Rune Byrkjeland

Inflammatory markers as related to disease severity in patients with chronic heart failure: Limited effects of exercise training

Abstract Background. Chronic heart failure (CHF) is associated with increased inflammation, and exercise training has in some studies been shown to have anti-inflammatory effect, although controversies exist. We investigated the effects of exercise training in CHF patients on markers of inflammation, and further explored any association between inflammation and the severity and etiology of the disease. Methods. Eighty patients in stable CHF were randomized to 4 months of group-based high intensity exercise training or to a control group. Physical capacity was measured by 6-minute walk test and cycle ergometer test. Blood samples were drawn at baseline, after 4 months and after 12 months follow-up for analyses of a range of biomarkers. Results. Physical capacity was significantly inversely related to CRP, IL-6, VCAM-1 and TGF-β, and NT pro-BNP levels were significantly correlated to CRP, TNF-α, IL-6, VCAM-1, ICAM-1 and TGF-β (p < 0.05 for all). Patients with hypertension as etiology of CHF showed higher levels of CRP (p < 0.01), IL-6 (p = 0.05) and TNF-α (p = 0.02) as compared to other etiologies. No significant differences in changes between the exercise group and the control group were obtained in any of the measured variables, except in patients with idiopathic dilated cardiomyopathy (IDCM), where significant reductions in CRP, ICAM-1, TGF-β and TNF-α levels were observed (p < 0.05 for all). Conclusions. Measures of CHF severity were significantly correlated with several markers of inflammation. We could not demonstrate over-all anti-inflammatory effect of exercise in this population of CHF patients. However, the etiology of CHF affected the inflammatory profile and the effect of exercise training.

Effects of exercise training on HbA1c and VO2peak in patients with type 2 diabetes and coronary artery disease: A randomised clinical trial

Objective: Few exercise trials have focused on patients with both type 2 diabetes and coronary artery disease. We investigated the effects of 1 year of exercise training on HbA1c and VO2peak in these patients. Methods: Patients with type 2 diabetes and coronary artery disease (n = 137) were randomised to combined exercise training or control group. HbA1c was measured at the beginning and end of the study. Changes in VO2peak, and also ventilatory threshold and time to exhaustion, were assessed by cardiopulmonary exercise testing. Results: No differences in changes between the randomised groups were observed in HbA1c and VO2peak, whereas ventilatory threshold and time to exhaustion increased significantly in the exercise group compared with the controls (p = 0.046 and p = 0.034). In patients without previous acute myocardial infarction and diabetes microvascular complications (n = 46), the exercise group did improve HbA1c and VO2peak compared with the controls (p = 0.052 and p = 0.035). Conclusion: No significant effects of exercise training on HbA1c or VO2peak were observed in patients with type 2 diabetes and coronary artery disease, although improvements were seen in patients without vascular complications beyond coronary artery disease, implying that the degree of vascular disease may influence exercise responses. Ventilatory threshold and time to exhaustion did increase significantly, indicating improved exercise performance despite the minor change in VO2peak.

Insulin levels and HOMA index are associated with exercise capacity in patients with type 2 diabetes and coronary artery disease

