Master of Science / Department of Kinesiology / Carl Ade / Adjuvant systemic chemotherapy for the treatment of certain cancers, particularly breast and lymphoma, adversely impacts cardiovascular health. However, the extent to which it impairs endothelial function is not well understood. Therefore, the purpose of this study was to determine if microvascular and macrovascular endothelial-dependent vasoreactivity is attenuated in breast cancer and lymphoma patients currently being treated with chemotherapy compared to healthy counterparts. With laser Doppler imaging, cutaneous microvascular function was evaluated via changes in cutaneous vascular conductance (CVC) in response to iontophoresis of acetylcholine (ACh). Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the brachial artery via ultrasonography. CVC responses to iontophoresis of ACh in the cutaneous microcirculation was significantly lower in cancer patients than in control subjects (cancer (n=7): 959.9 ± 187.3%; control (n=7): 1556.8 ± 222.2%; P = 0.03). Furthermore, FMD was significantly lower in cancer patients than in control subjects (cancer: 2.2 ± 0.6%; control: 6.6 ± 1.4%; P = 0.006). These data provide evidence of microvascular and macrovascular dysfunction in breast cancer and lymphoma patients currently undergoing adjuvant chemotherapy, which may contribute to the increased long-term risk of cardiovascular disease morbidity and mortality in those treated for cancer.

This research assessed the role of Hatha yoga in the modulation of vascular health. In study one, Hatha yoga practitioners were compared to sedentary controls to whom they were matched for age and body mass index. Practitioners of Hatha yoga were no different from sedentary individuals in terms of arterial stiffness or vascular endothelial function. Yoga practitioners possessed lower HbA1c (P < 0.05) levels and lower pulse pressure (P < 0.05) than their sedentary counterparts. Practitioners of Hatha yoga had lower body fat percentages, but this observed trend did not reach statistical significance (P = 0.052). In study two, a 12-week Hatha yoga intervention resulted in reductions in HbA1c levels (P < 0.05) and total cholesterol (P < 0.05) in previously sedentary adults. No changes were observed in carotid artery compliance or brachial artery flow-mediated dilation as a result of the intervention. In study three, obese and lean, apparently healthy adults completed an 8-week Bikram yoga intervention. Reductions in total- and LDL-cholesterol were observed in the lean subjects (P < 0.05), with no changes in lipid profiles in the obese group. The homeostasis model assessment of insulin resistance (HOMA-IR) decreased in the lean subjects, but this trend did not attain statistical significance (P = 0.06). Although an observed trend was shown at 60 minutes during the oral glucose tolerance test (P = 0.07), glucose tolerance remained unchanged in the obese subjects. Brachial artery flow-mediated improved by approximately 2% in the obese subjects, but this observed change did reach statistical significance (P = 0.10). Flexibility increased in both groups as a result of the Bikram yoga intervention. Therefore Hatha yoga improved lipid profiles and glycemic control in sedentary adults, but no effects on vascular health were demonstrated. / text

An increase in blood flow associated shear stress results in an endothelial dependent increase in vessel diameter (flow mediated vasodilation (FMD)). Assessment of FMD can provide an index of endothelial function. The stimulus profiles that have been used to investigate FMD in human conduit arteries fall into two categories: reactive hyperemia and sustained stimuli. Stimulus-response specificity proposes that the stimulus characteristics (e.g. magnitude, pattern) are essential determinants of the response characteristics (e.g. magnitude, mechanisms). Purpose: To investigate four specific aspects of FMD stimulus-response specificity: 1) The relative importance of the peak vs. the duration of reactive hyperemia in determining FMD response magnitude. 2) The nitric oxide (NO) dependence of FMD following different durations of reactive hyperemia. 3) The impact of sustained shear stress stimulus magnitude on FMD response dynamics and magnitude. 4) FMD dynamics and magnitude in response to steady vs. oscillatory shear stress evoked passively or via exercise. Methods: Doppler ultrasound was applied to the brachial or radial artery to measure blood flow velocity. Vessel diameter was measured with automated edge detection software. Shear rate, an estimate of shear stress was calculated as the blood flow velocity/vessel diameter. Results: 1) The duration of reactive hyperemia is an important determinant of peak FMD magnitude while the independent contribution of the peak shear to FMD is minimal. 2) NO is not obligatory to FMD following either a five or a ten minute duration occlusion. 3) FMD in response to a sustained stimulus is characterized by a generally bi-phasic response with a fast first phase followed by a slower final phase. 4) The endothelium transduces the mean shear stress when it is exposed passive or handgrip exercise induced oscillations in shear stress. Conclusions: The results indicate that future reactive hyperemia studies must account for the stimulus duration when interpreting FMD results. Further, they demonstrate that the role of NO in FMD is unclear and caution against oversimplified conceptual models of FMD mechanisms. FMD in response to sustained stimuli provides information distinct from reactive hyperemia investigations and exercise may provide a valuable stimulus creation technique. / Thesis (Ph.D, Kinesiology & Health Studies) -- Queen's University, 2007-08-16 18:11:18.941

