Neck-shoulder pain (NSP) is a highly prevalent musculoskeletal disorder with unclear causes, and effective prevention and treatment require a further understanding of the underlying mechanisms. Aberrant autonomic nervous system (ANS) regulation is a hypothesized causal element in the development and maintenance of chronic muscle pain. The overall aim of this thesis was to investigate possible differences in ANS regulation between chronic NSP and healthy control (CON) groups using both laboratory assessment and ambulatory monitoring in daily life. Four papers are included in this thesis, based on data from three groups with chronic NSP. Autonomic responses to laboratory stressors were assessed using heart rate variability (HRV), blood pressure, trapezius muscle activity and blood flow measurements (Study І) in NSP and CON. Long-term ambulatory monitoring of HRV, physical activity and perceived symptoms were assessed in Studies ІІ and IV to investigate group differences in real-life conditions. Finally, the effects of a ten-week intervention (using individually adjusted HRV biofeedback) to reinstating ANS balance in subjects with chronic NSP were evaluated using self-reported symptoms and health ratings, as well as autonomic regulation testing (i.e., evaluating HRV at rest and in response to stress) (Study ІІІ). The main findings from the four studies demonstrated aberrant ANS regulation in the NSP group compared to CON, which was predominantly characterized by diminished parasympathetic cardiac activity during rest and sleep, and altered sympathetic reactivity to laboratory stressors (Studies І, ІІ and IV). Different patterns in physical activity were observed between the NSP and CON groups, with reduced physical activity during leisure time in the NSP group (Studies ІІ and IV). Physical activity was found to be positively associated with HRV. Positive effects of HRV-biofeedback were found on perceived health, including social function, vitality and bodily pain, and improved HRV (Study ІІІ). In conclusion, imbalanced ANS regulation was demonstrated among persons with chronic NSP at both the systemic and local levels. Diminished parasympathetic activity in NSP was modulated by lower levels of physical activity in leisure time. Interventions targeting ANS functions might benefit persons with chronic NSP.

Motivation The prevalence of cardiovascular disease is on the increase in sub-Saharan Africa largely owing to lifestyle changes associated with urbanisation. Traditional diets are being replaced with diets high in saturated fat and sugar. In addition to the nutritional transition, urbanisation in developing African countries also contributes to a more sedentary lifestyle. Together these trends contribute to a higher prevalence of obesity and hypertension that are major risk factors for the development of cardiovascular disease. Adipose tissue is now widely recognised as an endocrine organ that secretes numerous inflammatory mediators as well as adipocytokines such as leptin. The primary role of leptin is to induce satiety after a meal and to suppress appetite. However, in recent years the role of leptin in the development of obesity-related cardiovascular disease has gained increasing attention and interest. Furthermore, leptin levels not only differ with regard to gender but also ethnicity. Africans have higher leptin levels than Caucasians due to higher subcutaneous fat in Africans. Furthermore, the prevalence of hypertension and stroke are also greater in the African population. Taken together, it is important to investigate mechanisms by which elevated leptin may contribute to the development of cardiovascular disease, especially in cardiovascular disease-prone Africans. Aim The general aim of this study is to increase our understanding of the role of leptin in cardiovascular disease development by investigating associations of leptin with markers of sympathetic activity, endothelial dysfunction, and cardiovascular reactivity and recovery in Africans and Caucasians. Methodology Data from the SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study was used and presented in the original research articles described in Chapter 2, 3 and 4. This study included 409 African and Caucasian schoolteachers working in the Potchefstroom district in the North West Province of South Africa. Groups were stratified by ethnicity, gender and ethnicity or obesity in order to demonstrate potential differences. We performed cardiovascular measurements and determined levels of leptin, renin, cortisol, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF) and urinary albumin-to-creatinine ratio (ACR). Independent t-tests were done to compare means between groups and Chi-square tests to compare proportions. Pearson’s correlations were determined to investigate associations as well as partial correlations after minimal adjustment for potential confounders. Multiple regression analyses were performed to investigate independent associations of leptin with cardiovascular and biochemical markers according to the specific focus of each research manuscript. Results and conclusions of the individual manuscripts  Leptin may contribute to obesity-related hypertension through its sympatho-activating effects. In the first research article (Chapter 2), we compared mean leptin levels and markers of autonomic activity between Africans and Caucasians. We also investigated associations between markers of autonomic activity and leptin. Africans had higher leptin, body mass index, blood pressure and heart rate compared to Caucasians. Furthermore, Africans also demonstrated reduced heart rate variability that is indicative of autonomic imbalance. Markers of autonomic activity that collectively reflected sympathetic overactivity associated with leptin in both Africans and Caucasians, independent of significant covariates and confounders including body mass index. These findings suggest that leptin may contribute to the development of hypertension by inducing autonomic dysfunction.  Leptin exerts direct vascular effects and may thereby contribute to increased cardiovascular disease risk in the obese. We therefore investigated associations between circulating markers of endothelial dysfunction (PAI-1, vWF and ACR) and leptin in lean and obese groups, irrespective of ethnicity (Chapter 3). As expected, leptin and plasminogen activator inhibitor-1 antigen levels were higher in the obese group. We found no differences for von Willebrand factor antigen and urinary albumin-to-creatinine ratio. In the obese group, all markers of endothelial dysfunction were positively associated with leptin in univariate analysis. However, after full adjustment in multiple regression analyses, only the association with plasminogen activator inhibitor-1 remained significant. Higher leptin levels in the obese may possibly induce endothelial dysfunction through mechanisms related to thrombotic vascular disease.  