BackgroundPrevious studies on type 2 diabetes have shown an association between exercise capacity and insulin resistance. In patients with coronary artery disease (CAD) exercise capacity is often reduced due to exercise-induced ischemia. We have investigated the association between glucometabolic control, including the homeostatic model assessment (HOMA) of insulin resistance, and exercise capacity in patients with type 2 diabetes and CAD with and without exercise-induced ischemia.MethodsIn 137 patients (age 63.1 ± 7.9) cardiopulmonary exercise testing on treadmill was performed using a modified Balke protocol. The highest oxygen uptake (VO2peak) was reported as 30-s average. Fasting blood samples were drawn for determination of glucose, insulin and HbA1c. Insulin resistance (IR) was assessed by the HOMA2-IR computer model. Exercise-induced ischemia was defined as angina and/ or ST-depression in ECG ≥ 0.1 mV during the exercise test.ResultsHOMA2-IR was inversely correlated to VO2peak (r = -0.328, p < 0.001), still significant after adjusting for age, gender, smoking and BMI. Patients with HOMA2-IR above the median value (1.3) had an adjusted odds ratio of 3.26 (95 % CI 1.35 to 7.83, p = 0.008) for having VO2peak below median (23.8 mL/kg/min). Insulin levels were inversely correlated to VO2peak (r = -0.245, p = 0.010), also after adjusting for age and gender, but not after additional adjustment for BMI. The correlation between HOMA2-IR and VO2peak was also significant in the subgroups with (n = 51) and without exercise-induced ischemia (n = 86), being numerically stronger in the group with ischemia (r = -0.430, p = 0.003 and r = -0.276, p = 0.014, respectively). Fasting glucose and HbA1c were not correlated with VO2peak or AT.ConclusionsInsulin resistance, as estimated by fasting insulin and the HOMA index, was inversely associated with exercise capacity in patients with type 2 diabetes and CAD, the association being more pronounced in the subgroup with exercise-induced ischemia. These results indicate that insulin resistance is related to exercise capacity in type 2 diabetic patients with CAD, possibly even more so in patients with exercise-induced ischemia compared to those without.

Reduced endothelial activation after exercise is associated with improved HbA1c in patients with type 2 diabetes and coronary artery disease.

Objective: We have previously reported insignificant changes in HbA1c after exercise in patients with both type 2 diabetes and coronary artery disease. In this study, we investigated the effect of exercise on endothelial function and possible associations between changes in endothelial function and HbA1c. Methods: Patients with type 2 diabetes and coronary artery disease (n = 137) were randomised to 12 months exercise or standard follow-up. Endothelial function was assessed by circulating biomarkers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, von Willebrand factor, tissue plasminogen activator antigen, asymmetric dimethylarginine and L-arginine/asymmetric dimethylarginine ratio). Differences between the randomised groups were analysed by analysis of covariance and correlations by Spearman’s rho or Pearson’s correlation. Results: No effect of exercise on endothelial function was demonstrated. The changes in HbA1c in the exercise group correlated with changes in E-selectin (r = 0.56, p < 0.001), intercellular adhesion molecule-1 (r = 0.27, p = 0.052), vascular cell adhesion molecule-1 (r = 0.32, p = 0.022) and tissue plasminogen activator antigen (r = 0.35, p = 0.011). HbA1c decreased significantly more in patients with versus without a concomitant reduction in E-selectin (p = 0.002), intercellular adhesion molecule-1 (p = 0.011), vascular cell adhesion molecule-1 (p = 0.028) and tissue plasminogen activator antigen (p = 0.009). Conclusion: Exercise did not affect biomarkers of endothelial function in patients with both type 2 diabetes and coronary artery disease. However, changes in biomarkers of endothelial activation correlated with changes in HbA1c, and reduced endothelial activation was associated with improved HbA1c after exercise.

A Double-Blinded Randomized Study Investigating a Possible Anti-Inflammatory Effect of Saxagliptin versus Placebo as Add-On Therapy in Patients with Both Type 2 Diabetes And Stable Coronary Artery Disease

Background Promising results regarding potential anti-inflammatory and antiatherosclerotic effects of gliptins have been reported. Our aim was to investigate whether saxagliptin treatment modifies expression of inflammatory markers, primarily in peripheral blood mononuclear cells (PBMCs) and in circulating leukocytes in patients with stable coronary artery disease (CAD) and T2DM. Methods Patients (n = 12) were randomized to saxagliptin 5 mg daily or placebo for 3 months. Samples were taken at baseline and end of study in fasting state prior to intake of medications. PBMCs were isolated and cryopreserved at −150°C until ex vivo exposed to 1 ng/mL of lipopolysaccharide (LPS) for 4 hours. Gene expression was performed with custom-designed TaqMan® Arrays and relative quantification by real-time PCR (RT-qPCR). Results HbA1c was reduced in the saxagliptin-treated group compared to that in the change with placebo (p = 0.042). In unstimulated PBMCs and in circulating leukocytes, we observed a significant increase in IL-10 expression in the saxagliptin group (p = 0.043, both), significantly different from that in the placebo (p = 0.009 and p = 0.032, resp.). No between group differences in changes were observed in any of the selected proinflammatory markers. Conclusion In our small cohort of patients with combined T2DM and CAD, a possible anti-inflammatory effect of saxagliptin, observed in the present study by upregulation of IL-10 in leukocytes, needs to be confirmed in larger studies.

