Dissertation submitted to the Faculty of Health Sciences, University of Witwatersrand in fulfillment of the Master of Science in Medicine in the School of Physiology / Introduction: The changing socio-economic landscape in Africa has brought with it unique health challenges previously uncommon in people of African ancestry. Noncommunicable diseases such as coronary artery disease and stroke have emerged as pressing public health concern highlighting the need to find more on-target diagnostic tools as well as therapeutic interventions. Although ambulatory blood pressure (AMBP) has in many studies conducted in the western world proved to be an independent predictor of carotid intima-media thickness (C-IMT), such results cannot outright be imputed to people of African ancestry living in Africa. That is because people of African ancestry living in Africa are not only of a different ethnicity but are still in the early phases of an epidemiological transition while people in the western countries who are mostly Caucasians, are believed to be in the middle to late phases of an epidemiological transition. Methods: The relationship between the intima-media thickness of the common carotid artery (SonoCalcTM IMT version 3.4) and AMBP (Space labs model 90207) was determined in 320 randomly selected participants of African descent living in an urban developing community in South Africa. Relationships were determined after adjustment for (clinic blood pressure) BPc, age, gender, alcohol and tobacco use, the presence or absence of diabetes mellitus or inappropriate blood glucose control measured by glycated hemoglobin (ghb), antihypertensive therapy and menopausal status. III Results: Mean age for the study population was 43.7± 16.0 years. Both BPc and AMBP parameters were strongly associated with C-IMT (p<0.001) in univariate analysis. In multivariate analysis with BPc. and AMBP entered into separate models and after adjusting for cofounders, BPc. and AMBP maintained significant associations with CIMT. [BPc (partial r=0.0648, p< 0.1612), systolic blood pressure 24 (SBP24) (partial r= 0.236, p< 0.001), systolic blood pressure day (SBPd) (partial r= 0.302, p<0.05), systolic blood pressure night (SBPn) (partial r= 0.0983, p<0.05)]. When adjustments were made with BPc. and SBP24 entered into the same model, BPc lost its association with C-IMT, [SBP24 (partial r=0.236, p<0.001) SBPd (partial r=0.149, p<0.05), SBPn (partial r=0.172, p<0.05)]. Importantly the relationship between SBP24 and C-IMT persisted independent of body mass index (BMI), BPc and age. SBP24 had the highest significant association with C-IMT. Conclusion: SBP24 independently predicts C-IMT even in a model that includes conventional systolic blood pressure (SBPc) leading to the conclusion that AMBP is a more effective tool at diagnosing C-IMT alterations while BPcdoes not have an independent relationship C-IMT.

Motivation - Brain-derived neurotrophic factor (BDNF) is a protein complex, synthesised and secreted mainly by the central nervous system and is involved in neuronal maintenance. Research suggests that BDNF is implicated in various neurological and psychiatric diseases, while recent evidence suggests a role for the neurotrophin on the periphery as well. Indeed, the specific functional role of BDNF and its action mechanism in the cardiovascular system, especially in that of Africans, is yet to be determined. The cardiovascular health profile of black South Africans is a major concern as research has shown that this group suffers from an array of cardiovascular risk factors that may result in organ damage. Sub-clinical atherosclerosis or structural endothelial dysfunction contributes to ever-increasing morbidity and mortality in the world. However, no studies regarding the associations between BDNF and structural vascular disease have been undertaken relating to black African participants. Objectives - The objective of this study was to determine whether BDNF is associated with changes in ambulatory blood pressure (BP) and whether a relationship between BDNF and structural endothelial dysfunction exists in black African male and female participants, determined by cross sectional wall area (CSWA) and albumin:creatinine ratio (ACR). Methodology - The study included 172 black African teachers (82 males and 90 females) who were employed by the Kenneth Kaunda Education district of the North-West Province, South Africa. Ambulatory blood pressure recordings were obtained with the use of a Meditech CE120 CardioTens ® apparatus. Blood pressure readings were measured at 30 min intervals during the day and 60 min intervals during the night. Anthropometric measurements were performed in triplicate by registered level II anthropometrists according to standardised procedures. A high-resolution ultrasound scan with carotid intima-media thickness (CIMT) images from at least two optimal angles of the left and right common carotid artery were obtained using a SonoSite Micromaxx ultrasound system. The lumen diameter between the near and far wall of the lumen-intima interface and