The sympathetic nervous system is crucial for controlling multiple cardiac functions and its overactivity is associated with many cardiovascular diseases (CVD). Chronic intermittent hypoxia (CIH) is a current model for sleep apnea, which constitutes a major risk factor for CVD through sympathetic overactivity. However, a comprehensive neuroanatomical map of the sympathetic innervation of the heart is unavailable which impedes our understanding of the remodeling of this map in pathological conditions. First, we used a combination of state-of-the-art techniques, including flat-mount tissue processing, immunohistochemistry for tyrosine hydroxylase (TH, a sympathetic marker), confocal microscopy and Neurolucida 360 software to trace, digitize, and quantitatively map the topographical sympathetic innervation in the whole heart of mice. Then we integrated our tracing data onto a 3D heart scaffold. Second, we determined the remodeling of sympathetic innervation in CIH, by exposing mice to either room air or CIH for 8-10 weeks. We found that (1) 4–5 extrinsic TH-IR nerve bundles entered the right atrium from the superior vena cava and the left atrium from the left precaval vein. Although these bundles projected to different areas of the atria, their projection fields partially overlapped. (2) TH-IR axon and terminal density varied considerably between different sites of the heart with the greatest density of innervation near the sinoatrial node region (P < 0.05, n = 6). (3) TH-IR axons also innervated blood vessels and adipocytes. (4) In ventricles: TH-IR axons formed dense terminal networks in the epicardium, myocardium, and vasculature. (5) TH-IR axons were traced and integrated into 3D heart scaffolds. (6) CIH significantly increased TH-IR innervation and complexity in the heart. Collectively, this work provided detailed mapping of catecholaminergic axons and terminal structures in the whole heart at single-cell/axon/varicosity scale in normal and CIH conditions. This work may provide a foundation for the functional study of sympathetic control of the heart and valuable neuromodulation strategies to treat CVD.

Cardiovascular disease (CVD) is one of the major causes of death worldwide. Disease management, as well as patient health, can be significantly improved by early detection of patient deterioration and proper intervention. Review of the patient's medical history and physical examination including stethoscope auscultation and electrocardiograms (ECG), echocardiography imaging, numerous blood testing, and computed tomography are common means of evaluating cardiac function. Seismocardiographic (SCG) signals are the vibrations of the chest wall due to the mechanical activity of the heart. These signals can provide useful information about heart function and could be used to diagnose cardiac problems. The variability in SCG waveforms may make it difficult to obtain accurate waveforms, limiting SCG clinical value. Breathing is a well-known source of change in SCG morphology. In this dissertation, SCG variability due to respiration is described, related signal characteristics changes are measured, and the effects of breathing states and maneuvers are discussed. Increased SCG variability understanding can aid in accounting for variability in signal as well as more accurate characterization of significant features in SCG that could correlate with heart health. Direct airflow measurement is frequently used to assess respiration. When direct airflow access is difficult or unavailable, indirect ways to breathing monitoring might be used. The seismocardiographic signal is influenced by respiration. As a result, this signal can be utilized to noninvasively determine the respiratory phases. Hence, SCG may reduce the requirement for direct airflow measurements in situations where SCG signals are easily available. This dissertation extracts respiration derived from SCG in healthy adults using machine learning techniques and compares the results with direct respiration airflow measurements. Finite element method (FEM) was implemented to perform SCG simulation during different breathing states by modeling the myocardial movements propagation to the surface of the chest. SCG waveforms predicted by FEM analysis were comparable with SCG signals measured at the surface of the chest suggesting that myocardial activity is the SCG main source. The effects of increased soft tissue in the chest wall on SCG signal were investigated and were found to decrease SCG amplitude. The research led to an enhanced understanding of the SCG variability sources as well as respiratory phase-detection methods. These discoveries could lead to better non-invasive, low-cost approaches development for managing cardiovascular disorders, which can enhance patient quality of life.

