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<p>The merits of low-volume high-intensity interval exercise (HIT) have been established in healthy populations; however, no studies have examined this exercise prescription in patients with coronary artery disease (CAD). The present thesis examined the acute and chronic effects of HIT in patients with CAD.</p> <p>The first study demonstrated transient improvements in brachial artery endothelial-dependent function, assessed using flow-mediated dilation (FMD), 60-minutes following a single bout of either HIT or moderate-intensity endurance exercise (END) in habitually active patients. The second study demonstrated no effects of training status on the acute endothelial responses to exercise; following 12-weeks of either HIT or END training. However, there was a significant reduction in endothelial-independent function immediately post-exercise, at both pre- and post-training, which requires further examination. The third study demonstrated comparable increases in fitness and resting FMD following 12-weeks of END and HIT, lending support to the notion that favorable adaptations are obtainable with a smaller volume of exercise. Lastly, the fourth study demonstrated no change in heart rate recovery following 12-weeks of END and HIT. However, pre-training heart rate recovery values reported by our sample were in a low risk range, which suggests training induced improvements may only be achievable in populations with attenuated pre-training values.</p> <p>The results of this thesis provide preliminary evidence supporting the use of HIT in patients with CAD. The findings of favorable transient and chronic improvements following HIT are notable, especially given the HIT protocol involves less time and work than END, which was modeled after the current exercise prescription in cardiac rehabilitation. Further investigations are necessary, including the assessment of additional physiological indices, the feasibility and adherence to HIT, the inclusion of CAD populations with co-morbidities including heart failure and diabetes, as well as other forms of HIT training including HIT combined with resistance training.</p> / Doctor of Philosophy (PhD)

Purpose: Evidence has accumulated to show that blood pressure variability (BPV) has a striking relationship with cardiovascular (CV) risk. Despite the mounting evidence implicating BPV as a CV risk factor, scant attention has been paid to: (1) the mechanisms by which high BPV confers greater CV risk; and (2) the efficacy of non-pharmacologic treatment modalities in the attenuation of BPV. In order to address these two unresolved questions, the purpose of this dissertation was twofold. The purpose of study #1 was to investigate the association between measures of short-term BPV (24-hour BPV) and long-term BPV (visit-to-visit BPV) with markers of endothelial health in a cohort of African Americans in order to determine if increased BPV may confer greater CV risk by eliciting injury to the endothelium. The purpose of study #2 was to investigate the effects of a 6-month aerobic exercise training (AEXT) intervention on visit-to-visit BPV and 24-hour BPV in the same cohort of African Americans in order to provide the first available data on the efficacy of a non-pharmacologic treatment modality in the lowering of BPV. Methods: We recruited 72 African Americans who were sedentary, non-diabetic, non-smoking, and free of CV and renal disease. Before and after a 6-month AEXT intervention, office blood pressure (BP) was measured at 3 separate visits and 24-hour ambulatory BP monitoring (ABPM) was conducted to measure visit-to-visit BPV and 24-hour BPV, respectively. Right brachial artery diameter was assessed at rest, during flow-mediated dilation (FMD), and after nitroglycerin-mediated dilation (NMD). Peak and area under the curve (AUC) were calculated as measures of FMD and NMD, and the FMD/NMD ratio was calculated as a measure of endothelial function normalized by smooth muscle function. Fasted blood samples were obtained and were analyzed for circulating EMPs expressed as CD31+CD42- and CD62E+ EMPs. Results: In study #1, participants with higher 24-hour diastolic BPV (DBPV) had significantly lower CD31+CD42- EMPs compared to participants with lower 24-hour