ischaemia was detected in 25% of cases and TAC was similar in those with and without ischaemia. In multiple linear regression models however, in addition to cardiovascular risk factors TAC was independently associated with both the presence of CAD and the extent of ischaemia at stress echocardiography. Several studies have used vascular function as an outcome measure in intervention trials, either lifestyle or pharmacologic. In chapter 10 we undertook a lifestyle and diet intervention study in a large group of healthy patients with type-II DM. The tests for IMT, BAR and TAC were used in addition to biochemical markers and fitness assessment. At follow-up the intervention group had significant changes in weight and BMI and significantly increased fitness but failed to show any changes in any of the vascular parameters. We conclude that while metabolic and fitness parameters respond to treatment in patients with type-II DM, the early changes seen in vascular structure, function and compliance may not change in the long term. Although TAC has been correlated with hypertension, LVH, myocardial ischaemia and heart failure there are few data existing regarding the relationship of TAC to outcome. In the final chapter of this thesis we sought whether TAC was predictive of outcome in a large, primary prevention group of patients with varying degrees of cardiovascular risk. We followed up 719 patients who were studied between 2001 and 2008 in Brisbane, Australia and examined TAC in relation to mortality and a composite endpoint of death or hospital admission. There were significant differences in groups having low and normal TAC for both death and the composite endpoint and in patients with intermediate and high Framingham 10-year risk TAC was an independent predictor of both death and the composite endpoint. We conclude that TAC correlates with outcome in patients with varying degrees of cardiovascular risk and also adds incremental benefit to Framingham risk alone in patients with intermediate risk.

[Formulae and special characters can only be approximated here. Please see the pdf version of the abstract for an accurate reproduction.] Two randomised controlled trials were conducted to explore the relationship between the consumption of alcoholic beverages and cardiovascular disease risk factors. Study 1 was primarily designed to test the hypothesis that the cardio-protective effect of light alcohol could be mediated, in part, via improvements in endothelial function. Study 1 was also designed to explore the effect of alcohol on both traditional risk factors for cardiovascular disease, such as changes in lipid profile, haemostatic factors and blood pressure, and novel risk factors such as homocysteine, markers of inflammation and oxidative stress. The experimental design of this study also allowed us to determine whether reducing alcohol intake in these moderate-to-heavy drinkers could improvement insulin sensitivity, a component of the metabolic syndrome. In this group of sixteen healthy middle-aged men with a history of moderate to heavy alcohol intake of seven standard drinks per day, reducing intake down to approximately one standard drink per day for four weeks had no beneficial effects on conduit vessel endothelial function as assessed by post-ischaemic brachial artery flow-mediated dilatation, nor were there any detectable changes in soluble E-selectin, endothelin-1 and von Willebrand Factor, which are considered biomarkers of endothelial activation. As this study did not investigate the effect of alcohol on endothelial function in resistance vessels, it cannot exclude the possibility that alcohol may affect endothelial cells resident in that vascular bed. This study does show and confirm, however, that the relationship between alcohol and risk factors for cardiovascular disease is an extremely complex one. On the one hand it demonstrated that alcohol was potentially harmful, increasing blood pressure, plasma F2-isoprostane (oxidative stress), and homocysteine. On the other hand it showed that increasing alcohol intake led to significant reductions in two (i.e. fibrinogen and IL-6) of five inflammatory markers, in addition to improving the HDL-cholesterol profile of these subjects. Although the effects of alcohol on blood pressure, fibrinogen and HDL-cholesterol are not in themselves new, they support our choice of study design and strengthen the argument in favour of accepting the more novel findings of this study, specifically, the lack of effect on endothelial function and insulin sensitivity, and the harmful effect of alcohol in increasing oxidative stress and homocysteine. Study 2 was primarily designed to test the hypothesis that the consumption of red wine may confer greater cardio-protection than beer via improvements in endothelial function. Simultaneously, the study was also designed to determine whether drinking red wine for 4-weeks would have different effects than beer on either traditional risk factors for cardiovascular disease (i.e. blood pressure and lipid profile) or the more novel risk factors, homocysteine and oxidative stress. Using a randomised controlled cross-over study design, Study 2 provides evidence that the regular daily consumption of 4 standard drinks of either beer or red wine does not alter endothelial function, as measured by post-ischaemic flow-mediated vasodilatation of the brachial artery in healthy middle-aged men, nor was there evidence of any beneficial effect of de-alcoholised red wine on brachial artery response. As compliance with drinking protocol was confirmed with increased serum γ-GT and HDL during red wine and beer periods, and increased 24-hr urinary excretion of 4OMGA during red wine and de-alcoholised red wine periods, we are confident that there was excellent compliance with the beverage treatments. Study 2 also provides the first evidence from a carefully controlled intervention study that both red wine and beer elevate blood pressure to a similar degree, with no detectable difference in the magnitude of either treatment. As with endothelial function, there was also no evidence of any beneficial effect of de-alcoholised red wine on blood pressure. In addition, although post hoc analysis found evidence that alcohol increased both plasma homocysteine and urinary excretion of F2-isoprostane and endothelin-1, there was no apparent protective effect conferred from either red wine or de-alcoholised red wine on these cardiovascular risk markers. The results from this study cannot disprove the hypothesis that red wine is more beneficial for cardiovascular health; however, they suggest that if red wine has properties beyond those of beer to confer protection, they are not via any interactions with the nitric oxide regulatory function of the endothelium in conduit vessels nor are they via moderation of the vasopressor, homocysteine-raising, and oxidative stress effects of alcohol. The interpretation of the findings from both intervention studies and their place in the context of our current understanding of the role that alcoholic beverages play in the development and/or prevention of cardiovascular disease are explored in this thesis.