<p>Background: Genome wide association studies (GWAS) performed in Caucasian populations have identified several single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD), although their cumulative impact in other ethnicities is unknown. Using a genetic risk score (GRS), we examined the impact of CAD related SNPs on myocardial infarction (MI) in a multi-ethnic population.</p> <p>Methods: We included 4083 MI cases and 4473 controls from the INTERHEART case: control study, stratified by six ethnic groups: European, South Asian, other Asian, Arab, Latin American, and African. We created a GRS comprised of 25 SNPS, and tested its association with MI in individual ethnicities using logistic regression, and across ethnic groups through meta-analyses. Results were adjusted for age, sex, and modifiable risk factors.</p> <p>Results: The GRS was significantly associated with MI in Europeans (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04-1.12 per risk allele), South Asians (OR = 1.09, 95% CI 1.05-1.14), other Asians (OR = 1.09, 95% CI 1.04-1.15), and Arabs (OR = 1.07, 95% CI 1.03-1.12). In Latin Americans and Africans the GRS was not significant. Meta-analysis of ethnic groups demonstrated a 1.06 (95% CI 1.03-1.09) increase in the odds of MI with the GRS per risk allele. Significant heterogeneity was observed, which was reduced by exclusion of Latin Americans (I2=63% to 0%). Above clinical risk factors, the GRS modestly increased population attributable risk (PAR) (0.92 to 0.94), concordance statistic (0.73 to 0.74), net reclassification improvement (0.14), and integrated discriminatory improvement (0.007).</p> <p>Conclusions:<strong> </strong>The GRS was associated with a significant increase in the odds of MI in multiple ethnic groups. Improvements in PAR, discrimination and reclassification were modest above clinical factors.</p> / Master of Science (MSc)

No description available.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg 2016 / Introduction: The African continent, particularly sub-Saharan Africa, is facing a high burden of disease from the human immunodeficiency virus (HIV) pandemic and nutritional deficiencies, while at the same time, facing ever increasing rates of cardiovascular diseases (CVDs). The mortality rates from CVD are almost equal to the death rates from communicable diseases. In Sub-Saharan countries CVD prevention and management faces many barriers. One such difficulty is the shortage of data for the descriptive epidemiology of CVD risk factors. In an attempt to address this shortage of data, we established the Heart of Soweto (HOS) study in one of the largest African urban communities in South Africa. The purpose of this study was to identify and describe some of the factors contributing to the emergence of chronic diseases of lifestyle, such as heart disease, high blood pressure, diabetes and obesity in a black urban African population, within the framework of the HOS study. We also investigated the impact of a dietary intervention on cardiac function in subjects with chronic heart failure (CHF) in this black urban cohort. Methods: Data was collected as part of the “Heart of Soweto” (HOS) study, which was a prospectively designed registry that recorded data relating to the presentation, investigation and treatment of patients with newly diagnosed cardiovascular disease presenting to Chris Hani Baragwanath Hospital (CHBH), Soweto in 2006. Data collected included socio-demographic profile and all major cardiovascular diagnoses. Heart disease was defined as non-communicable (ND) e.g. coronary artery disease or communicable (CD) e.g. rheumatic heart disease. A survey was also conducted on consecutive patients attending two pre-selected primary care clinics in Soweto (644 and 667 patients from the Mandela Sisulu and Michael Maponya clinics, respectively). Data collected included, ethnicity, duration of residence in Soweto, highest level of education and employment status. Clinical data collected included prior or current diagnoses of diabetes and hypertension and pharmacological therapy related to the treatment of hypertension, as well as smoking status and exposure to second-hand smoking. Weight, height, and waist and hip circumference were measured. Questions were asked regarding the duration of night-time sleep and napping during the day. Descriptive studies were undertaken at the Heart Failure Clinic at CHBH, Soweto to firstly describe the food choices and macro-and micronutrients intake of 50 consecutive patients presenting with heart failure using an interviewer-administered quantitative food frequency questionnaire (QFFQ). Food data were translated into nutrient data using the Medical Research Council (MRC) Food Finder 3, 2007, which is based on South African food composition tables. Secondly we performed a randomized controlled study of a multidisciplinary, community-based, chronic HF management