The development of a first myocardial infarction is associated with a large number of contributing factors. Age, male sex, hypertension, smoking, diabetes, body mass index and hypercholesterolemia are considered as established risk factors. The primary aim of the present dissertation was to evaluate whether specific biomarkers could improve the prediction of subjects at risk for a first myocardial infarction when considered in addition to established cardiovascular risk factors. The biomarkers investigated include: tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), thrombomodulin (TM), von Willebrand factor (VWF), dehydroepiandrosterone sulfate (DHEAS), lipoprotein (a) (Lp(a)), leptin, apolipoproptein A1 (ApoA1), proinsulin, homocysteine and homozygosity for the 5,10- methylenetetrahydrofolate reductase (MTHFR) C>T genotype. A secondary objective was to determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared to baseline. The study population consisted of 36 405 subjects screened and included in the Västerbotten Intervention Program and the Northern Sweden MONICA cohorts between January 1, 1985 and September 30, 1994. A nested incident case-referent study design was used. Seventy eight cases with a first myocardial infarction were identified, and from the same cohort twice as many sex and age matched referents were randomly selected. Moreover, a follow-up health survey (average 8.5 years between surveys) was conducted with 50 cases and 56 matched referents. High plasma levels of tPA and PAI-1 mass concentration, VWF, proinsulin, leptin and Lp(a) and low plasma levels of ApoA1 were associated with subsequent development of a first myocardial infarction in univariate conditional logistic regression analysis. For PAI-1 and tPA, this relation was found in both men and women. For tPA, but not for PAI-1 and VWF, this association was independent of established risk factors. In women, high plasma concentrations of TM were associated with significant increases in risk of a first myocardial infarction. No predictive values of DHEAS, homocysteine or for the point mutation C677>T in the gene for MTHFR was found regarding the risk of a first myocardial infarction. The summarised importance of haemostatic and metabolic variables (proinsulin, lipids including Lp(a) and leptin) in predicting first myocardial infarction in men, as well as possible interactions among these variables, were studied. High tPA and Lp(a) and low ApoA1 remained significant risk markers in multivariate analysis independent of established risk factors. There were non-significant synergic interactions between high Lp(a) and leptin and tPA respectively, and between high Lp(a) and low ApoA1. In the follow-up study plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not at baseline was associated with first myocardial infarction but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline and follow-up. In conclusion, the present results support the hypothesis that biomarkers, in addition to the traditional cardiovascular risk factors, carry predictive information on the risk of developing a first myocardial infarction.

Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions. The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated. The first study used a cross-sectional design and included 72 men and women  recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten  Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels. In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.

Being able to effectively match energy intake to energy expenditure (EE) is an important aspect in preventing weight re-gain in the post-obese. Although it is generally agreed upon that resting EE decreases concomitantly with weight loss, there is no set standard comparing the deviations with differing weight loss protocols and additionally, controversy remains as to whether this decrease is greater than can predicted. In order to address these issues 2977 subjects were analyzed using a systematic review and the differences of both the protocol and length of various interventions in addition to sex were compared. Next, data was selected from this systematic review and 815 subjects were analyzed for weight loss-induced changes in resting EE, FM and FFM. Another subgroup of studies (n = 1450) was analyzed and compared against the Harris-Benedict prediction equation to determine whether the changes in resting EE were greater than what was expected. Finally, in order to determine which factors may be involved in regulating changes in resting EE during weight loss, a secondary analysis was performed on 28 post-menopausal women (age= 50.4 ± 2.0 yrs; BMI= 32.4 ± 5.2 kg/m²) who were submitted to a 6-month caloric restriction. Body composition (DXA), resting EE (indirect calorimetry), physical activity EE (PAEE) and total EE (TEE) (doubly-labelled water) were measured before and after the 6 month weight loss. Blood samples were collected before and after to measure leptin and peptide YY. The results indicate that there was indeed a depression in resting EE during weight loss regardless of the type of intervention utilized. Furthermore, these findings suggest that the changes could not fully be explained by changes of FM and FFM alone and that leptin may be an important contributor to the changes of resting EE during weight loss.