DBPV. When categorized according to visit-to-visit DBPV, participants with higher visit-to-visit DBPV had a significantly lower FMD/NMD ratio, and significantly higher %NMDpeak and NMDAUCs compared to participants with lower visit-to-visit DBPV. When analyzed as continuous variables, 24-hour mean arterial pressure variability (MAPV) was inversely associated with CD31+CD42- EMPs visit-to-visit DBPV was inversely associated with the FMD/NMD ratio and positively associated with %NMDpeak and NMDAUC; and 24-hour DBPV was positively associated with NMDAUC. All associations were independent of age, gender, BMI, mean BP, and pulse pressure. In study #2 investigating the effects of AEXT in 33 participants who completed the study, 24-hour DBPV and 24-hour MAPV were significantly increased after AEXT. The increase in 24-hour DBPV was independent of changes in BMI, mean BP, and self-reported sleep time. Heart rate variability (HRV) derived from ABPM was associated with the changes in 24-hour DBPV and 24-hour MAPV. There were no significant changes in visit-to-visit BPV after AEXT. Conclusions: The results from study #1 provide evidence that BPV is associated with vascular health as endothelial function was decreased in participants with high visit-to-visit DBPV, while smooth muscle function was increased in participants with higher visit-to-visit and 24-hour DBPV. The findings from study #2 show that 6-months of AEXT do not elicit beneficial changes in BPV. The finding of an association between changes in 24-hour BPV with HRV could indicate, however, that changes in activity levels during ABPM, in part, contributed to the observed changes in 24-hour BPV. / Kinesiology

Purpose: Evidence has accumulated to show that elevated subclinical inflammation and impaired endothelial function has been associated with higher risk of cardiovascular disease (CVD). Despite data on these emerging risk factors, scant attention has been paid to: (1) the interactions of inflammation with endothelial function in relatively healthy African Americans; and (2) the efficacy of non-pharmacologic treatment modalities, such as exercise training, on inflammation and endothelial function. The aim of study 1 was to assess the levels of inflammatory markers, to assess the endothelial function in asymptomatic African Americans. The aim of study 2 was to determine the effects of six-months of exercise training on inflammatory markers and endothelial function in the same cohort. Methods: We recruited 79 African Americans who were sedentary, non-diabetic, non-smoking, and free of CV and renal disease. Before and after 6-month AEXT intervention, inflammatory markers (CRP, TNF-a and IL-6) were measured. Right brachial artery diameter was assessed at rest, during flow-mediated dilation (FMD), and after nitroglycerin-mediated dilation (NMD). Peak dilation was calculated as a measure of FMD and NMD, and the FMD/NMD ratio was calculated as a measure of endothelial function normalized by smooth muscle function. Fasted blood samples were obtained and were analyzed for the metabolic profile. Results: In study 1, the mean CRP for the group was 3.3 ± 0.3 mg/L which falls in the high-risk CRP category as per AHA/CDC guidelines. When divided into tertiles for CRP, low-risk (CRP 3 mg/L); VO2max was significantly higher in the low-risk category compared to average-risk category (P =0.004), and significantly higher in the low-risk category compared to high-risk category (P <0.001). Further, Cardiorespiratory fitness was significantly correlated with CRP (Figure. 1; r = -0.456, P <0.001) and BMI (r = -0.362, P = 0.002). CRP was correlated with BMI (r = 0.424, P <0.001). In a multivariable regression model that included age, gender, BMI, CVD risk factors (total cholesterol, triglycerides, HDL lipoprotein, LDL lipoprotein, plasma glucose, BP, and CRP), the following variables were significantly associated with fitness: fitness [B-coeff = -0.434 ± 0.05 (SE), P <0.001] independently predicted CRP. Fitness explained 22% of variance in CRP levels. In study 2, 6-month AEXT intervention significantly increased VO2max, (P=0.001), indicating that the prescribed exercise program may have been sufficient to elicit improvements in cardiovascular fitness. Significant reductions were observed for CRP (P =0.014). On repeated measures ANCOVA, the mean CRP values were significantly different (F (1,32) =6.703, P=0.014) between before vs. after training (Mean ± SEM; 3.1 ± 0.4 mg/L vs. 2.4 ± 0.4 mg/L), after adjusting for changed variables (BMI, mean BP and VO2max) as covariates. For endothelial measures, significant increase in endothelial function were observed for %FMDpeak (P =0.043) [Figure. 