Effects of long-term exercise training on adipose tissue expression of fractalkine and MCP-1 in patients with type 2 diabetes and stable coronary artery disease: a substudy of a randomized controlled trial

Purpose Adipose tissue inflammation plays a role in atherosclerosis and type 2 diabetes (T2DM). We aimed to investigate whether 12 months of exercise training in patients with both T2DM and coronary artery disease (CAD) reduced the genetic expression of the proinflammatory markers fractalkine (CX3CL1) and its receptor (CX3CR1) and monocyte chemoattractant protein-1 (MCP-1) in the subcutaneous adipose tissue. Expression of the genes in the circulating leukocytes and circulating levels of the markers were also investigated. Patients and methods A total of 137 patients with T2DM and CAD were included to study the effects of exercise on atherosclerosis progression and glucose control. Patients were randomized to exercise training (combined aerobic and strength training) or control. At inclusion and after 12 months, fasting blood samples and a subcutaneous adipose tissue sample were taken. RNA was extracted from the adipose tissue and circulating leukocytes, and the expression levels were examined by reverse transcription-polymerase chain reaction. Circulating fractalkine and MCP-1 were determined by enzyme-linked immunosorbent assay. Results The analyses were performed in 114 patients who completed the study and adhered to the intervention principle. At baseline, gene expression of fractalkine and CX3CR1 in the adipose tissue was similar in the two groups. There were no change within either group and no between-group differences in changes from baseline. Circulating fractalkine increased after 12 months in the exercise group (P=0.044), significantly more compared to controls (P=0.042), however only in the patients with advanced vascular disease. Neither the expression levels of MCP-1 nor the circulating levels changed significantly in either group. At baseline, CX3CR1 expression in the adipose tissue was associated with body mass index (P<0.001). Conclusion No significant effects of long-term exercise training on adipose tissue expression of fractalkine, CX3CR1, or MCP-1 were found in our patients with combined CAD and T2DM. However, a slight increase in circulating fractalkine after the intervention was recorded. The association of CX3CR1 expression with body mass index might indicate increased immune activation in the adipose tissue.

Procoagulant activity in patients with combined type 2 diabetes and coronary artery disease: No effects of long-term exercise training.

We investigated the effects of 12-month exercise training on hypercoagulability in patients with combined type 2 diabetes mellitus and coronary artery disease. Associations with severity of disease were further explored. Patients (n = 131) were randomized to exercise training or a control group. Blood was collected at inclusion and after 12 months. Tissue factor, free and total tissue factor pathway inhibitor, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer were determined by enzyme-linked immunosorbent assay and ex vivo thrombin generation by the calibrated automated thrombogram assay. Tissue factor and ex vivo thrombin generation increased from baseline to 12 months (p < 0.01, all), with no significant differences in changes between groups. At baseline, free and total tissue factor pathway inhibitor significantly correlated to fasting glucose (p < 0.01, both) and HbA1c (p < 0.05, both). In patients with albuminuria (n = 34), these correlations were strengthened, and elevated levels of D-dimer, free and total tissue factor pathway inhibitor (p < 0.01, all) and decreased ex vivo thrombin generation (p < 0.05, all) were observed. These results show no effects of exercise training on markers of hypercoagulability in our population with combined type 2 diabetes mellitus and coronary artery disease. The association between poor glycaemic control and tissue factor pathway inhibitor might indicate increased endothelial activation. More pronounced hypercoagulability and increased tissue factor pathway inhibitor were demonstrated in patients with albuminuria.