Sustained nitroglycerin (GTN) therapy impairs endothelial function in healthy volunteers and patients with cardiovascular disease, caused by an increase in vascular oxidative stress. This study aims to estimate the effect of rosiglitazone on vascular endothelial function in healthy volunteers continuously dosed to transdermal GTN (0.6mg/hr) for 7 days. To assess endothelial function, forearm blood flow was measured by venous occlusion strain-gauge plethysmography in response to intra-brachial infusions of acetylcholine. GTN-treated subjects experienced significant attenuation of endothelium-dependent responses to acetylcholine (p<0.05; compared to placebo), but was reversed with vitamin C (p=ns; compared to placebo). Endothelium-dependent responses to acetylcholine were blunted in groups randomized to rosiglitazone alone (p<0.05; compared to placebo) and rosiglitazone + GTN (p<0.05 compared to placebo). Interestingly, this effect was not modified by vitamin C. In conclusion, rosiglitazone impairs endothelial function and concurrent therapy with rosiglitazone does not attenuate the adverse effects of transdermal GTN on the vasculature.

Sustained nitroglycerin (GTN) therapy impairs endothelial function in healthy volunteers and patients with cardiovascular disease, caused by an increase in vascular oxidative stress. This study aims to estimate the effect of rosiglitazone on vascular endothelial function in healthy volunteers continuously dosed to transdermal GTN (0.6mg/hr) for 7 days. To assess endothelial function, forearm blood flow was measured by venous occlusion strain-gauge plethysmography in response to intra-brachial infusions of acetylcholine. GTN-treated subjects experienced significant attenuation of endothelium-dependent responses to acetylcholine (p<0.05; compared to placebo), but was reversed with vitamin C (p=ns; compared to placebo). Endothelium-dependent responses to acetylcholine were blunted in groups randomized to rosiglitazone alone (p<0.05; compared to placebo) and rosiglitazone + GTN (p<0.05 compared to placebo). Interestingly, this effect was not modified by vitamin C. In conclusion, rosiglitazone impairs endothelial function and concurrent therapy with rosiglitazone does not attenuate the adverse effects of transdermal GTN on the vasculature.

Charles University in Prague Faculty of Pharmacy in HradecKrlov Department of Biological and Medical Sciences Evaluation of endoglin and P-selectin expression and co-expression in aortas of apoE-deficient mice Diploma thesis MonikaBrlicov Supervisor: Mgr.JanaRathousk Background: We observed the expression and the reciprocal co-expression of endoglin (receptor III for TGF- cytokine) and P-selectin (adhesion molecule and marker of endothelial dysfunction) in ascending aortas of apoE-deficient mice which were fed by standard diet for rodents and Western type diet (high-cholesterol diet) for achieving of different phases of the atherosclerotic process. The changes of total cholesterol levels in mice after administration of both types of diets were also evaluated. Methods: The modified strain C57BL/6J of mice with a deficiency of apolipoprotein E, which is prone to aterogenesis was used for this diploma thesis. Mice were divided into three groups. The first group was fed by standard diet (so-called "chow" diet) for a period of two months and the second two groups were fed by Western type diet for a period of two and four months. The levels of total cholesterol in the blood were biochemically determinated and then we statistically evaluated this levels in all groups. Immunohistochemical...

Obesity is a serious health problem worldwide. Consumption of fat rich food is a common cause of obesity. Some of the food components (i.e. saturated free fatty acids (SFAs)) have been identified as inflammatory inducers (Egger G at al., 2010). After a meal, absorbed free fatty acids (FFAs) will be stored in the liver and adipose tissue. On the luminal surfaces of endothelium in adipose tissue microcirculation, lipoprotein lipase hydrolyses absorbed triglycerides into FFAs. Then, in order to be available for adipocyte storage, FFAs have to cross the capillary endothelium barrier, which connected by tight junctions (Stremmel W et al., 2001). Increased leukocyte infiltration is a featured sign of adipose tissue inflammation found in obesity. Endothelial adhesion molecules up-regulation contributes to leukocyte infiltration during inflammation. Some clinical data suggested an increase of leukocyte-endothelium interaction in healthy volunteers after ingestion of high-fat meals (Shimabukuro M et al., 2007). Other lab results also showed that neutrophil infiltration occurred at a very early stage with high-fat feeding in mice (Talukdar S et al., 2012). However, the detailed mechanism of the above phenomena is still unknown. This thesis provides exciting preliminary data which will guide the further study in this area. First of all, we successfully established a stable protocol that CD31 antibody conjugated microbeads were used to isolate primary microvascular endothelial cells from fresh mice lung tissue. After second sorting, CD31+ cells reach 83.3% by FACS analysis. Previous literatures showed that FFAs activate recruitment of inflammatory cells through up-regulation of endothelial adhesion molecules via reduced eNOS derived eNO production (Rizzo NO et al., 2010; Davenpeck KL et al., 1994; Ahluwalia A et al., 2004). In this thesis, it was found that SFAs palmitate exposure dose dependently reduced endothelial AMPK thr172 and eNOS ser1177 phosphorylation by western blot. Moreover, our study demonstrated that endothelial calpain, a calcium dependent protease associated with endothelial dysfunction, was activated by palmitate, specifically its μ-calpain isoform. Altogether, these data suggested that a new role of calpain as a key mediator of palmitate induced endothelial dysfunction and indicated both AMPK and eNOS1177 phosphorylation contribute to this pathological process. Further investigations are still needed to explore connections among those molecules. This thesis may also lead to a novel way of clinical treatment for the obese related vascular diseases. / Physiology

