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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.

The adipocyte-derived hormone leptin is associated with insulin resistance and reduced fibrinolytic status--or dysfibrinolysis--in humans. As leptin associates differentially to the development of cardiovascular disease and diabetes in men and women, we hypothesized that leptin and insulin sensitivity are related to dysfibrinolysis in a sex-dependent manner. Thirty-two men and 40 women were recruited from the Monitoring of trends and determinants in Cardiovascular disease (MONICA) population sample, representing the highest and lowest quartiles of fasting insulin levels. Lipids, fibrinolytic status [plasminogen activator inhibitor 1 (PAI-1) activity, tissue plasminogen activator (tPA) mass and activity, and tPA-PAI complex], leptin, testosterone and sex-hormone-binding globulin were measured. Insulin sensitivity was estimated using the euglycaemic clamp technique. Body composition was determined by bioimpedance. Determinants for circulating levels of fibrinolytic factors were explored in a multivariate linear regression analysis. Levels of fibrinolytic variables and estimated insulin sensitivity did not differ between men and women. Leptin was independently associated with reduced fibrinolytic status (high PAI-1 activity, low tPA activity, high tPA mass, and high tPA-PAI complex) in men (P < 0.001-0.002). In women, fat mass and/or insulin sensitivity were related to these factors (P < 0.001-0.03), and leptin only to reduced tPA activity (P = 0.002). Hyperleptinemia, dysfibrinolysis, insulin sensitivity and androgenicity associate differentially in men and women.

Leptin, an adipocyte-derived hormone, is involved in the regulation of body weight and is associated with obesity-related complications, notably cardiovascular disease (CVD). A putative link between obesity and CVD could be induction of plasminogen activator inhibitor-1 (PAI-1) synthesis by leptin. In this study, we hypothesized that the beneficial effect of the angiotensin-converting enzyme inhibitor (ACE(i)) enalapril on PAI-1 levels is mediated by effects on leptin levels. The association between leptin and components of the fibrinolytic system was evaluated in a non-prespecified post hoc analysis of a placebo-controlled randomized, double-blind trial where the effect of the ACE(i) enalapril on fibrinolysis was tested. A total of 46 men and 37 women were randomized to treatment with enalapril or placebo after (median 12 months) an uncomplicated myocardial infarction. At baseline, the participants were stable and had no signs of congestive heart failure. Leptin and fibrinolytic variables (mass concentrations of PAI-1, tissue plasminogen activator (tPA) and tPA-PAI complex) were measured at baseline, and after 10 days, 6 months and 12 months. Enalapril treatment did not change leptin levels, which increased significantly during 1 year of follow-up (p = .007). Changes in leptin levels were strongly associated with changes of tPA mass (p = .001), tPA-PAI complex (p = .003) and of PAI-1 (p = .006) in men, but not in women. Leptin levels are not influenced by treatment with an ACE(i). In contrast, leptin associates strongly with changes in fibrinolytic variables notably with a sex difference, which could be of importance for obesity-related CVD.

Physical activity is associated with improved fibrinolytic activity and reduced risk for cardiovascular disease. High levels of leptin and low levels of adiponectin, both adipocyte-derived hormones, or adipokines, are related to dysfibrinolysis and risk for cardiovascular disease. In this study, we explored if improved fibrinolytic activity during exercise could be linked to changes in leptin and adiponectin levels.

Twenty healthy men (mean age 36 years) participated in a 14-day long skiing expedition in the Swedish mountains. They were randomly assigned to either a 40% or a 30% fat-based diet. Anthropometry, lipids, fibrinolytic activity (PAI-1 activity, tPA activity and mass) and adipokines (leptin and adiponectin) were measured before, during and six weeks after the expedition.

PAI-1 activity and circulating levels of leptin decreased whereas levels of adiponectin increased during exercise. The fall in PAI-1 activity showed a strong linear association with changes in leptin and adiponectin levels (p = 0.001 and p < 0.001, respectively). Changes in leptin and adiponectin levels were independent of decreasing waist circumference. However, the association between anthropometric measures and adipokines changed considerably during the expedition. Adiponectin was weakly and negatively associated with BMI at baseline. In contrast, there was a strong positive association between adiponectin and BMI after two weeks of exercise, whereas the association between leptin and BMI became less pronounced. In addition, increasing leptin and decreasing adiponectin levels were associated with increasing PAI-1 activity during the six weeks following the expedition. After six weeks of normal activity, fibrinolytic activity and hormone levels returned towards baseline levels.

Heavy exercise induced improved fibrinolytic activity, which was associated independently with changes in circulating levels of the adipocyte-derived hormones leptin and adiponectin. Improved fibrinolytic activity (and reduced risk for cardiovascular disease) related to physical activity could possibly be mediated by leptin and adiponectin.

Objectives: Chronic low back pain (CLBP) is one of the most common chronic pain conditions that cause both individual suffering and a burden to society. For these patients, several interventional treatment options such as surgery, blocks, radiofrequency, and spinal cord stimulation are available. Lately, dorsal root ganglion stimulation (DRG-S) also has been mentioned as an option by targeting bilateral T12 dorsal ganglia. In this study, we present the outcome of 11 patients with CLBP treated with bilateral T12 DRG-S.

Materials and Methods: Thirteen patients with CLBP with and without leg pain were treated with bilateral T12 DRG-S. Three of the patients also received a third lumbar lead owing to leg pain. Eleven of the patients had >50% pain relief during the peri- or/and postoperative testing and received a fully implantable neurostimulator. Pain intensity, general health status, quality of life, pain catastrophizing, mental status, sleeping disorder, physical activity, and patient satisfaction were followed using numeric rating scale (NRS), Patient-Reported Outcomes Measurement Information System 29 version 2.1, Pain Catastrophizing Score, Generalized Anxiety Disorder 7-item scale, Patient Health Questionnaire Depression Module, Insomnia Severity Index, and Patient Satisfaction Questionnaire at baseline before implantation and at three months and six months. The results were analyzed on the basis of six domains: pain relief, sleeping disorder, social ability, mental status, physical activity, and satisfaction. To be identified as a responder, the patients should show a significant improvement in the pain relief domain together with at least two other domains. All responders also were given the opportunity to test 4-Hz DRG-S and compare it with traditional 20-Hz stimulation.

Results: All 11 patients were identified as responders at six months. Five of the patients had >80% pain relief, with an average NRS score reduction of 71% for the whole group. Significant improvement could be observed in three domains for one patient, four domains for three patients, five domains for six patients, and six domains for one patient. Seven patients chose to try 4-Hz stimulation. All seven identified 4-Hz stimulation as at least as good as or better than 20-Hz stimulation and chose to continue with 4-Hz stimulation.

Conclusions: Bilateral T12 DRG-S seems to be an effective treatment for chronic low back pain, with significant beneficial effect not only on pain but also on quality of life, pain catastrophizing, mental status, sleeping disorder, and physical activity. 4-Hz DRG-S gave a result comparable with or better than 20-Hz stimulation.