22] and FMD/NMD Ratio (P =0.047) increased post-AEXT. On repeated measures ANCOVA, the mean %FMD was statistically significantly different (F (1,16) =5.582, P=0.031) between before vs. after training (Mean ± SEM; 6.4 ± 2.6% vs. 9.4 ± 2.1%), after adjusting for changed variables (BMI, total-cholesterol and C-reactive protein) as covariates. Conclusions: The results from study 1 provide evidence of the prevalence of high levels of inflammation in the putatively healthy cohort of African Americans. When the group was categorized into tertiles for CRP and the cardio-metabolic, clinical and vascular profiles assessed, statistically significant differences, and rising trends were observed for CRP, body weight, BMI, BBF%, VO2max, SBP and DBP among the three CRP categories indicating a subclinical high cardiovascular risk profile in this cohort of putatively healthy population. Study 2, showed statistically significant improvements in inflammatory marker (CRP) and vascular measures (%FMDpeak, FMD/NMD Ratio and IMT); metabolic profile (triglycerides and FBS); clinical parameters (weight, BMI); cardiorespiratory fitness (VO2max). As we hypothesized, a marked reduction in CRP (-13.5%) post-AEXT was noticed, independent of change in(BMI, MAP and VO2max). Further, baseline CRP and BMI predicted change in CRP on regression analysis. Next, a marked increase in vascular measures, %FMDpeak (23.9%), FMD/NMD Ratio (25.4%) and IMT (-7.4%) were noticed independent of Ä(BMI, total cholesterol, MAP and VO2max). This may suggest: 1) the dominant anti-inflammatory role of exercise training. 2) that long-term exercise training improves clinical vascular measures in our cohort. / Kinesiology

Obstructive sleep apnea (OSA) is a disorder that affects a significant portion of middle-aged adult population. Patients exhibit recurring episodes of upper airway obstruction during sleep that decrease blood oxygen concentration (hypoxia) and are terminated by brief arousals. Epidemiologically, OSA has been extensively linked to cardiovascular dysfunction and is an independent risk factor for the development of hypertension. The proposed mechanism of cardiovascular dysfunction in patients is chronic sympathoexcitation and altered vascular tone, with a predominance of the vasoconstrictor endothelin-1 (ET-1) and removal of the vasodilator nitric oxide (NO). Means to reduce the effects of ET-1 and increase synthesis of NO may have beneficial effects on the cardiovascular co-morbidity commonly associated with OSA. OBJECTIVES: The major aim of this study was to assess the relative importance of circulating biomarkers of ET-1 and NO in hemodynamic function in OSA patients. Potential production of ET-1 by circulating mononuclear cells was also measured to assess their contribution to plasma ET-1 levels. Biomarker levels before and after 12 wk of continuous partial airway pressure (CPAP) therapy were used to assess standard treatment. Mild/moderate exercise training was initiated with CPAP therapy in a subgroup of OSA patients to evaluate the potential benefits of physical activity on hemodynamic function and NO and ET-1 levels. METHODS: Overall, 16 newly diagnosed OSA patients (5 female, 11 male; age 45.4 ± 2.7 yr; RDI 24.6 ± 4.0 events/hr) were selected for study. Seven apparently healthy control volunteers (5 female, 2 male; age 39.43 ± 2.6 yr) screened for OSA served as control subjects. Blood pressure was recorded over one complete day and prior to, during, and following maximal exercise testing on a cycle ergometer. Blood samples were taken prior to exercise testing and assessed for nitrate and nitrite by HPLC and for big endothelin-1 and ET-1 by ELISA. Relative gene expression of preproendothelin-1 was measured by real-time RT-PCR. Following initial testing, patients were stratified into either a standard therapy group (nCPAP) or a standard therapy group with a mild/moderate intensity aerobic