Objective:  Obesity has become the leading cause of mortality worldwide; however, the fundamental pathophysiology underlying this association remains unclear. The discovery of adipokines, i.e., cytokines produced by adipose cells (adipocytes), revealed that adipose tissue is a highly endocrine organ, thus opening new lines of investigation. The prototypical adipokine leptin increases in obesity, and leptin receptors are found in vascular cells. However, results are contradictory regarding the role of leptin in vascular and endothelial functions. Leptin has been shown to elicit vasodilatation, but has also been linked with atherosclerotic and thrombotic disease. The main aim of the present thesis was to study the association of circulating levels of leptin with markers of endothelial function, and to analyze the effects of leptin infusion in vivo  on vasomotor function and endogenous fibrinolysis. Material:  Four associative studies and two interventional studies were conducted. The former included DISARM (studies 1 and 2), the PIVUS study (study 3), and the Scottish post-infarction study (study 4). The DISARM studies and study 4, respectively, recruited 20 men and 83 men and women with stable ischemic heart disease. Study 3 included a random sample of 1016 subjects (54% women, 70 years old) living in the community of Uppsala, Sweden. For the interventional studies (studies 5 and 6), 10 healthy men were recruited for each study. Methods:  In all studies, endothelial function was estimated based on forearm blood flow (FBF) as measured by strain-gauge venous occlusion plethysmography, at rest or during infusion of vasodilators. In study 3, additional measurement techniques were used, such as brachial ultrasound flow-mediated dilation (FMD) and the aortic augmentation index (AoAIx) by tonometry in the radial artery. Fibrinolytic status was estimated based on basal and stimulated levels of tissue plasminogen activator antigen (t-PA), and by assessment of the endothelial release of t-PA (net t-PA release). Plasma leptin levels were measured by radioimmunoassay. In the associative studies, endothelial function and fibrinolytic status were related to circulating plasma leptin levels. In the experimental studies, exogenous leptin was administered in the brachial artery and endothelial function was assessed by strain-gauge plethysmography Results:  In elderly men and women, leptin was independently associated with decreased endothelial-dependent and -independent vasodilatation, reflecting disturbed endothelial function in resistance vessels. This association was attenuated after adjustment for BMI, and when analyzed among subjects with high plasma leptin levels. FMD (a measure of endothelial function in conduit vessels) was not associated with leptin. Exogenous leptin infusion did not alter vasomotor tone, but the endothelium-dependent and -independent vasodilatation was impaired during concomitant infusion of leptin and vasodilators. Infused leptin in the forearm did not affect blood pressure or pulse rate. Chronic hyperleptinemia, but not acutely induced hyperleptinemia, was associated with release of endothelial tissue plasminogen activator (net t-PA). Conclusions:  In humans, leptin was associated with impaired vasodilatation. However, this relationship was blunted after adjustment for BMI, suggesting that leptin could be the mediator between obesity and impaired vascular function. Furthermore, the observed lack of association in hyperleptinemic subjects may reflect a state of leptin resistance. The experimental result showing attenuated vascular reactivity following leptin infusion is in accordance with the results of the associative studies. The augmented net t-PA release in patients with chronic hyperleptinemia may indicate a state of “vascular activation,” which was not observed in healthy endothelium during a short period of leptin infusion. This thesis addresses several controversial issues regarding the action of leptin on vascular tissue in humans. The final results indicate that the in vivo action of leptin on vascularity is complex and mediated by several mechanisms. Our findings suggest that leptin is an important mediator between obesity and endothelial dysfunction, and should stimulate further investigation of this matter. / Manuel Cruz Gonzalez