Being able to effectively match energy intake to energy expenditure (EE) is an important aspect in preventing weight re-gain in the post-obese. Although it is generally agreed upon that resting EE decreases concomitantly with weight loss, there is no set standard comparing the deviations with differing weight loss protocols and additionally, controversy remains as to whether this decrease is greater than can predicted. In order to address these issues 2977 subjects were analyzed using a systematic review and the differences of both the protocol and length of various interventions in addition to sex were compared. Next, data was selected from this systematic review and 815 subjects were analyzed for weight loss-induced changes in resting EE, FM and FFM. Another subgroup of studies (n = 1450) was analyzed and compared against the Harris-Benedict prediction equation to determine whether the changes in resting EE were greater than what was expected. Finally, in order to determine which factors may be involved in regulating changes in resting EE during weight loss, a secondary analysis was performed on 28 post-menopausal women (age= 50.4 ± 2.0 yrs; BMI= 32.4 ± 5.2 kg/m²) who were submitted to a 6-month caloric restriction. Body composition (DXA), resting EE (indirect calorimetry), physical activity EE (PAEE) and total EE (TEE) (doubly-labelled water) were measured before and after the 6 month weight loss. Blood samples were collected before and after to measure leptin and peptide YY. The results indicate that there was indeed a depression in resting EE during weight loss regardless of the type of intervention utilized. Furthermore, these findings suggest that the changes could not fully be explained by changes of FM and FFM alone and that leptin may be an important contributor to the changes of resting EE during weight loss.

The mechanism of weight gain due to treatment with olanzapine, a serotonin receptor antagonist, has not been fully understood. Weight gain and food intake are under the control of neuropeptides/hormones, POMC (proopiomelanocortin), CART (cocaine and amphetamine regulated transcript), AgRP (Agouti-related peptide) and NPY (neuropeptide Y) that are synthesized and secreted from the arcuate nucleus (ARC) of hypothalamus. In this study, the altereration of the ARC neuropeptide/hormone levels both in humans and rats were determined as one of the weight gain mechanism. To examine olanzapine&rsquo / s weight gain effects, male first attack psychotic patients (pre-treatment), were hospitalized and treated for 4 -weeks (post-treatment), (n = 22), and healthy control group (n = 26) were included to the study. Case-control association design was used to analyze the changes in body mass index (BMI), peripheral leptin and the ARC neuropeptides levels. In patients, after 4-weeks of the olanzapine treatment / BMI and the waist circumference were significantly increased with average weight gain of 4.33 kg. In pre-treatment group, NPY levels were significantly lower while &alpha / -MSH, the anorexigenic product of POMC levels were significantly higher vs. control. At post-treatment, both leptin and NPY levels were significantly increased but the CART levels did not change. To further understand the underlying mechanism of olanzapine induced weight gain, the drug was orally administrated to 10 healthy male Wistar rats to analyze both the hypotalamic gene expression and peripheral levels of those candidate neuropeptides. In rats food consumption was increased and hypotalamic mRNA levels of NPY, AgRP and POMC were decreased while CART levels did not show any alteration. Consistent with the expression data, circulating levels of NPY, AgRP and &alpha / -MSH decreased significantly but CART levels were also reduced unexpectedly. In conclusion, it may be presumed that the antagonistic effect of olanzapine on the ARC neurons might be the basis for a disregulation of the neurohormones secretion which may cause weight gain in the treated psychotic patients.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 90-106).