the averages of both the left and right common carotid arteries were calculated. Subsequently, the carotid cross-sectional wall area (CSWA) was calculated. Participants, who fasted overnight, provided eight-hour blood and urine samples to determine serum BDNF and metabolic markers, for example, hyperglycaemia (HbA1c) and gamma glutamyl transferase (GGT). Urinary albumin and creatinine levels were determined by means of a turbidimetric method with the use of a Unicel DXC 800 analyser from Beckman and Coulter (Germany) and expressed as a ratio between albumin and creatinine (ACR). BDNF median split x Gender interaction effects for structural ED justified stratification of BDNF into low and high (≤ / > 1.37 ng/ml) gender groups. Results and Conclusion - On average, male participants were overweight (BMI 25-30kg/m2) and abused more alcohol.21 African men revealed a vulnerable cardiometabolic profile with values exceeding cut–points (European Society of Hypertension). These men demonstrated increased acute and chronic glucose (HbA1c) levels indicating a pre-diabetic state; as well as a disturbed lipid profile with lower HdL and increased triglycerides. Overall BDNF levels were lower than reference ranges (6.97 – 42.6 ng/ml). The men revealed mean lower BDNF levels, ambulatory BP values exceeding guideline cut-points (ambulatory SBP > 130mmHg; DBP > 80mmHg) as well as a hypertensive state compared to their female counterparts. Pertaining to structural endothelial dysfunction, the mean ACR value in men exceeded normal laboratory values (< 3.5mg/mmol). The African women displayed an obese state with low grade inflammation (CRP, 12.27 ± 11.67mg/l). A single two-way ANCOVA interaction on main effects (BDNF median split x Gender) demonstrated significant interaction for CIMTf [F (1,164); 3.99, p=0.05] and cholesterol [F (1,164); 4.12, p=0.05]. Therefore, a median split approach was followed which stratified gender groups into lower (≤ 1.37 ng/ml) and higher BDNF levels (>1.37 ng/ml). The low BDNF men revealed higher cholesterol than the high BDNF group, independent of BMI and age. Only the low BDNF women indicated significantly higher values for structural vascular markers (p< 0.05) than the high BDNF female group. In conclusion, we accept our hypothesis, as hypertrophic remodelling of the carotid artery was associated with lower BDNF levels. This may imply attenuated or possibly down-regulated BDNF levels acting as a compensatory mechanism for the mean higher BP levels. In women, metabolic risk and hypertrophic remodelling were evident within higher circulating levels of BDNF, underpinning different underlying mechanisms for impaired neurotrophin health in men and women. Novel findings of BDNF revealed the impact of central neural regulation on the circulatory system, which may contribute to cardiometabolic risk in Africans. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014

Motivation - Brain-derived neurotrophic factor (BDNF) is a protein complex, synthesised and secreted mainly by the central nervous system and is involved in neuronal maintenance. Research suggests that BDNF is implicated in various neurological and psychiatric diseases, while recent evidence suggests a role for the neurotrophin on the periphery as well. Indeed, the specific functional role of BDNF and its action mechanism in the cardiovascular system, especially in that of Africans, is yet to be determined. The cardiovascular health profile of black South Africans is a major concern as research has shown that this group suffers from an array of cardiovascular risk factors that may result in organ damage. Sub-clinical atherosclerosis or structural endothelial dysfunction contributes to ever-increasing morbidity and mortality in the world. However, no studies regarding the associations between BDNF and structural vascular disease have been undertaken relating to black African participants. Objectives - The objective of this study was to determine whether BDNF is associated with changes in ambulatory blood pressure (BP) and whether a relationship between BDNF and structural endothelial dysfunction exists in black African male and female participants, determined by cross sectional wall area (CSWA) and albumin:creatinine ratio (ACR). Methodology - The study included 172 black African teachers (82 males and 90 females) who were employed by the Kenneth Kaunda Education district of the North-West Province, South Africa. Ambulatory blood pressure recordings were obtained with the use of a Meditech CE120 CardioTens ® apparatus. Blood pressure readings were measured at 30 min intervals during the day and 60 min intervals during the night. Anthropometric measurements were performed in triplicate by registered level II anthropometrists according to standardised procedures. A high-resolution ultrasound scan with carotid intima-media thickness (CIMT) images from at least two optimal angles of the left and right common carotid artery were obtained using a SonoSite Micromaxx ultrasound system. The lumen diameter between the near and far wall of the lumen-intima