training regimen (nCPAP+Ex). Baseline testing was repeated following 12 wk of treatment. Statistical significance was set at p < 0.05 a priori. RESULTS: 24 hr ambulatory systolic and diastolic blood pressure were elevated in OSA patients vs. control subjects (systolic: 128.9 ± 3.8 mmHg vs. 108.8 ± 1.3 mmHg, respectively; diastolic: 97.5 ± 2.0 mmHg vs. 82.1 ± 1.9 mmHg, respectively). OSA patients experienced significant elevations in systolic (OSA 209.7 ± 5.7 mmHg; Control 174.5 ± 6.2 mmHg) and mean arterial pressures (OSA 125.8 ± 3.2 mmHg; Control 109.05 ± 4.5 mmHg) at peak exercise. No differences in nitrate, nitrite, or big endothelin-1 were noted. Plasma endothelin-1 concentrations were below assay detection limit. Big endothelin-1 levels were significantly correlated with BMI in both OSA patients (r=0.955; p=0.001) and control subjects (r=0.799; p=0.045). Relative gene expression of preproendothelin-1 was not elevated in OSA patients (0.40 ± 0.20 fold increase over control subjects). Group nCPAP usage was above minimum therapeutic threshold, but was non-uniform in both groups, with an overall range of 182 to 495 min mean usage per night. A mild/moderate exercise training program failed to elicit a training response through standard hemodynamic or cardiopulmonary indices. Plasma nitrite levels rose from 55.3 ± 4.7 μg/ml to 71.0 ± 7.6 μg/ml in the nCPAP group. CONCLUSIONS: Moderate OSA is associated with elevated blood pressure at rest and during exercise stress that bears no relationship to circulating biomarkers of NO and ET-1 or immune preproendothelin production in patients without diagnosed hypertension. nCPAP therapy failed to elicit significant improvements in hemodynamic function, with or without moderate exercise. Plasma nitrite levels rose following nCPAP therapy, indicating a possible increase in basal nitric oxide formation. Higher intensity exercise regimens may be needed to elicit the positive benefits of exercise training in OSA patients without significant cardiovascular dysfunction. / Ph. D.

Research has indicated that the frontal and temporal lobes are involved in the mediation of heart rate and blood pressure. However, whereas these regions of the brain have been identified in the mediation of heart rate and blood pressure, the specific cerebral processes involved in determining the direction and magnitude of change in heart rate and blood pressure has not been adequately addressed. The present paper proposes that changes in the magnitude of cerebral activation between the left and right frontal and temporal lobes is partly that which determines the direction and magnitude of changes in heart rate and blood pressure. The present investigation sought to test part of this proposition, namely, that increasing magnitude of cerebral activity within the right anterior temporal region generates increasing levels of sympathetic control of heart rate and blood pressure and that the right lateral frontal region acts to inhibit sympathetic activity. A total of 45 right handed men, with no history of significant head injury, were exposed to 55 dB, 75 dB, and 90 dB white noise presentations. Right frontal lobe functioning was assessed by performance on the Ruff Figural Fluency Test (RFFT), with the participants scoring in the lower one-third classified as Low Fluency. Those scoring in the upper one-third were classified as High Fluency. Quantitative electroencephalography, measured at 19 electrodes sites arranged according to the International 10/20 System, as well as heart rate and blood pressure responses to white noise presentation were measured. Although the results failed to support any of the hypotheses concerning the effects of varying intensity of white noise on cardiovascular activity, partial support was found for the hypotheses that varying intensity of white noise would generate differential changes in high beta magnitude between the Low and High Fluency groups. The results are discussed in terms of support for the model being tested. Alternative explanations of the findings are also provided that demonstrate correspondence between the QEEG and cardiovascular data. Finally, limitations of the model and the methods of the present investigation are discussed and suggestions for improvement are provided. / Ph. D.