Flow-mediated dilation (FMD) can be used to assess the risk of atherosclerosis; however, an inverse relationship between vessel size and FMD has been identified using reactive hyperemia (RH) to create a shear stress (SS) stimulus in human conduit arteries. RH creates a transient and uncontrolled SS stimulus that is inversely related to baseline arterial diameter. It is therefore unclear whether differences in FMD between groups with non-uniform artery sizes are indicative of differences in vascular health or due to the creation of a greater SS stimulus in smaller vessels. Unlike RH, exercise can effectively create sustained and controlled increases in conduit artery SS. The purpose of this study was to compare the FMD responses of two differently sized upper limb arteries (brachial (BA) and radial artery (RA)) to matched graded levels of SS. Using exercise, three distinct sustained shear rate stimuli were created ((SR)=blood flow velocity/vessel diameter; estimate of SS) in the RA and BA. Artery diameter and mean blood flow velocity were assessed with echo and Doppler ultrasound respectively in 15 healthy male subjects (19-25yrs). Data are means ±SE. Subjects performed 6-min each of adductor pollicis and handgrip exercise to increase SR in the RA and BA respectively. Exercise intensity was modulated to achieve uniformity of SR between the RA and BA at three SR targets (40s-1, 60s-1, 80s-1). Three distinct SR levels were successfully created (steady state exercise: 39.8±0.6s-1, 57.3±0.7s-1, 72.4±1.2s-1; p<0.001 between SR levels). The %FMD at the end of exercise was greater in the RA vs. BA (SR40 RA: 5.4±0.8%, BA: 1.0±0.2%; SR60 RA: 9.8±1.0%, BA: 2.5±0.5%; SR80 RA: 15.7±1.5%, BA: 5.4±0.7%; p<0.001). The mean slope of the within-subject FMD-SR dose-response regression lines was significantly greater in the RA (RA: 0.33±0.04, BA: 0.13±0.02; p<0.001) and a strong within-subjects relationship between FMD and SR was observed in both arteries (RA r2: 0.92±0.02; BA r2: 0.90±0.03). These findings suggest that the response to SS is not uniform across differently sized vessels, which is in agreement with previous RH studies. Future research is required to investigate the potential mechanisms that mediate the functional differences observed between differently sized vessels. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2010-09-22 11:01:26.028

Shear stress is the frictional force exerted on the vascular wall by blood flowing through an artery. It is a major regulator of endothelial cell function, which is essential for vasoprotection and local regulation of vascular tone. Using handgrip exercise (HGEX) to increase shear stress is an increasingly popular method for assessing brachial artery (BA) endothelial cell function via flow-mediated dilation (FMD, dilation which increases with improved endothelial function). However, different exercise duty-cycles (ratio of handgrip relaxation to contraction in seconds) produce different patterns of BA shear stress with different anterograde and retrograde flow magnitudes. PURPOSE: To determine the impact of HGEX duty-cycle on BA %FMD while maintaining a constant mean shear stress. METHODS: N=16 healthy males. BA diameter (BAD) and blood velocity (BV) were assessed via echo and Doppler ultrasound. Shear stress was estimated as shear rate (SR=BV/BAD) and reported as mean SR during the last minute of baseline (target 10 s 1) and each minute of HGEX (75 s-1). Subjects performed 3 six minute HGEX trials on each of 2 separate days (like trials averaged). Each trial was one of 3 randomly ordered HGEX duty-cycles (1:1, 3:1, 5:1). %FMD was calculated as the increase in BAD from baseline to the end of HGEX and at each minute (subset N=10) during HGEX. RESULTS: Data are means ± SD. As intended, mean SR was similar between duty-cycles (main effect, p=0.835), despite significant differences in anterograde and retrograde SR (P<0.001). There was no impact of duty cycle on blood pressure (p=0.188) or heart rate (p=0.131) responses. End exercise %FMD (4.0 ± 1.3%, 4.1 ± 2.2%, 4.2 ± 1.4%, p=0.860) and minute by minute %FMD (main effect p=0.939; interaction, p=0.545) were also not different between duty-cycles. CONCLUSION: Distinct HGEX duty-cycles create markedly different shear stress patterns in the BA. However, duty cycle had no impact on %FMD magnitude suggesting that mean shear stress is the most important stimulus for FMD in the BA. Using a 5:1 duty cycle may yield the best vessel image and diameter measurement quality due to the long period of arm stability between contractions. / Thesis (Master, Kinesiology & Health Studies) -- Queen's University, 2012-09-06 14:31:50.467