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Fatty acid (FA) transport proteins are important regulators of FA uptake at the cell surface and the mitochondria where they are oxidized. Tight regulation of this process is necessary in order to meet metabolic requirements, while preventing excess lipid accumulation. In an obese state, there is an increase in FA uptake and increased storage of lipids in skeletal muscle, including diacylglycerol (DAG) and ceramides, which interfere with insulin-stimulated glucose uptake. Leptin administration has been shown to reduce muscle triacylglycerol accumulation and restore insulin response in obese rodents. However, it is not known whether this is mediated through a redistribution of the FA transport proteins to the cell surface and mitochondria. In addition to hyperglycemia, post-prandial lipidemia is also observed in the obese state, suggesting a resistance to insulin-stimulated FA uptake. The possibility that insulin-stimulated FA transporter translocation is impaired has received little attention. Lastly, while recent studies have demonstrated that the transverse (t)-tubules may be an important site for glucose uptake in muscle, this has not yet been examined with regards to the FA transporters. In the first study of this thesis, the recovery of insulin response with short-term (2 week) chronic leptin administration in high-fat fed rats was associated with a decrease in muscle reactive lipid species (DAG, ceramide) and an increase in markers of oxidative capacity. Contrary to our expectations, this was not mirrored by an alteration in the distribution of FA transport proteins (FAT/CD36 or FABPpm) at the sarcolemma or the two major mitochondrial populations. To gain further insight into FA transporters and their localization at the cell surface, the second study of this thesis analyzed both the sarcolemma and t-tubules (constitute 40 and 60% of the cell surface, respectively). The novel observation was made that the t-tubules contain FA transport proteins (FAT/CD36, FABPpm, FATP1 and FATP4), and that the distribution and response of these transporters to acute metabolic stimuli (insulin and muscle contraction) was unique from that of the sarcolemma. The third study of this thesis characterized the translocation of FA transport proteins in response to insulin in the obese, insulin resistant Zucker rat. FA transport proteins were chronically increased on both membrane fractions in muscle from the obese rats. Furthermore, a blunting of the insulin-induced translocation of FA transporters to both cell surface domains was observed, demonstrating that insulin resistance extends to the movement of FA as well as glucose transport proteins. The t-tubules appear to play an important role regarding substrate uptake. Together the data from this thesis suggests that a chronic elevation in FA transporters at both cell surface domains contributes to lipid accumulation in obese skeletal muscle, and that reduced sensitivity of both FA and glucose transport proteins to translocate in response to insulin may explain the lipidemia and hyperglycemia that often characterizes post-prandial situations in the obese condition. As the prevalence of obesity reaches epidemic proportions, research into the functional role of FA transport proteins in the progression of obesity related pathologies is warranted as we work to further our knowledge of this significant health issue. / Natural Sciences and Engineering Research Council, Canadian Institute of Health Research

HIV and hypertensive disorders in pregnancy, in particular pre-eclampsia, are the main causes of maternal mortality in South Africa. In HIV associated pre-eclampsia, it is biologically plausible that the immune activation associated with pre-eclampsia may be neutralised by the immune suppression of HIV infection. The precise aetiology of pre-eclampsia is unknown, however leptin has been implicated in its development. Leptin is an adipocyte hormone, also produced by the placenta. It has a role in the development of inflammation. Adipose tissue is reduced in HIV infected individuals, resulting in lower leptin levels with consequent impaired immune function. This study aimed to compare serum and placental leptin levels in HIV infected and uninfected normotensive and pre-eclamptic pregnancies. Since insulin levels may affect the secretion of leptin, the study also compared insulin levels in these pregnancies. Following ethical clearance and hospital permission, 180 participants were recruited during their antenatal period. The groups were HIV- normotensive (n = 30), HIV+ normotensive (n = 60), HIV– pre-eclamptic (n = 30) and HIV+ pre-eclamptic (n = 60). Blood samples were collected ante-natally and placental samples post delivery. Serum leptin and insulin levels were determined by ELISA. Placental leptin levels were determined by ELISA and immunohistochemistry with morphometric image analysis. The placental production of leptin was determined by RT PCR. There was a non-significant increase in serum leptin levels in HIV- pre-eclampsia compared to HIV- normotensive pregnancies (p = 0.42). However leptin was decreased significantly in HIV+ pre-eclampsia compared to HIV- normotensive (p = 0.03). Based on HIV status leptin levels were decreased in HIV+ groups compared to HIV- groups in both pre-eclamptic (p < 0.01) and normotensive pregnancies (p < 0.01). Insulin levels of the HIV positive groups were lower than those of the HIV negative groups (p < 0.001). Insulin levels were also decreased in pre-eclampsia compared to normotensive pregnancies, irrespective of HIV status (p = 0.02). Immunohistochemistry demonstrated an increase in immuno-reactivity of leptin in the exchange villi of pre-eclamptic compared to normotensive placentae, irrespective of HIV status (p < 0.001). Supporting this finding, ELISA also demonstrated elevated leptin levels in the placenta of pre-eclamptic compared to normotensive pregnancies (p < 0.001). Placental leptin levels were similar in both HIV positive and negative pregnancies (p = 0.36). However, the placental leptin mRNA expression was up-regulated in HIV negative pre-eclampsia (p = 0.04) but not in HIV positive pre-eclampsia (p = 1.00). In conclusion, the elevated placental leptin in pre-eclampsia, irrespective of HIV status, is consistent with hypoxia. These elevated levels are not reflected in the maternal serum which raises the possibility of decreased leptin expression by adipose tissue especially in HIV infection where serum leptin levels are decreased. This would negate the increased placental leptin expression in pre-eclampsia. Furthermore, the elevated placental leptin levels are suggestive of an autocrine role of leptin in the placenta. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2013.