Owe Johnson

Leptin is associated with increased risk of myocardial infarction

Abstract. Söderberg S, Ahrén B, Jansson J‐H, Johnson O, Hallmans G, Asplund K, Olsson T (Umeå University, Umeå; and Lund University, Malmö, Sweden). Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999; 246: 409–418.

Leptin is a risk marker for first-ever hemorrhagic stroke in a population-based cohort

BACKGROUND AND PURPOSE Leptin, important for body weight regulation, may be involved in the pathogenesis of the insulin resistance syndrome, associated with cardiovascular disease. We tested to determine whether leptin is a risk marker for first-ever stroke in a nested case-referent study. METHODS We identified 113 patients with first-ever stroke (94 with ischemic and 19 with hemorrhagic stroke) who, before the stroke, had participated in population-based health surveys in northern Sweden. Referents were matched for sex, age, date and type of health survey, and geographic region. Blood pressure (BP), body mass index (BMI), and presence of smoking, diabetes, and hypertension were recorded. Total cholesterol, insulin, and leptin were analyzed in stored samples. Risk markers for first-ever stroke were analyzed by conditional logistic regression analysis. RESULTS Patients with hemorrhagic stroke had higher levels of BMI and systolic and diastolic BPs. Leptin levels were 72% and 59% higher in males and females, respectively, with hemorrhagic stroke versus referents. Patients with ischemic stroke more often had hypertension, diabetes mellitus, and higher fasting glucose and insulin levels. A diagnosis of hypertension and elevated systolic and diastolic BPs were significant risk markers for first-ever hemorrhagic stroke in univariate analysis. High leptin (OR=20.55; 95% CI, 1.12 to 376.7) levels together with hypertension (OR=16.28; 95% CI, 1.49 to 177.3) remained as significant risk markers in a multivariate model. The combination of high leptin and high systolic or diastolic BP were associated with a profoundly increased risk for hemorrhagic stroke (OR=22.11; 95% CI, 1.57 to 310.9). Diabetes, hypertension, and obesity (BMI >/=27), together with high levels of insulin, glucose, systolic and diastolic BP, were significant risk markers for first-ever ischemic stroke in univariate analysis. Hypertension (OR=2.10; 95% CI, 1.14 to 3.86) remained as an independent risk marker in a multivariate model. CONCLUSIONS Plasma leptin is strongly associated with an increased risk for first-ever hemorrhagic stroke, independent of other risk markers for cardiovascular disease. Leptin may be an important link in the development of cardiovascular disease in obesity.

Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women

Abstract. Söderberg S, Olsson T, Eliasson M, Johnson O, Ahrén B (Umeå University Hospital, Luleå County Hospital and Lund University, Malmö, Sweden). Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women. J Intern Med 1999; 245: 533–543.

Lipoprotein(a) and acute-phase proteins in acute myocardial infarction

Lipoprotein(a) (Lp(a)) and the acute-phase proteins, orosomucoid, haptoglobin and alpha 1-antitrypsin, were studied in 32 patients with acute myocardial infarction. Samples were taken at admission and, after fasting overnight, on the following 6 days. In a subgroup of 21 patients total serum cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides were also estimated. In a linear regression model a significant relation between the relative values of Lp(a) and the time in days was obtained (p = 0.001). Compared with the acute-phase proteins, however, Lp(a) showed a weak increase and the individual responses were very variable. There were no correlations between the individual changes in Lp(a) and the changes in the acute-phase proteins, but Lp(a) changes correlated significantly with the changes in total cholesterol and low-density lipoprotein (LDL) cholesterol. It is suggested that the Lp(a) reaction in myocardial infarction is linked to the reaction of the lipoproteins. There may also be several clinical conditions, including different medications, which influence the Lp(a) level.