interface and the averages of both the left and right common carotid arteries were calculated. Subsequently, the carotid cross-sectional wall area (CSWA) was calculated. Participants, who fasted overnight, provided eight-hour blood and urine samples to determine serum BDNF and metabolic markers, for example, hyperglycaemia (HbA1c) and gamma glutamyl transferase (GGT). Urinary albumin and creatinine levels were determined by means of a turbidimetric method with the use of a Unicel DXC 800 analyser from Beckman and Coulter (Germany) and expressed as a ratio between albumin and creatinine (ACR). BDNF median split x Gender interaction effects for structural ED justified stratification of BDNF into low and high (≤ / > 1.37 ng/ml) gender groups. Results and Conclusion - On average, male participants were overweight (BMI 25-30kg/m2) and abused more alcohol.21 African men revealed a vulnerable cardiometabolic profile with values exceeding cut–points (European Society of Hypertension). These men demonstrated increased acute and chronic glucose (HbA1c) levels indicating a pre-diabetic state; as well as a disturbed lipid profile with lower HdL and increased triglycerides. Overall BDNF levels were lower than reference ranges (6.97 – 42.6 ng/ml). The men revealed mean lower BDNF levels, ambulatory BP values exceeding guideline cut-points (ambulatory SBP > 130mmHg; DBP > 80mmHg) as well as a hypertensive state compared to their female counterparts. Pertaining to structural endothelial dysfunction, the mean ACR value in men exceeded normal laboratory values (< 3.5mg/mmol). The African women displayed an obese state with low grade inflammation (CRP, 12.27 ± 11.67mg/l). A single two-way ANCOVA interaction on main effects (BDNF median split x Gender) demonstrated significant interaction for CIMTf [F (1,164); 3.99, p=0.05] and cholesterol [F (1,164); 4.12, p=0.05]. Therefore, a median split approach was followed which stratified gender groups into lower (≤ 1.37 ng/ml) and higher BDNF levels (>1.37 ng/ml). The low BDNF men revealed higher cholesterol than the high BDNF group, independent of BMI and age. Only the low BDNF women indicated significantly higher values for structural vascular markers (p< 0.05) than the high BDNF female group. In conclusion, we accept our hypothesis, as hypertrophic remodelling of the carotid artery was associated with lower BDNF levels. This may imply attenuated or possibly down-regulated BDNF levels acting as a compensatory mechanism for the mean higher BP levels. In women, metabolic risk and hypertrophic remodelling were evident within higher circulating levels of BDNF, underpinning different underlying mechanisms for impaired neurotrophin health in men and women. Novel findings of BDNF revealed the impact of central neural regulation on the circulatory system, which may contribute to cardiometabolic risk in Africans. / MSc (Physiology), North-West University, Potchefstroom Campus, 2014

Stroke is the 2nd leading cause of death in the UK and worldwide. 150,000 people have a stroke each year in the UK (ischaemic stroke being the most common) and a significant proportion of NHS resources go towards the treatment of these individuals (~£2.8 billion). Twin and family history studies have shown that having affected relatives makes you between 30 and 76% more likely to suffer a stroke, suggesting that there is a genetic component to the disease. So far, no genes have been convincingly associated with stroke. Intermediate traits may be useful tools for identifying genetic factors in complex disease. For stroke, two commonly used intermediate traits are carotid intima-media thickness (CIMT) and white matter hyperintensities (WMHs), which both show high heritabilities. These traits have both been studied widely for associations with many candidate gene polymorphisms. In this thesis I systematically reviewed the literature for all genetic association studies of these two traits. Where particular associations have been studied in large numbers I meta-analysed the available data, developing novel methods for meta-analysis of genetic association data. I found there was substantial heterogeneity and small study bias in the literature and most polymorphisms have still been studied in too small numbers to make accurate conclusions. Apolipoprotein E (APOE) ε is the only polymorphism which shows a consistent association with CIMT, even when only the largest studies are analysed (MD 8μm (95% CI 6 to 11) between E4 and E3, and E3 and E2). No polymorphism has shown a convincing association with WMHs and interestingly APOE appears unlikely to be associated with this trait. This is consistent with previous work that shows that APOE is associated with large artery but not small artery stroke. Taking this hypothesis I attempted to investigate the association of APOE comparing patients who have had a large artery stroke with those who have had a small artery stroke in the Edinburgh Stroke Study cohort. However, genotyping of this polymorphism failed and I present investigatory analyses of problems from the genotyping laboratory.