program in Soweto, compared with usual care, at CHBH Heart Failure Clinic located at the Soweto Cardiovascular Research Unit (SOCRU), or at the General Cardiac ix Clinic (standard care) in Soweto. In this study 49 consenting, eligible patients were individually randomized on a 1:1 basis to either usual care or to the study intervention and cardiac function was measured before and after the intervention. Results: Data collected at Chris Hani Baragwanath hospital (CHBH) cardiology clinic from 5328 suspected cases of heart disease, demonstrated that the most prevalent form of heart disease was hypertensive heart failure (22.0%). It was found that those participants who presented with ND (35.0%) were older and had higher BMI and mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) than those with CD (39.0%; all comparisons p<0.001). Within this cohort of 5328 de novo cases of heart disease, 2505 (47%) were diagnosed with HF, of which 697 (28%) were diagnosed with r i g h t h e a r t f a i l u r e ( RHF). There were more women than men diagnosed with RHF (379 vs. 318 cases), and on an adjusted basis, compared with the remainder of the Heart of Soweto cohort (n = 4631), RHF cases were more likely to be African (adjusted OR 2.33, 95% CI 1.59 – 3.41), with a history of smoking (OR 1.72, 95% CI 1.42 – 2.10), a lower body mass index (OR 0.96, 95% CI 0.94 – 0.97 per kg/m2) and were less likely to have a family history of heart disease (OR 0.79, 95% CI 0.64 – 0.96). Data collected at 2 primary health care clinics in Soweto from 862 women (mean age 41 ± 16 years and mean BMI 29.9 ± 9.2 kg/m2) and 449 men (38 ± 14 years and 24.8 ± 8.3 kg/m2) indicated that in females, former smokers had a higher BMI (p<0.001) than current smokers, while exposure to second hand smoking was associated with a lower BMI (p<0.001) in both genders. Longer sleep duration in females was associated with a lower BMI (p=0.01). Napping during the day for > 30 minutes in males was related to a lower BMI and waist circumference (β=-0.03, p<0.05 for both) and lower systolic (β=-0.02, p<0.05) and diastolic BP (β=-0.02, p<0.05). Longer night time sleep duration was associated with lower diastolic (β=0.004, p<0.01) and systolic BP (β=0.003, p<0.05) in females. Within this same cohort, o b e s i t y w a s m o r e p r e v a l e n t i n f e m a l e s ( 4 1 . 8 % ) t h a n m a l e s ( 1 4 . 1 % ; p < 0 . 0 0 1 ) , 16% (n = 205) had an abnormal 12- lead ECG with more men than women showing a major abnormality (24% vs. 11%; OR 2.63, 95% CI 1.89–3.46). Of 99 cases (7.6%) subject to advanced cardiologic assessment, 29 (2.2%) had newly diagnosed heart disease which included hypertensive heart failure (13 women vs. 2 men, OR 4.51 95% CI 1.00–21.2), coronary artery disease (n = 3), valve disease (n = 3), dilated cardiomyopathy (n = 3) and 2 cases of acute myocarditis. Nutritional deficiencies were observed in a cohort presenting with HF at the cardiology outpatient clinic, CHBH. In women, food choices likely to negatively impact on heart health included added sugar [consumed by 75%: median daily intake (interquartile range) 16 g (10–20)], sweet drinks [54%: 310 ml (85–400)] and salted snacks [61%: 15 g (2–17)]. Corresponding figures for men were added sugar [74%: 15 g (10–15)], sweet drinks [65%: 439 ml (71–670)] and salted snacks [74%: 15 g (4–22)]. The women’s intake of calcium, vitamin C and vitamin E was only 66%, 37% and 40% of the age-specific requirement, respectively. For men, equivalent figures were 66%, 87% and 67%, respectively. Mean sodium intake was 2 372 g/day for men and 1 972 g/day for women, 470 and 294% respectively, of daily recommended intakes (DRI). In men, vitamin C intake was 71 ± 90 (79% of DRI). Similarly, in women vitamin C intake was 66 ± 80 (88% of DRI). Data collected from our HF management programme study supported the deficient intake of vitamin C in African subjects presenting with heart failure. Thus, plasma vitamin C concentrations (normal range 23 – 85 μmol/L) were markedly deficient in both standard care [6.53 (3.80, 9.22) μmol/L] and managed care [3.65 (1.75, 8.23) μmol/L] groups. In terms of clinical presentation, males were significantly older (49.9 ± 10.9 years; p<0.005) than females (37.2 ± 12.8) and at follow-up females had a significantly higher ejection fraction (34.8 ± 9.56 %) than males (29.5 ± 8.27; p<0.05) and when the groups were combined, the ejection fraction was significantly higher (32.2 ± 9.27; p<0.05) at follow-up compared to baseline (29.9 ± 8.80). We found that heart rate was significantly lower at follow-up (89.9 ± 14.6 beats/min) compared to baseline (93.4 ± 17.2; p<0.05) only in the managed care group. Furthermore, if diastolic blood pressure increased over the follow-up period, ejection fraction fell by 5.98% (p=0.009) in comparison to cases where diastolic blood pressure remained the same or fell. In addition, thiamine levels