The extrinsic fibrinolytic system in survivors of myocardial infarction

The extrinsic fibrinolytic system was assessed among 124 consecutive survivors of acute myocardial infarction below 70 years of age. In samples drawn 3 months after discharge from hospital, the PAI-1 levels were higher and the tPA activities were lower than among elderly healthy controls. In contrast, the AMI survivors had higher tPA antigen levels at rest and after venous occlusion, and higher tPA activities after venous occlusion. Among patients having PAI-1 levels greater than 10 IU/ml, there was a positive correlation between PAI-1 and serum triglycerides, and a negative correlation between PAI-1 and age; this group was also significantly younger than the subgroup having less than or equal to 10 IU/ml of PAI-1. There were thus multiple disturbances of the extrinsic fibrinolytic system among these patients. As cardiovascular risk factors, these disturbances appear to be relatively more important the younger the patients are.

Conversion towards an atherogenic lipid profile in rheumatoid arthritis patients during long‐term infliximab therapy

Objectives: To analyse the effects of infliximab infusions on serum levels of lipids in patients with rheumatoid arthritis (RA) treated for 2 years. Methods: Fifty‐two patients (41 females and 11 males) with RA undergoing infliximab treatment (3 mg/kg) were consecutively recruited into the study. The mean (±SD) age of the patients was 54.6±12.5 years and mean disease duration was 14.1±8.6 years. Blood was sampled before infusion at baseline, and at 3, 6, 12, 18 and 24 months. Forty‐one of the patients were also treated with methotrexate, 13 with other disease‐modifying anti‐rheumatic drugs (DMARDs) and 28 with prednisolone (<10 mg daily). For comparison, lipid levels were followed for 2 years in 70 consecutively included patients with early RA during treatment with conventional DMARDs. Results: There was an initial increase in plasma levels of cholesterol, high density lipoprotein (HDL)‐cholesterol, low density lipoprotein (LDL)‐cholesterol, and LDL/HDL and total/HDL cholesterol ratios. However, after 3 months HDL‐cholesterol decreased significantly, followed after 6 months by cholesterol and LDL‐cholesterol. The LDL/HDL and total/HDL‐cholesterol ratios remained significantly raised. HDL‐cholesterol increased and the ratios improved in patients with early RA receiving conventional treatment. The changes over time differed significantly between the patient groups. Conclusion: During infliximab infusion a pro‐atherogenic lipid profile developed despite reduced inflammatory activity. The long‐term decrease in HDL‐cholesterol was unexpected considering the known effects of tumour necrosis factor‐alpha (TNFα).

A strong association between biologically active testosterone and leptin in non-obese men and women is lost with increasing (central) adiposity.

OBJECTIVE: In both humans and rodents, males have lower levels of leptin than females at any level of adiposity. Experimental data support the idea that testosterone exerts a negative influence on leptin levels. There are, however, major inconsistencies in available data concerning the possible association between androgenicity and leptin in humans. Reasons could be the influence of androgenicity on leptin production being dependent on body composition, and incomplete measures of biologically active testosterone levels. In the present study we have characterized the relationship between biologically active testosterone and leptin after careful stratification for gender and adiposity.DESIGN AND SUBJECTS: Healthy subjects (n=158; 85 men and 73 pre- and postmenopausal women) from the Northern Sweden MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) population were studied with a cross-sectional design.MEASUREMENTS: Anthropometric measurements (body mass index (BMI) and waist circumference) and oral glucose tolerance tests were performed. Circulating levels of leptin, insulin, testosterone, androstenedione, sex hormone-binding globulin (SHBG) and insulin-like growth factor-1 (IGF-1) were measured by radioimmunoassays or microparticle enzyme immunoassays. Apparent concentrations of free testosterone and non-SHBG-bound testosterone were calculated.RESULTS: After adjustments for age, BMI and insulin, leptin levels were inversely correlated to testosterone levels in non-obese men (r=−0.56, P<0.01) and obese women (r=−0.48, P<0.05). In contrast, leptin and testosterone correlated in a positive manner in non-obese women (r=0.59, P<0.01). Levels of SHBG were negatively associated with leptin in men with low waist circumference (r=−0.59, P<0.01). The following factors were associated with leptin in a multivariate model: low levels of biologically active testosterone and SHBG in men with low and medium waist circumference, insulin in men with high waist circumference, high levels of testosterone and insulin in non-obese women, and BMI in obese women.CONCLUSION: We conclude that low leptin levels are associated with androgenicity in non-obese men and women and that the direction of this association is dependent on gender and body fat distribution. Based on these results we suggest that the relation between testosterone and leptin contributes to the gender difference in circulating leptin levels.