Made available in DSpace on 2017-07-10T14:17:05Z (GMT). No. of bitstreams: 1 Jeferson Toregeani.pdf: 4855703 bytes, checksum: 73138fe4322e7ec033e3fe59b166567e (MD5) Previous issue date: 2013-01-05 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Atherosclerotic disease, one of the leading causes of morbidity and mortality in the world, expresses inflammatory markers that can be evaluated in the laboratory or by Doppler ultrasound, that can detect common carotid artery intima-media thickening (IMT), which is a precursor morphological change of atherosclerotic disease. The atherosclerotic disease risk factors most relevant are diabetes, hypertension, hypercholesterolemia and smoking. Periodontal disease, which has a high prevalence worldwide, has been increasingly correlated to atherosclerotic disease, where the bacterial activity and the inflammatory process in the periodontal tissues seem to aggravate atherosclerosis. The objectives of this research were to evaluate the treatment of periodontal disease and the influence of this treatment on the variation of thickness of the common carotid artery miointimal complex and the variations of laboratory parameters. Forty-four volunteers patients were divided into 2 groups, healthy patients 23 (GI) and 21 patients with moderate to severe periodontitis (GII). All patients underwent clinical and nutritional assessment. Also periodontal clinical parameters were evaluated: plaque index (PI), gingival index (IS), probing depth (PS), clinical attachment level (NI) and bleeding on probing (SS). The patients were submitted to assess carotid intima-media thickness and to laboratory evaluation by collecting of counting blood cells, creatinine, total cholesterol and fractions, triglycerides, fibrinogen, C-reactive protein, homocysteine, erythrocyte sedimentation rate, fasting blood glucose and glycated hemoglobin. All patients received the basic periodontal treatment and only group II were submitted to mechanical control with scaling and root planning and coronary sinus polishing. Data were obtained in the pre-treatment, with 6 months and after 12 months from the beginning of the study. The results showed a significant improvement in periodontal clinical parameters in both groups (p < 0,05), more evident between the first and second evaluations and greater in GII (p < 0,05). There were a decrease of triglycerides and low-density lipoprotein in GI and increase in their levels in GII (p < 0,05), increased Fibrinogen along the GI study (p < 0,05) and decrease in glycated hemoglobin concentration in both groups. The average counts of erythrocytes, hematocrit, hemoglobin and platelets were lower in the last reviews. The variation of the amount of platelets was significantly higher in the first phase of the GI (p < 0,05). There was a decrease IMT in 2 groups in the first phase, and fall of systolic and diastolic velocity, pulsatility and resistivity index in the second phase of both groups (p < 0,05). Thus, based on the results, treatments imposed were effective in improving the periodontal clinical parameters of patients with periodontitis and toothbrushing associated with dental floss and the motivation of oral hygiene was also effective in the improvement of clinical periodontal parameters even in relatively healthy patients. The improvement of periodontal parameters promoted significant effect on reduction of IMT in both groups, in the initial period of 6 months. At the end of the study (360 days), there was no significant effect of changes in periodontal clinical parameters in IMT variations in both groups I and II / A doença aterosclerótica, que é uma das principais causas de morbimortalidade no mundo, expressa marcadores inflamatórios que podem ser avaliados laboratorialmente ou por exames como a ultrassonografia Doppler, o qual pode detectar o espessamento miointimal da artéria carótida comum (IMT), que é uma alteração morfológica precursora da doença aterosclerótica. Os fatores de risco da doença aterosclerótica mais relevantes são o diabetes, a hipertensão arterial, a hipercolesterolemia e o tabagismo. A doença periodontal, que tem elevada prevalência no mundo, vem sendo cada vez mais correlacionada à doença aterosclerótica, onde a atividade bacteriana e o processo inflamatório no periodonto parecem agravar o risco da aterosclerose. Os objetivos desta pesquisa foram avaliar o efeito do tratamento da doença periodontal na variação da espessura do complexo miointimal da artéria carótida comum e dos parâmetros laboratoriais de marcadores inflamatórios. Quarenta e quatro pacientes voluntários foram distribuídos em 2 grupos, sendo 23 pacientes periodontalmente sadios (GI) e 21 pacientes com periodontite moderada a grave (GII). Todos os pacientes foram submetidos à avaliação clínica e nutricional. Também foram avaliados os parâmetros clínicos periodontais de índice de