at baseline correlated negatively with systolic blood pressure (r=-0.68, p=0.04) at follow-up. Conclusion: Non-communicable heart disease and other diseases of lifestyle, such as high blood pressure, obesity and diabetes, are drastically increasing in Sub-Saharan Africa in general and in a black urban African community, such as Soweto, specifically. Soweto can clearly be described as a community in epidemiological and nutrition transition and is facing a double or even triple burden of disease. This is a community that is still being burdened by historically prevalent forms of communicable or infectious diseases juxtaposed against people who have lived their whole lives in Soweto and are increasingly suffering from newer or non-communicable diseases of lifestyle. Women seem to be especially burdened by this increase in non-communicable diseases, with a predominance of women suffering from heart disease and obesity. Certain exacerbating risk factors have been identified from the HOS in this community, namely the gender specific effects of sleep, smoking and other environmental factors on BMI and blood pressure, and the adverse effects of changing dietary patterns particularly the increased consumption of refined and processed foods, high in sugar, salt and fats and insufficient intakes of fruits and vegetables. Although there are some limitations to our HF management study, it serves as an indication that targeted, culturally sensitive care, adapted to an urban African population, might contribute to improved patient outcomes. However, prevention should always be our first priority through community-based and gender specific screening and the development and implementation of targeted prevention programs. / MT2017

Following cervical or upper thoracic level spinal cord injury (SCI), motor, sensory and autonomic systems are disrupted. One form of this autonomic dysfunction is the condition autonomic dysreflexia (AD), which is characterised by episodes of high blood pressure in response to afferent input from regions below the injury level. An animal model of autonomic dysreflexia, the T4 transected rat, was used in this thesis to gain insight into the cardiovascular and temperature components of the disorder, possible peripheral mechanisms and interventions to prevent its development. Chapter 2 of the thesis includes the charaterisation of a T4 transection rat model of spinal cord injury. This characterisation includes confirmation of decreased baseline mean arterial pressure (MAP, 71 down from 117 mmHg) and elevated heart rate (HR, 431 bpm from 366 bpm) for 6 weeks post injury (p.i.). Documentation of the development of AD found that hypertensive responses were fully developed (+20 mmHg) by 4 weeks p.i. Further, during episodes of AD at Weeks 4 and 5 p.i., tail surface temperatures decreased significantly (mid-tail, -1.7oC), indicative of extensive vasoconstriction. Comparison of vascular responses of intact and SCI animals to adrenergic agonists (phenylephrine, PHE and methoxamine, METH) following ganglionic blockade in vivo found that SCI animals experienced prolonged vasoconstriction in blood vessels above and below injury level in response to PHE but not METH. Possible mechanisms of this change included decreased neuronal reuptake of PHE (METH is not a substrate for neuronal reuptake). The presence of prolonged vasoconstriction in blood vessels throughout the body, not just regions below injury level, suggests a widespread mechanism for the change, such as the decreased basal MAP, norepinephrine levels or neural activity present following injury. Thus, it was hypothesised that increased activity from an early stage post injury may prevent the peripheral adaptation and perhaps hinder development of AD. For this, the common rehabilitation technique, treadmill training, was used. Surprisingly, rather than preventing AD, the training actually accelerated its development, producing exaggerated hypertensive responses to colorectal distension (CRD) at Weeks 3 and 4 post-injury (Week 4, Trained: +38.5 ?? 1.5 mmHg; Sedentary: 23.4 ?? 3.1mmHg). Comparison of vascular responses of both groups to PHE injection found no significant difference indicating that the enhanced responses were not a result of peripheral vascular changes. Investigation of the central morphology following SCI, made via immunohistochemical processing of the post-mortem spinal cords, found that Treadmill Trained SCI animals had elevated calcitonin gene related peptide (CGRP) immunoreactivity within lamina III/IV of lumbar segments, compared to intact cords. It is possible that this finding indicates afferent sprouting that may have accelerated the development of AD in Treadmill Trained animals. The results within this thesis highlight the importance of awareness and examination of autonomic function in SCI patients, especially those undergoing rehabilitative training.