No description available.

A disfunção endotelial atua tanto na aterogênese como na precipitação das síndromes coronárias agudas. A redução da biodisponibilidadedo óxido nítrico é expressão de endotélio disfuncional. O mecanismo desta redução não está elucidado. A presença de disfunção endotelialfoi correlacionada com fatores de risco (FR), nitrato sanguíneo e fatores genéticos (polimorfismo da óxido nítrico sintase endotelial, fibrinogênio e PAI-1) em um grupo de 128 pacientes com infarto do miocárdio (IAM) e idade = 40 anos, submetidos a ultra-som de artéria braquial. Os resultados foram comparados com um grupo jovens saudáveis. Verificou-se que pacientes jovens com IAM apresentavam disfunção endotelial em associação com FR, alterações bioquímicas e níveis aumentados de nitrato, porém sem alterações genéticas / The endothelial dysfunction plays an important roll in the atherogenesis and precipitation of acute coronary syndromes. The reduction of bioavailability of the nitric oxide is the expression of endothelial dysfunction. The exact mechanism of this reduction is not yet well explained. In order to evaluate the presence of endothelial dysfunction and correlation with risk factors (FR), nitrate blood levels and genetic factors (endothelial nitric oxide synthease polymorphism, fibrinogen and PAI-1) a 128 myocardial infarction patients group with age = 40 year was studied, and underwent a brachial artery ultra-sound. The results were compared with a group of young health individuals. The study found that the young patients with myocardial infarctions showed endothelial dysfunction with associated risks factors, biochemical changes and higher levels of nitrate, although without any significant genetic changes

A disfunção endotelial atua tanto na aterogênese como na precipitação das síndromes coronárias agudas. A redução da biodisponibilidadedo óxido nítrico é expressão de endotélio disfuncional. O mecanismo desta redução não está elucidado. A presença de disfunção endotelialfoi correlacionada com fatores de risco (FR), nitrato sanguíneo e fatores genéticos (polimorfismo da óxido nítrico sintase endotelial, fibrinogênio e PAI-1) em um grupo de 128 pacientes com infarto do miocárdio (IAM) e idade = 40 anos, submetidos a ultra-som de artéria braquial. Os resultados foram comparados com um grupo jovens saudáveis. Verificou-se que pacientes jovens com IAM apresentavam disfunção endotelial em associação com FR, alterações bioquímicas e níveis aumentados de nitrato, porém sem alterações genéticas / The endothelial dysfunction plays an important roll in the atherogenesis and precipitation of acute coronary syndromes. The reduction of bioavailability of the nitric oxide is the expression of endothelial dysfunction. The exact mechanism of this reduction is not yet well explained. In order to evaluate the presence of endothelial dysfunction and correlation with risk factors (FR), nitrate blood levels and genetic factors (endothelial nitric oxide synthease polymorphism, fibrinogen and PAI-1) a 128 myocardial infarction patients group with age = 40 year was studied, and underwent a brachial artery ultra-sound. The results were compared with a group of young health individuals. The study found that the young patients with myocardial infarctions showed endothelial dysfunction with associated risks factors, biochemical changes and higher levels of nitrate, although without any significant genetic changes