placa, índice de sangramento, profundidade de sondagem, nível de inserção clínica e sangramento à sondagem. Foram submetidos à avaliação da espessura do complexo miointimal e à avaliação laboratorial através da coleta de hemograma, creatinina, colesterol total e frações (HDL, LDL, VLDL), triglicerídeos (TGs), fibrinogênio (FB), proteína C reativa, velocidade de hemossedimentação, homocisteína, hemoglobina glicada (HBGLI) e glicemia de jejum. Todos os pacientes receberam o tratamento periodontal básico e somente os pacientes do grupo GII foram submetidos ao controle mecânico com a raspagem e alisamento radicular e o polimento coronário. Os dados foram obtidos no pré-tratamento, com 6 meses e após 12 meses do início do estudo. Os resultados demonstraram uma significativa melhora nos parâmetros clínicos periodontais em ambos os grupos (p<0,05), mais evidentes entre a primeira e a segunda avaliações e maiores no GII (p<0,05). Não ocorreu alteração significativa dos marcadores inflamatórios. Houve queda das concentrações de TGs e LDLs no GI e aumento no GII (p<0,05), aumento do FB ao longo do estudo no GI (p<0,05) e diminuição da concentração de HBGLI em ambos os grupos. As médias das quantidades dos eritrócitos, hematócrito, hemoglobina e das plaquetas foram menores nas últimas avaliações. A variação da quantidade de plaquetas foi significativamente maior na primeira fase do GI (p<0,05). Nas avaliações ultrassonográficas, houve diminuição do IMT nos 2 grupos na primeira fase, e queda das velocidades sistólica e diastólica e índices de pulsatilidade e resistividade na segunda fase de ambos os grupos (p<0,05). Com base nos resultados, os tratamentos instituídos foram efetivos na melhoria dos parâmetros clínicos periodontais dos pacientes portadores de periodontite e a escovação associada ao fio dental e a motivação da higiene oral também foi efetiva na melhora dos parâmetros clínicos periodontais mesmo em pacientes sadios. A melhora dos parâmetros periodontais promoveu efeito significativo na diminuição do IMT em ambos os grupos, no período inicial de 6 meses. Ao final do estudo, não houve efeito significativo das variações dos parâmetros clínicos periodontais nas variações do IMT em ambos os grupo I e II

Marital quality is linked to health benefits for men and women. Although women have less risk factors than men for cardiovascular disease prior to menopause, their risk increases substantially after menopause. The purpose of this study was to assess the impact of marital quality and vasomotor symptoms on cardiovascular risk factors including C-reactive protein (CRP) and carotid intima-media thickness (cIMT) in women before, during, and after the menopausal transition. The final sample consisted of 92 married women between the ages of 40 and 60 years. Hypotheses were tested using hierarchical regression and general linear modeling. Results suggest that greater marital quality reduces the negative effect of a lower level of vasomotor symptoms on cIMT but not CRP. Contrary to hypotheses, marital quality did not predict CRP or cIMT and vasomotor symptoms were not correlated with CRP or cIMT. While analyses did not support an interaction between menopausal status and lower marital quality on vasomotor symptoms or CRP, there was limited support for an interaction between menopausal status and lower marital quality on cIMT (p = .057) suggesting that for postmenopausal women higher marital quality is related to lower levels of cIMT. Overall, findings suggest that it is important to consider the impact of psychosocial aspects of a middle aged woman's life (i.e., marital quality) in conjunction with biological stressors when assessing cardiovascular risks in women during the menopausal transition.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Paraoxonase (PON) 1 is a high density lipoprotein (HDL) - bound antioxidant enzyme that was originally discovered and better known for its role in protecting against organophosphate (OP) - induced neurotoxicity. In the past two decades, the enzyme has gained prominence as a protective agent against atherosclerosis on account of increasing evidence that it accounts for many of the anti-atherogenic roles attributed to HDL. PON1 is a polymorphic enzyme displaying a high variability in human populations which is associated with a considerable degree of inter-individual differences in enzyme phenotype that translates to differential risk for OP toxicity and cardiovascular disease (CVD). In a series of studies and analyses, this thesis describes investigations regarding the possible involvement of PON 1 in the risk for CVD in a mixed ancestry population from Bellville, Western Cape, South Africa. This was done by evaluating the distribution of PON1 coding region polymorphisms (Q192R and L55M) and their influence on PON1 phenotype as well as the latter‟s relation to CVD risk factors (oxidative stress, inflammation and atherogenic dyslipidemia) and possible involvement in early CVD assessed by measuring intima media thickness of the carotid artery (CIMT). Since PON1 is increasingly measured in samples that have been stored for varied periods of time, the main study was preceded by a pilot study evaluating the influence of baseline conditions on the stability of PON 1 activity and antioxidant status in human sera stored for up to 12 months. It was shown that baseline glycemic status enhances the degradation of antioxidants in stored samples with indications of also accelerating the decline of PON1 levels and activity. Thus baseline glycemic status should be a factor to be considered in analyses involving stored samples. The Q192R polymorphism was found to be the functional variant influencing both concentration and activity of plasma PON1. Contrary to expectation, the L55M was nonfunctional, possibly due to its unusual distribution in this population where the 55M (83%) allele overwhelmingly predominated over the L55 allele. The R allele was the more frequent (60.4%) of the 192 polymorphism. The R allele has previously been associated with less efficient breakdown of lipid peroxides and a subsequent higher risk for atherosclerotic heart disease while the 55M is recognized as a “low concentration/activity” variant. Thus the predominant PON1 genotype distribution in this population constitutes a risk profile that may relate to increased risk for CVD. The risk for CVD was confirmed to be very high in this population indicated by high prevalence of the metabolic syndrome (48%) and its key components (and CVD risk factors) diabetes (28%), obesity (53%) and high blood pressure (57%). Paraoxonase activity associated inversely with indices of inflammation (high sensitive C- reactive protein [hs-CRP] and leptin) and oxidative stress (oxidized low density lipoprotein [LDL]) and directly with adiponectin and markers of systemic antioxidant status. These findings suggest that low paraoxonase-I activity contributes to increased cardiovascular risk possibly via involvement in early atherogenesis. However, only a modest inverse relation was observed between PON1 phenotype and CIMT thus suggesting that PON1 may not play a major role in early atherosclerosis. Taken together, the findings presented in this thesis demonstrate the presence of a risk PON1 genotypic profile and indication that the enzyme may play a role in the enhanced CVD risk in this population possibly via interactions with inflammation and oxidative stress. However, conclusive evidence for the involvement of PON1 in early CVD was not demonstrated indicating a need to explore the participation of PON1 in later stages of CVD. / AFRIKAANSE OPSOMMING: Paraoksonase (PON) 1 is 'n antioksidant ensiem wat aan HDL gebind is. Oorspronklik is dit ontdek en het bekend geword as 'n beskermer teen organofosfaat (OF)-gedrewe neurotoksisiteit. In die afgelope twee dekades het die ensiem belangrik geraak as 'n beskermer teen arterosklerose as gevolg van toenemende bewyse dat dit 'n belangrike rol speel in die beskermende effekte van HDL teen arterosklerose. PON1 is 'n polimorfiese ensiem wat groot variasie toon in verskillende populasies. Daar is ook inter-individuele verskille in ensiem fenotipe wat uitloop op 'n differensiele risiko vir OF toksisiteit en kardiovaskulêre hartsiekte (KVH). Hierdie tesis beskryf 'n reeks analises en ondersoeke betreffende die moontlike betrokkenheid van PON1 in die risiko vir KVH in 'n gemengdeafkoms populasie van Bellville, Wes-Kaap, Suid Afrika. Dit was gedoen deur die evaluering van die verspreiding van die PON-1 koderende omgewing polimorfismes (Q192R en L55M), hulle invloed op PON1 fenotipe en laasgenoemde se verhouding tot KVH risikofaktore (oksidatiewe stress, inflammasie en arterogeniese dislipedimie) en moontlike voorkoms in vroeë kardiovaskulêre siekte bepaal deur die meting van die intima media dikte van die karotied slagaar. Aangesien PON1 al hoe meer gemeet word in monsters wat vir verskeie tydperke gestoor word, was die hoofstudie voorafgegaan deur 'n loodsstudie wat die invloed van basislyn kondisies op die stabiliteit van PON1 aktiwiteit en antioksidant status in menslike sera wat vir tot 12 maande gestoor was, bepaal het. Dis is duidelik aangetoon dat basislyn glisemiese status die afbraak van antioksidante in gestoorde monsters verhoog het, asook aanduidings van die afname van PON1 vlakke en aktiwitetit. Basislyn glisemiese status behoort dus ook as 'n faktor ingereken te word in analises van gestoorde monsters. Die Q192R polimorfisme is aangetoon om 'n funksionele variant te wees wat beide die konsentrasie asook die aktiwiteit van PON1 beïnvloed het. Anders as wat verwag is, was die L55M polimorfisme nie-funksioneel, moontlik as gevolg van sy ongewone distribusie in hiedie populasie waar die voorkoms van