A randomized lifestyle intervention with 5-year follow-up in subjects with impaired glucose tolerance: Pronounced short-term impact but long-term adherence problems

Aims: To compare data on cardiovascular risk factor changes in lipids, insulin, proinsulin, fibrinolysis, leptin and C-reactive protein, and on diabetes incidence, in relation to changes in lifestyle. Methods: The study was a randomized lifestyle intervention trial conducted in northern Sweden between 1995 and 2000, in 168 individuals with impaired glucose tolerance (IGT) and body mass index above 27 at start. The intensive intervention group (n = 83) was subjected to a 1-month residential lifestyle programme. The usual care group (n = 85) participated in a health examination ending with a single counselling session. Follow-up was conducted at 1, 3 and 5 years. Results: At 1-year follow-up, an extensive cardio-metabolic risk factor reduction was demonstrated in the intensive intervention group, along with a 70% decrease of progress to type 2 diabetes. At 5-year follow-up, most of these beneficial effects had disappeared. Reported physical activity and fibre intake as well as high-density lipoprotein cholesterol were still increased, and fasting insulin and proinsulin were lower. Conclusions: The intervention affected several important cardio-metabolic risk variables beneficially, and reduced the risk for type 2 diabetes, but the effects persisted only as long as the new lifestyle was maintained. Increased physical activity seemed to be the behaviour that was most easy to preserve.

Interactions between fibrinolysis, lipoproteins and leptin related to a first myocardial infarction.

Background The summarized importance of haemostatic and metabolic variables (insulin, lipids including lipoprotein (a) [Lp(a)] and leptin) in predicting first myocardial infarction, as well as possible interactions among these variables, have not been reported. Design A prospective case-control study nested within the Northern Sweden Health and Disease Cohort. Methods Sixty-two men diagnosed with a first myocardial infarction were sex- and age-matched with 124 controls. Conditional logistic regression was conducted including established risk factors, plasma levels of plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) mass concentration, von Willebrand factor, insulin, proinsulin, specific insulin, apolipoprotein A-I (apo A-I), Lp(a), and leptin. Interaction analysis was also performed for tPA, apo A-I, Lp(a), leptin and proinsulin. Results Smoking, low plasma levels of apo A-I and high plasma levels of cholesterol, Lp(a), tPA, PAI-1, proinsulin and leptin were associated with myocardial infarction in univariate conditional logistic regression analysis. High tPA [odds ratio (OR), 21.3; 95% confidence interval (CI), 2.04-222] and Lp(a) (OR, 7.21; 95% CI, 1.31-39.8) and low apo A-I (OR, 0.15; 95% CI, 0.02-0.93) remained significant risk determinants in multivariate analysis with smoking habits, body mass index, hypertension, cholesterol, and diabetes included as covariates. There were non-significant synergic interactions between high Lp(a) and leptin and tPA, respectively, and between high Lp(a) and low apo A-I. Conclusion Plasma levels of tPA, Lp(a), and apo A-I are independently associated with subsequent development of a first myocardial infarction in men.

Changes in Lp(a) lipoprotein levels during the treatment of hypercholesterolaemia with simvastatin

SummaryThirty-six patients with total serum cholesterol levels above 6.5 mmol/l and Lipoprotein(a) levels above 100 mg · 1−1 were evaluated in a 24 week double-blind, placebo controlled, cross-over study to assess the possible changes in Lp(a) during treatment with the HMG CoA reductase inhibitor simvastatin.The median plasma Lp(a) increased from 359 to 464 mg·l−1 during simvastin treatment as compared to placebo (not significant). Individual changes in Lp(a) varied. In a multivariate linear regression analysis the individual change in Lp(a) was correlated with the baseline Lp(a) (r = 0.64), the change in serum triglycerides (r = 0.48) and the baseline apolipoprotein B (r = 0.36). Differences between the Lp(a) phenotypes may explain some of the varied Lp(a) responses. It appears that the effect of simvastatin on the Lp(a) level in individuals is usually insignificant, but in patients with a high Lp(a) simvastatin may further increase it.