Greater cardiovascular reactivity to stress and prolonged recovery thereafter associates with increased cardiovascular disease risk. In the final research article (Chapter 4), we therefore investigated the relationship between cardiovascular reactivity and recovery to acute stress, induced by the cold pressor test, and leptin in Africans and Caucasians. Africans demonstrated greater cardiovascular reactivity compared to Caucasians. Associations of blood pressure, stroke volume, cardiac output, total peripheral resistance and arterial compliance reactivity with leptin were investigated during the stressor application and 1, 3 and 5 minutes post-stressor. There were no independent associations between cardiovascular reactivity and leptin during the stressor, and a few correlations at 1 and 3 minutes post-stressor. Associations were mostly evident at 5 minutes post-stressor and in Africans. We argue that higher leptin levels relate to impaired post-stress recovery and thereby could contribute to hypertension development in Africans. General conclusion Elevated leptin relates to sympathetic overactivity, vascular damage and delayed post-stress recovery, and thereby could contribute to increased cardiovascular disease risk. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015

Motivation The prevalence of cardiovascular disease is on the increase in sub-Saharan Africa largely owing to lifestyle changes associated with urbanisation. Traditional diets are being replaced with diets high in saturated fat and sugar. In addition to the nutritional transition, urbanisation in developing African countries also contributes to a more sedentary lifestyle. Together these trends contribute to a higher prevalence of obesity and hypertension that are major risk factors for the development of cardiovascular disease. Adipose tissue is now widely recognised as an endocrine organ that secretes numerous inflammatory mediators as well as adipocytokines such as leptin. The primary role of leptin is to induce satiety after a meal and to suppress appetite. However, in recent years the role of leptin in the development of obesity-related cardiovascular disease has gained increasing attention and interest. Furthermore, leptin levels not only differ with regard to gender but also ethnicity. Africans have higher leptin levels than Caucasians due to higher subcutaneous fat in Africans. Furthermore, the prevalence of hypertension and stroke are also greater in the African population. Taken together, it is important to investigate mechanisms by which elevated leptin may contribute to the development of cardiovascular disease, especially in cardiovascular disease-prone Africans. Aim The general aim of this study is to increase our understanding of the role of leptin in cardiovascular disease development by investigating associations of leptin with markers of sympathetic activity, endothelial dysfunction, and cardiovascular reactivity and recovery in Africans and Caucasians. Methodology Data from the SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study was used and presented in the original research articles described in Chapter 2, 3 and 4. This study included 409 African and Caucasian schoolteachers working in the Potchefstroom district in the North West Province of South Africa. Groups were stratified by ethnicity, gender and ethnicity or obesity in order to demonstrate potential differences. We performed cardiovascular measurements and determined levels of leptin, renin, cortisol, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF) and urinary albumin-to-creatinine ratio (ACR). Independent t-tests were done to compare means between groups and Chi-square tests to compare proportions. Pearson’s correlations were determined to investigate associations as well as partial correlations after minimal adjustment for potential confounders. Multiple regression analyses were performed to investigate independent associations of leptin with cardiovascular and biochemical markers according to the specific focus of each research manuscript. Results and conclusions of the individual manuscripts  Leptin may contribute to obesity-related hypertension through its sympatho-activating effects. In the first research article (Chapter 2), we compared mean leptin levels and markers of autonomic activity between Africans and Caucasians. We also investigated associations between markers of autonomic activity and leptin. Africans had higher leptin, body mass index, blood pressure and heart rate compared to Caucasians. Furthermore, Africans also demonstrated reduced heart rate variability that is indicative of autonomic imbalance. Markers of autonomic activity that collectively reflected sympathetic overactivity associated with leptin in both Africans and Caucasians, independent of significant covariates and confounders including body mass index. These findings suggest that leptin may contribute to the development of hypertension by inducing autonomic dysfunction.  Leptin exerts direct vascular effects and may thereby contribute to increased cardiovascular disease risk in the obese. We therefore investigated associations between circulating markers of endothelial dysfunction (PAI-1, vWF and ACR) and leptin in lean and obese groups, irrespective of ethnicity (Chapter 3). As expected, leptin and plasminogen activator inhibitor-1 antigen levels were higher in the obese group. We found no differences for von Willebrand factor antigen and urinary albumin-to-creatinine ratio. In the obese group, all markers of endothelial dysfunction were positively associated with leptin in univariate analysis. However, after full adjustment in multiple regression analyses, only the association with plasminogen activator inhibitor-1 remained significant. Higher leptin levels in the obese may possibly induce endothelial dysfunction through mechanisms related to thrombotic vascular disease.  Greater cardiovascular reactivity to stress and prolonged recovery thereafter associates with increased cardiovascular disease risk. In the final research article (Chapter 4), we therefore investigated the relationship between cardiovascular reactivity and recovery to acute stress, induced by the cold pressor test, and leptin in Africans and Caucasians. Africans demonstrated greater cardiovascular reactivity compared to Caucasians. Associations of blood pressure, stroke volume, cardiac output, total peripheral resistance and arterial compliance reactivity with leptin were investigated during the stressor application and 1, 3 and 5 minutes post-stressor. There were no independent associations between cardiovascular reactivity and leptin during the stressor, and a few correlations at 1 and 3 minutes post-stressor. Associations were mostly evident at 5 minutes post-stressor and in Africans. We argue that higher leptin levels relate to impaired post-stress recovery and thereby could contribute to hypertension development in Africans. General conclusion Elevated leptin relates to sympathetic overactivity, vascular damage and delayed post-stress recovery, and thereby could contribute to increased cardiovascular disease risk. / PhD (Physiology), North-West University, Potchefstroom Campus, 2015