die 55M (83%) alleel die L55 alleel oorheers het. Die R alleel was die mees algemene (60.4%) van die 192 polimorfisme. Die R alleel is voorheen reeds geassosieer met minder effektiewe afbraak van lipied peroksides en gevolglike hoër voorkoms van arteriosklerotiese hartsiekte, terwyl die 55M erken word as 'n “lae konsentrasie/aktiwiteit” variant. Die oorheersende PON1 genotipe distribusie in hierdie populasie behels dus 'n risikoprofiel wat betrekkking mag hê op verhoogde KVH. Die risiko vir KVH was bevestig om baie hoog te wees in hierdie populasie, soos aangedui deur 'n hoë voorkoms van die metaboliese sindroom (48%) en die sleutelkomponente daarvan (insluitend KVH risikofaktore), diabetes (28%), obesiteit (53%) en hipertensie (57%). Paraoksinase aktiwiteit was omgekeerd geassosieer met indekse van inflammasie (hoë C-reaktiewe proteïen [hs-CRP] en leptien) en oksidatiewe stres (geoksideerde lae digtheid lipoproteïen [LDL], en direk geassosieer met adiponektien en merkers van sistemiese antioksidantstatus. Hierdie bevindings mag aandui dat lae paraoksonase-1 aktiwiteit bydra tot verhoogde kardiovaskulêre risiko, moontlik via betrokkenheid in vroeë arterogenese. Slegs 'n klein omgekeerde verhouding is egter waargeneem tussen die PON1 fenotipe en karotied intima media dikte, wat mag aandui dat PON1 nie 'n beduidende rol speel in vroeë arterosklerose nie. In geheel, die bevindinge voorgedra in hierdie tesis demonstreer die voorkoms van 'n risiko PON1 genotipiese profiel wat 'n aanduiding mag wees dat die ensiem 'n rol mag speel in die verhoogde KVH risiko in hierdie populasie, moontlik deur interaksies met inflammasie en oksidatiewe stress. Afdoende bewys van die betrokkenheid van PON1 in vroeë KVH was egter nie gedemonstreer nie, wat die nodigheid aandui om die deelname van PON1 in latere stadiums van KVH te ondersoek.

BACKGROUND: There are many studies that have documented the increasing impact of stress and anxiety on an individual’s health and well-being. Everyone handles stress and anxiety differently with these conditions having varying physiological effects. To better recognize whether or not a person may need help in tackling these conditions, scholars have developed reliable validated instruments. Two prominent instruments that effectively assess stress and anxiety levels are the Perceived Stress (PSS) and Generalized Anxiety Disorder (GAD-7) scales. Furthermore, the literature has shed light onto the importance of the carotid intima-media thickness (c-IMT) measurement as a tool in evaluating the risk of cardiovascular disease. After all, heart disease has been reported as being the number one killer of Americans in recent years. The specific aims of this study were to determine if there was an association between perceived stress / generalized anxiety and c-IMT (static association), and also if higher levels of perceived stress / generalized anxiety result in a significant increase in c-IMT (changes over time). METHODS: Data was collected on about 700 participants comprised of employees from Emory University in Atlanta, Georgia. At baseline, six, twelve, and twenty-four months, the largest number of participants had completed and calculated their scores on the PSS and GAD-7 scales. At these same time points, participants had their IMT measured and recorded for the left and right common carotid arteries by a trained sonographer of the Emory Predictive Health Institute. Due to incomplete measurements and scores, only 228 participants were included for statistical analyses. This was still considered a suitable sample size given that this study only involved four measurement time points. Various statistical models were fitted for the data. All variables in the models were treated as categorical except for time which was continuous. Four separate models were built that included the variables perceived stress, age group, gender and time. In a similar manner, four models were built that included the variables generalized anxiety, age group, gender and time. AIC values, -2 log-likelihoods, partial correlations, p-values, and other relevant information were reported for these models. All statistical analyses were performed using the Statistical Analysis System (SAS), version 9.2. RESULTS: The mean c-IMT measurements for the Emory participants were higher than established normal ranges. A strong correlation existed between the PSS and GAD-7 two-year averages when treated as continuous variables (.7316, p <.0001). Likewise, a meaningful relationship existed when both scales were categorical (.4154, p < .0001). The analyses revealed that the left and right mean IMT measurements for the common carotid arteries modeled a linear trend with an unstructured covariance the best. The partial correlations for perceived stress and generalized anxiety revealed weak, but significant positive associations with the mean