Pre-eclampsia is a pregnancy-related disorder characterised by high blood pressure, proteinuria and oedema. The aetiology of the disease is unclear but evidence suggests that endothelial dysfunction is central to the development of the maternal syndrome. Kinins are endogenous peptides released by the endothelium that contribute to the regulation of cardiovascular homeostasis by inducing vasodilation, fibrinolysis and angiogenesis. Given that pre-eclampsia is associated with reduced endotheliumdependent relaxation, coagulation abnormalities and an angiogenic imbalance, it was hypothesised that alterations of kinin receptor-mediated responses may be involved in the pathogenesis of the condition. To investigate whether changes in kinin receptor activity are involved in the impairment of endothelium-dependent relaxation observed in pre-eclampsia, the effects of specific B2 and B1 receptor agonists and antagonists on myometrial vascular tone were tested on arteries from healthy pregnancy and pre-eclampsia. The results demonstrated that in addition to classical bradykinin B2 receptor-mediated relaxation, a subset of healthy patients exhibited nitric oxide-dependent relaxation to the B1 receptor agonist Lys-des- Arg9-BK (LDABK) which could not be inhibited by either B1 or B2 receptor antagonists. Also, vessels that exhibited this novel response to LDABK were more sensitive to bradykinin. Furthermore, this study revealed that patients with pre-eclampsia had an attenuated response to both bradykinin and LDABK. Immunolocalisation and mRNA expression of the kinin receptors in the myometrium revealed no differences between healthy pregnancy and pre-eclampsia suggesting that disturbances of kinin receptor signalling rather than changes in receptor distribution or expression levels may be involved in the reduction of kinin-mediated responses in these patients. The role of kinins in mediating placental angiogenesis in healthy pregnancy and preeclampsia was determined using the endothelial tube formation assay in primary human umbilical vein endothelial cells (HUVECs) isolated from healthy women and women with pre-eclampsia. B2 and B1 receptor agonists induced endothelial tube formation via a VEGF-dependent, nitric oxide-independent mechanism in healthy HUVECs cultured in normoxic conditions. HUVECs isolated from women with pre-eclampsia cultured under normoxia and HUVECs from healthy pregnancies cultured under hypoxia exhibited greater levels of angiogenic branching compared with healthy normoxic cells, but were unresponsive to bradykinin and LDABK. Incubation of these cells with a VEGF receptor inhibitor reduced the elevated levels of tube formation indicating that this effect may be due to hypoxic upregulation of VEGF or an intrinsic difference in their angiogenic capacity. Further studies are required to determine the cause for the differences in angiogenic potential between healthy and pre-eclamptic cells and the impact this could have on placental vascular development and the pathogenesis of preeclampsia.

abstract: In adults, consuming a high-fat meal can induce endothelial dysfunction while exercise may mitigate postprandial endothelial dysfunction. Whether exercise is protective against postprandial endothelial dysfunction in obese youth is unknown. The purpose of this study was to determine if high-intensity interval exercise (HIIE) performed the evening prior to a high-fat meal protects against postprandial endothelial dysfunction in obese adolescent males. Fourteen obese adolescent males (BMI%tile=98.5±0.6; 14.3±1.0yrs) completed the study. After initial screening, participants arrived, fasted at 9:00 in the morning where brachial artery flow-mediated dilation (FMD) was measured using duplex ultrasound after 20min of supine rest (7.0±3.0%) and completed a maximal exercise test on a cycle ergometer (VO2peak=2.6±0.5 L/min). Participants were randomized and completed 2 conditions: a morning high-fat meal challenge with evening prior HIIE (EX+M) or a morning high-fat meal challenge without prior exercise (MO). The EX+M condition included a single HIIE session on a cycle ergometer (8 X 2min at &#8805;90%HRmax, with 2min active recovery between bouts, 42min total) which was performed at 17:00 the evening prior to the meal challenge. In both conditions, a mixed-meal was tailored to participants body weight consisting of 0.7g of fat/kg of body weight consumed (889±95kcal; 65% Fat, 30% CHO). FMD was measured at fasting (>10hrs) and subsequently measured at 2hr and 4hr after high-fat meal consumption. Exercise did not improve fasting FMD (7.5±3.0 vs. 7.4±2.8%, P=0.927; EX+M and MO, respectively). Despite consuming a high-fat meal, FMD was not reduced at 2hr (8.4±3.4 vs. 7.6±3.9%; EX+M and MO, respectively) or 4hr (8.8±3.9 vs. 8.6±4.0%; EX+M and MO, respectively) in either condition and no differences were observed between condition (p(condition*time)=0.928). These observations remained after adjusting for baseline artery diameter and shear rate. We observed that HIIE, the evening prior, had no effect on fasting or postprandial endothelial function when compared with a meal only condition. Future research should examine whether exercise training may be able to improve postprandial endothelial function rather than a single acute bout in obese youth. / Dissertation/Thesis / Ph.D. Exercise and Wellness 2014