Background: Endothelial dysfunction (ED) is one of the earliest subclinical indicators of impaired cardiovascular health and several non-invasive tools have been developed to evaluate vascular function, including strain gauge plethysmography (SGP), brachial artery flow-mediated dilation (FMD) via ultrasound, and peripheral artery tonometry (PAT). While these tools have extensively been studied during a resting condition, the responses following acute exercise are not as well characterized. Purpose: The purpose of this study was to compare the pre- and post-exercise vascular function values obtained with SGP, FMD, and PAT. Relationships among the primary outcome variables obtained with each assessment tool were also evaluated. Methods: Vascular function was assessed in 17 sedentary, apparently healthy male subjects (24±4 yrs; 24.5±3.2 kg/m2) at rest and following an acute submaximal exercise bout with SGP, FMD, and PAT. Results: During rest, post-occlusion reactive hyperemia resulted in significant (p<0.05) increases in forearm blood flow (FBF; 2.13±1.03 vs 6.35 ± 2.90 mL/min/100 mL tissue) and area under the curve (AUC; 226.77 ± 111.20 vs 588.22 ±283.33 mL/min/100 mL) as determined by SGP. Brachial artery diameter (BAD) as assessed with FMD was increased by 5.3% (p<0.05). Resting reactive hyperemia index (RHI) as assessed by PAT was observed to be 1.73±0.34. Significant exercise-induced increases (p<0.05) were observed in baseline and post-occlusion FBF and baseline AUC values utilizing SGP. Additionally, FMD baseline blood velocity was significantly increased (91.8±11.1 vs 108.0±17.1 cm/sec, p<0.05) and the PAT augmentation index (AI) was significantly more negative (-8.8 ±9.4 vs -18.9±8.4%, p<0.05) after exercise. There were no significant correlations observed among the primary outcome measures obtained from each assessment technique. There was, however, a moderate correlation between pre-exercise vascular reactivity as assessed by SGP and change in blood velocity as assessed by FMD (r= 0.566, p= 0.035). Conclusions: The addition of an exercise stress to vascular function assessment may offer greater insight into the health of the vasculature. This initial study was undertaken to further evaluate the pre- to post-exercise responses obtained using three commonly employed vascular function assessment techniques in healthy individuals. Additional research as to the value of the addition of an exercise stress to vascular function assessment in individuals with traditional cardiovascular disease risk factors or known cardiovascular disease is warranted.