c-IMT measurement. Although the slope coefficients were not significant for perceived stress, an increase from below average to above average perceived stress level still resulted in an increase in mean c-IMT measurement. Conversely, mild generalized anxiety was found to be statistically significant in the regression model of the left mean c-IMT. This was after controlling for age group and gender. The p-value for mild generalized anxiety was 0.0258, and the slope coefficient was 0.04856. IMT measurements were consistently higher for males on both sides compared to females. They were also higher on the left side compared to the right. CONCLUSIONS: Failure to control anxiety could lead to c-IMT soaring to dangerous levels resulting in a myocardial infarction and/or cerebrovascular accident. Individuals should engage in healthy lifestyle practices that lower stress and anxiety levels to decrease the chances of cardiovascular disease. Based on this study’s findings, a person can certainly use their c-IMT readings, as well as their perceived stress and generalized anxiety scores, as indicators that lifestyle modifications may be needed.

abstract: Cardiovascular disease (CVD) is the leading cause of mortality yet largely preventable, but the key to prevention is to identify at-risk individuals before adverse events. For predicting individual CVD risk, carotid intima-media thickness (CIMT), a noninvasive ultrasound method, has proven to be valuable, offering several advantages over CT coronary artery calcium score. However, each CIMT examination includes several ultrasound videos, and interpreting each of these CIMT videos involves three operations: (1) select three enddiastolic ultrasound frames (EUF) in the video, (2) localize a region of interest (ROI) in each selected frame, and (3) trace the lumen-intima interface and the media-adventitia interface in each ROI to measure CIMT. These operations are tedious, laborious, and time consuming, a serious limitation that hinders the widespread utilization of CIMT in clinical practice. To overcome this limitation, this paper presents a new system to automate CIMT video interpretation. Our extensive experiments demonstrate that the suggested system significantly outperforms the state-of-the-art methods. The superior performance is attributable to our unified framework based on convolutional neural networks (CNNs) coupled with our informative image representation and effective post-processing of the CNN outputs, which are uniquely designed for each of the above three operations. / Dissertation/Thesis / Masters Thesis Computer Science 2016

Introduction: Atherosclerosis remains asymptomatic until it progresses to cause flow-limiting disease. Identifying patients at high risk in the early stages of the atherosclerotic process may allow modification of cardiovascular risk by effective preventive strategies. Various non-invasive tests have been studied and have shown promising results in predicting future adverse cardiovascular events. The objective of this study was to establish the carotid ultrasonographic markers that best correlate with angiographic coronary artery disease (CAD) and the relationship between left ventricular geometry, carotid atherosclerosis, biomarkers and CAD in patients with unobstructed coronary arteries, chronic stable angina (CSA) and acute coronary syndromes (ACS). Methods: Carotid ultrasound examination, echocardiography and serum biomarker estimation were performed in consecutive patients who underwent coronary angiography for evaluation of stable or acute chest pain. Results: A total of 146 subjects were recruited into the study with a mean age of 56.9 ± 10.6 (range 29 to 85) years; 120 were men (82%) and 26 (18%) women. Twenty-one percent of the study population had unobstruced coronaries, 42% had stable CAD and 37% had presented with ACS. There was no significant difference in the carotid intima media thickness (CIMT) measurements between the three groups. CIMT correlated with abnormal left ventricular geometry but not with the presence or severity of CAD. The presence of carotid plaque and plaque score correlated with obstructive CAD, but was not significantly different between stable CAD and ACS patients. There was a trend towards more echogenic plaque in the stable CAD group. The composite score of IMT and plaque was positively correlated with the presence and severity of CAD. The averaged myocardial peak systolic and early diastolic velocities were significantly lower in those with obstructive CAD. CRP and osteopontin levels were higher in the ACS patients. Conclusions: Carotid plaque and not CIMT was associated with angiographic coronary artery disease. Averaged systolic and early diastolic myocardial velocities by tissue doppler imaging correlated with obstructive CAD. Novel serum biomarkers are promising and further studies are needed.