No description available.

The endothelium is an integral mediator of vascular homeostasis and a dysfunctional endothelium is now recognized as an early marker of atherosclerosis. Importantly, the non-invasive measurement of endothelial function by flow-mediated dilation (FMD) predicts future cardiovascular events. However, the appropriate method of its assessment and the mechanisms that govern FMD are still poorly understood. We investigated alternative parameters and methods of FMD measurement in healthy volunteers and cardiovascular disease patients. We found time to peak FMD to be highly variable both within and between individuals. Accordingly, continuous arterial diameter measurement post-cuff release was more sensitive in discriminating between health and disease compared to the measurement of diameter at 60’’ post-cuff release. Reperfusion to an ischemic tissue can paradoxically contribute to endothelial dysfunction development and further tissue damage, in a phenomenon known as ischemia and reperfusion (IR) injury. Previous exposure to sublethal ischemia (ischemic preconditioning (IPC)) can reduce sensitivity to IR injury and pharmacologic agents have since been shown to mimic this response. Using the FMD technique, we investigated various preconditioning strategies to prevent IR-induced endothelial dysfunction in the forearm vasculature of healthy volunteers. The sodium-hydrogen exchanger inhibitor amiloride and the angiotensin-converting enzyme inhibitor captopril were found not to provide endothelial protection from IR. In contrast, potent protection from IR-induced endothelial dysfunction was observed during the high-estrogen, late follicular phase of the menstrual cycle in pre-menopausal women. Finally, daily episodes of IPC were found to provide endothelial protection equipotent to an acute episode of IPC. The findings from the FMD methodological study highlight the importance of continuous arterial diameter measurement post-cuff deflation, and provide mechanistic insight that may contribute to measurement standardization and normalization. The results of the preconditioning studies improve our understanding of potential approaches to mitigate the detrimental effects of IR on the endothelium in humans.

The endothelium is an integral mediator of vascular homeostasis and a dysfunctional endothelium is now recognized as an early marker of atherosclerosis. Importantly, the non-invasive measurement of endothelial function by flow-mediated dilation (FMD) predicts future cardiovascular events. However, the appropriate method of its assessment and the mechanisms that govern FMD are still poorly understood. We investigated alternative parameters and methods of FMD measurement in healthy volunteers and cardiovascular disease patients. We found time to peak FMD to be highly variable both within and between individuals. Accordingly, continuous arterial diameter measurement post-cuff release was more sensitive in discriminating between health and disease compared to the measurement of diameter at 60’’ post-cuff release. Reperfusion to an ischemic tissue can paradoxically contribute to endothelial dysfunction development and further tissue damage, in a phenomenon known as ischemia and reperfusion (IR) injury. Previous exposure to sublethal ischemia (ischemic preconditioning (IPC)) can reduce sensitivity to IR injury and pharmacologic agents have since been shown to mimic this response. Using the FMD technique, we investigated various preconditioning strategies to prevent IR-induced endothelial dysfunction in the forearm vasculature of healthy volunteers. The sodium-hydrogen exchanger inhibitor amiloride and the angiotensin-converting enzyme inhibitor captopril were found not to provide endothelial protection from IR. In contrast, potent protection from IR-induced endothelial dysfunction was observed during the high-estrogen, late follicular phase of the menstrual cycle in pre-menopausal women. Finally, daily episodes of IPC were found to provide endothelial protection equipotent to an acute episode of IPC. The findings from the FMD methodological study highlight the importance of continuous arterial diameter measurement post-cuff deflation, and provide mechanistic insight that may contribute to measurement standardization and normalization. The results of the preconditioning studies improve our understanding of potential approaches to mitigate the detrimental effects of IR on the endothelium in humans.