Motivation In the black population of South Africa, cardiovascular disease (CVD) is rapidly increasing due to urbanisation. Stroke is usually accompanied by a prothrombotic haemostatic profile. Changing lifestyle factors that accompany the urbanisation process could have a negative impact on the haemostatic profile of black South Africans. Elevated levels of pro-coagulant factors, von Willebrand factor (vWF), fibrinogen and fibrin D-dimer have been reported in the black population, which could increase the black population’s susceptibility to CVD. However, low levels of plasminogen activator inhibitor-1 (PAI-1) previously reported in the black population could contribute towards a pro-fibrinolytic state, which may counteract the hypercoagulant state. This may have a beneficial effect on the haemostatic profile of the black population. More investigation into the haemostatic profile of black South Africans is therefore needed to determine if an altered haemostatic profile exists in this group, and if so, to what extent these alterations may relate to cardiovascular dysfunction. This study included markers of both the coagulation (vWF, fibrinogen, fibrin D-dimer) and fibrinolytic (PAI-1, fibrin D-dimer and fibrinolytic potential) systems in an attempt to investigate the haemostatic profile of the black population of South Africa, and for comparison purposes that of the white population as well. The relationship of these markers’ with selected markers of cardiovascular function was also examined to determine if they could possibly contribute to an increase in cardiovascular risk, especially in the black population. Aims The aims of this study were to first compare coagulation and fibrinolysis markers in the black and white populations of South Africa. Furthermore, to determine if associations exist between the selected components of the haemostatic system and markers of cardiovascular function, especially in the black population of South Africa, who tends to be at a higher cardiovascular risk due to altered metabolic and haemostatic profiles. Methodology The Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study was a prospective cohort study that consisted of 409 participants at baseline (2008-2009) that were equally distributed according to both ethnicity (200 black; 209 white) and gender (black, 101 men, 99 women; white, 101 men, 108 women). At follow-up (2011/2012) the cohort totalled 359 participants (170 black, 88 men and 82 women; 189 white, 93 men and 96 women). Data from baseline measurements were used for the first two manuscripts (chapters 2 and 3), while followup data was used for the third manuscript (chapter 4). vWF, fibrinogen, PAI-1, fibrin D-dimer, CLT, serum peroxides, glutathione, glutathione peroxidase and reductase activity were determined, and ambulatory blood pressure and the retinal vessel calibres were measured. The groups were stratified by ethnicity as specified by statistical interaction terms. T-tests and chi-square tests were used to compare means and proportions, respectively. Pearson and partial regression analyses were used to determine correlations between the components of the haemostatic system and cardiovascular function markers. This was followed by multiple linear regression analyses to investigate whether independent associations exist between the variables in both ethnic groups. P-values ≤0.050 were deemed significant. Results and conclusion of each manuscript The first manuscript (chapter 2) compares the haemostatic profiles of the black and white population to determine whether ambulatory blood pressure is related to components of the haemostatic system. The black participants displayed a prothrombotic profile with significantly higher vWF, fibrinogen, PAI-1, fibrin D-dimer and a longer CLT than their white counterparts. Furthermore, partial and multiple linear regression analyses showed a positive association of systolic and diastolic blood pressure with fibrin D-dimer in the black population, while a negative association existed between ambulatory blood pressure and CLT in the white population. These associations suggest that fibrin D-dimer may contribute, at least in part, to the high prevalence of hypertension in the black population. The second manuscript (chapter 3) determined associations between markers of the haemostatic and oxidant-antioxidant systems in the black and white populations. In addition to the prothrombotic profile that exists in the black population, this group also had significantly higher serum peroxides (oxidative stress) and lower glutathione peroxidase activity (antioxidant) levels. Multiple linear regression analyses indicated positive associations between fibrinogen and serum peroxides in both populations. In the white population, an additional positive association was found between serum peroxide and CLT. In the black population, vWF and CLT were negatively associated with GPx activity. The results suggest that there are ethnic-specific relationships between the haemostatic and oxidant-antioxidant systems. The third manuscript (chapter 4) investigated the relationships between the retinal vessel calibres and components of the haemostatic system in the black and white population. The investigation focussed specifically on arteriolar diameters in the lower median, since a narrow arteriolar diameter is known to be associated with elevated blood pressure. In both ethnic groups, a narrower arteriolar calibre was accompanied by narrower venular calibres. Independent positive associations were found between the central retinal vein equivalent (CRVE) and fibrinogen in the black population, as well as vWF and CLT in the white population. In addition, independent negative associations were found between the central retinal artery equivalent and CLT in the black population and with vWF in the white population. The results suggest that haemostatic alterations are linked to early vascular changes that may differ between ethnicities. General conclusion Ethnic-specific relationships between the components of the haemostatic system and measures of cardiovascular function are evident. The prothrombotic profile that is observed in the black population, together with the adverse associations of the haemostatic components with blood pressure, a compromised oxidant-antioxidant profile, and retinal vessel calibres may contribute, at least in part, to the high cardiovascular and cerebrovascular risk evident in this population group. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015