Following cervical or upper thoracic level spinal cord injury (SCI), motor, sensory and autonomic systems are disrupted. One form of this autonomic dysfunction is the condition autonomic dysreflexia (AD), which is characterised by episodes of high blood pressure in response to afferent input from regions below the injury level. An animal model of autonomic dysreflexia, the T4 transected rat, was used in this thesis to gain insight into the cardiovascular and temperature components of the disorder, possible peripheral mechanisms and interventions to prevent its development. Chapter 2 of the thesis includes the charaterisation of a T4 transection rat model of spinal cord injury. This characterisation includes confirmation of decreased baseline mean arterial pressure (MAP, 71 down from 117 mmHg) and elevated heart rate (HR, 431 bpm from 366 bpm) for 6 weeks post injury (p.i.). Documentation of the development of AD found that hypertensive responses were fully developed (+20 mmHg) by 4 weeks p.i. Further, during episodes of AD at Weeks 4 and 5 p.i., tail surface temperatures decreased significantly (mid-tail, -1.7oC), indicative of extensive vasoconstriction. Comparison of vascular responses of intact and SCI animals to adrenergic agonists (phenylephrine, PHE and methoxamine, METH) following ganglionic blockade in vivo found that SCI animals experienced prolonged vasoconstriction in blood vessels above and below injury level in response to PHE but not METH. Possible mechanisms of this change included decreased neuronal reuptake of PHE (METH is not a substrate for neuronal reuptake). The presence of prolonged vasoconstriction in blood vessels throughout the body, not just regions below injury level, suggests a widespread mechanism for the change, such as the decreased basal MAP, norepinephrine levels or neural activity present following injury. Thus, it was hypothesised that increased activity from an early stage post injury may prevent the peripheral adaptation and perhaps hinder development of AD. For this, the common rehabilitation technique, treadmill training, was used. Surprisingly, rather than preventing AD, the training actually accelerated its development, producing exaggerated hypertensive responses to colorectal distension (CRD) at Weeks 3 and 4 post-injury (Week 4, Trained: +38.5 ?? 1.5 mmHg; Sedentary: 23.4 ?? 3.1mmHg). Comparison of vascular responses of both groups to PHE injection found no significant difference indicating that the enhanced responses were not a result of peripheral vascular changes. Investigation of the central morphology following SCI, made via immunohistochemical processing of the post-mortem spinal cords, found that Treadmill Trained SCI animals had elevated calcitonin gene related peptide (CGRP) immunoreactivity within lamina III/IV of lumbar segments, compared to intact cords. It is possible that this finding indicates afferent sprouting that may have accelerated the development of AD in Treadmill Trained animals. The results within this thesis highlight the importance of awareness and examination of autonomic function in SCI patients, especially those undergoing rehabilitative training.

Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Göteborg : Univ. , 2007. / Härtill 4 uppsatser.