Acute myocardial infarction is the commonest cause of death in firefighters, accounting for 45% of all deaths on duty. Compared with an average life expectancy of 77 years in the general population, the average age of cardiovascular death in firefighters is 50 years suggesting that occupational hazards are responsible for premature disease. The risk of acute myocardial infarction is increased 12- to 136-fold during rescue and firefighting duties, and is likely to reflect a combination of factors including strenuous physical exertion, mental stress, heat and pollutant exposure. Previous studies have established that the duties of a firefighter, in particular fire suppression, put inordinate strain on the cardiovascular system yet the exact mechanisms underlying the increased risk of myocardial infarction remain poorly defined. In a series of studies, I assessed the effect of occupation-specific risk factors on cardiovascular health in a combination of controlled and real-life studies in order to better define these mechanisms, hypothesising that exposure to high temperatures, strenuous physical exertion, psychological stress and air pollution either alone or in combination caused vascular dysfunction and thrombosis. In order to assess if firefighters had a greater cumulative risk of cardiovascular disease due to their occupation at baseline, I assessed the cardiovascular function of group of healthy, off-duty firefighters and compared this to a group of healthy age- and sex-matched off-duty police officers; an occupational group with similar responsibilities but a much lower risk of on-duty cardiovascular events. I was able to demonstrate that traditional cardiovascular risk factors, vascular endothelial function and thrombogenicity were similar in the two groups concluding that the excess of cardiovascular events and deaths in on-duty firefighters are due to the acute and transient effects of strenuous physical exertion, psychological stress, heat and exposure to air pollutants. Having established that off-duty firefighters had no apparent increased risk of cardiovascular events, I then went on to clarify the effects of combustion derived air pollution in the form of wood smoke on the cardiovascular system. The suppression of wildland or forest fires is globally the single most important duty of the fire service. Previous work within our institution has demonstrated the adverse effects of combustion derived air pollution, in the form of diesel exhaust, on the cardiovascular system. In a similar fashion, I assessed the effect of a wood smoke inhalation in a group of healthy off-duty firefighters by performing controlled exposures to wood smoke utilising a unique and well characterised facility. Interestingly, unlike diesel-exhaust, the exposure to wood smoke had no adverse effect on vascular endothelial function or thrombogenicity in this group concluding that cardiovascular events during wildland fire suppression may not be directly related to wood smoke inhalation but instead precipitated by other mechanisms such as strenuous physical exertion or dehydration. Latterly, I proceeded to evaluate the effects of strenuous physical exertion and heat exposure by comprehensively assessing a number of cardiovascular end points following controlled exposure to a fire simulation activity in a group of healthy, off-duty firefighters. I was able to demonstrate that exposure to extreme heat and physical exertion impaired vasomotor function and increased thrombus formation. Moreover, I demonstrated cardiac troponin concentrations increased suggesting that fire suppression activity may cause myocardial injury. These important findings suggest pathogenic mechanisms to explain the association between fire suppression activity and acute myocardial infarction. In the final phase of work, I endeavoured to assess the effects of real-life firefighter activities on the cardiovascular system. In an ambitious study, I attempted to undertake a comprehensive assessment of cardiovascular function in healthy firefighters following three periods of duty: fire suppression, alarm response and non-emergency activity. I was unable to complete enough studies to adequately power an analysis and draw any firm conclusions about the effect of these duties on cardiovascular health. Further work is required in a real-world setting to more clearly define the occupational risk factors underlying the increased risk of cardiovascular events associated with specific firefighter duties Understanding the biological mechanisms and environmental factors that predispose firefighters to cardiovascular events is essential if we are to develop effective methods for the prevention of acute myocardial infarction on-duty. This body of work has greatly improved the understanding of the mechanisms underlying the increased risk of cardiovascular events on duty and calls for the immediate evaluation of current practice in order to minimise risk to firefighters in the future. Examples of where improvements should be made include strategies to ensure adequate hydration and cooling following exposure to heat and physical exertion, change to working patterns to limit the duration of extreme exposures, and education, training and screening programmes to reduce the impact of traditional and occupational cardiovascular risk factors.

No description available.

Thesis (M.S.M.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Endothelial dysfunction is a key modulator of the development of cardiovascular disease. Prior studies in selected samples have suggested that the association of age and vascular function may vary between men and women. To investigate the sex-specific patterns of this association, we utilized non-invasive vascular function testing in the Framingham Heart Study. We measured brachial artery flow-mediated vasodilation, a measure of conduit artery function, and hyperemic flow velocity, a measure of small vessel function, in 6790 participants (49±14 years, 53% women) in the Offspring and Third Generation cohorts. We found evidence of effect modification by sex on the relation of age and flow-mediated dilation (P=0.0001) and the relation of age and hyperemic flow velocity (P<0.0001). Using restricted cubic spine analysis, we observed that the relation of age and flow-mediated dilation was linear in men but nonlinear in women. To further characterize the patterns of vascular aging, we divided the cohort by the median age of 47 years old. In multivariable regression models adjusting for cardiovascular risk factors, there was a greater decline in flow-mediated dilation with increasing age in older as compared to younger women (β=-0.113 95% CI -0.129,-0.098 vs β=-0.046 95%CI -0.064,-0.029, p<0.0001 for difference). Whereas in men the association of age and flow-mediated dilation was similar in old and young men (β=-0.038 95%CI-0.054,-0.021 vs β=-0.038 95%CI-0.061,-0.023, p=0.199 for difference). For reactive hyperemia, we found a greater decline in older participants for both men and women (for young men, β=-0.087 95%CI-0.200,0.027 compared to older men β=-0.776 95%CI-0.883,-0.669 p<0.0001 for difference, for young women β=0.141 95%CI 0.033,0.249 compared to older women, β=-1.054 95%CI-1.156,-0.952, p<0.0001 for difference). In a large, community-based cohort the patterns of association between age and conduit vessel vasodilation differed in men and women with an accelerated decline in women after age 47. Small vessel function declined more rapidly in older participants in both men and women, however the decline was more pronounced in women. Our findings suggest that the process of vascular aging differs based on sex and between conduit vessels and the microcirculation. Further studies are needed to evaluate the longitudinal patterns of vascular aging in men and women. / 2031-01-01

Made available in DSpace on 2014-06-11T19:32:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-07-30Bitstream added on 2014-06-13T19:43:54Z : No. of bitstreams: 1 macedo_mls_dr_botfm_prot.pdf: 3586847 bytes, checksum: 528671d32509cb0d8b738be7fcab29b3 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / 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. / 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.