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Biomedical subjects

Stig S Frøland

Publications and source records attributed to Stig S Frøland.

At least 19 recordsLinked to original sources
PubMed2006

Enhanced expression of the homeostatic chemokines CCL19 and CCL21 in clinical and experimental atherosclerosis: possible pathogenic role in plaque destabilization.

OBJECTIVE: Based on their role in T-cell homing into nonlymphoid tissue, we examined the role of the homeostatic chemokines CCL19 and CCL21 and their common receptor CCR7 in coronary artery disease (CAD). METHODS AND RESULTS: We performed studies in patients with stable (n=40) and unstable (n=40) angina and healthy controls (n=20), in vitro studies in T-cells and macrophages, and studies in apolipoprotein-E-deficient (ApoE-/-) mice and human atherosclerotic carotid plaques. We found increased levels of CCL19 and CCL21 within the atherosclerotic lesions of the ApoE-/- mice, in human atherosclerotic carotid plaques, and in plasma of CAD patients. Whereas strong CCR7 expression was seen in T-cells from murine and human atherosclerotic plaques, circulating T-cells from angina patients showed decreased CCR7 expression. CCL19 and CCL21 promoted an inflammatory phenotype in T-cells and macrophages and increased matrix metalloproteinase (MMP) and tissue factor levels in the latter cell type. Although aggressive statin therapy increased CCR7 and decreased CCL19/CCL21 levels in peripheral blood from CAD patients, conventional therapy did not. CONCLUSIONS: The abnormal regulation of CCL19 and CCL21 and their common receptor in atherosclerosis could contribute to disease progression by recruiting T-cells and macrophages to the atherosclerotic lesions and by promoting inflammatory responses in these cells.

Angioplasty, Balloon, Coronary↗
PubMed2006

Increased levels of neutrophil-activating peptide-2 in acute coronary syndromes: possible role of platelet-mediated vascular inflammation.

OBJECTIVES: We sought to investigate the role of the CXC chemokine neutrophil-activating peptide-2 (NAP-2) in atherogenesis and plaque destabilization. BACKGROUND: Chemokines are involved in atherogenesis, but the role of NAP-2 in atherosclerotic disorders is unclear. Based on its potential pro-atherogenic properties, we hypothesized a pathogenic role for NAP-2 in coronary artery disease. METHODS: We tested this hypothesis by differential experimental approaches including studies in patients with stable (n = 40) and unstable angina (n = 40) and healthy control subjects (n = 20). RESULTS: The following results were discovered: 1) patients with stable, and particularly those with unstable, angina had markedly raised plasma levels of NAP-2 compared with control subjects, accompanied by increased expression of CXC receptor 2 in monocytes; 2) platelets, but also peripheral blood mononuclear cells (PBMCs), released large amounts of NAP-2 upon stimulation, with a particularly prominent PBMC response in unstable angina; 3) NAP-2 protein was detected in macrophages and smooth muscle cells of atherosclerotic plaques and in monocytes and platelets of coronary thrombi; 4) in vitro, recombinant and platelet-derived NAP-2 increased the expression of adhesion molecules and chemokines in endothelial cells; and 5) whereas aspirin reduced plasma levels of NAP-2, statin therapy increased NAP-2 with stimulating effects both on platelets and leukocytes. CONCLUSIONS: Our findings suggest that NAP-2 has the potential to induce inflammatory responses within the atherosclerotic plaque. By its ability to promote leukocyte and endothelial cell activation, such a NAP-2-driven inflammation could promote plaque rupture and acute coronary syndromes.

Acute Disease↗
PubMed2006

Increased levels of soluble CD40L in African tick bite fever: possible involvement of TLRs in the pathogenic interaction between Rickettsia africae, endothelial cells, and platelets.

The pathophysiological hallmark of spotted fever group rickettsioses comprises infection of endothelial cells with subsequent infiltration of inflammatory cells. Based on its ability to promote inflammation and endothelial cell activation, we investigated the role of CD40L in African tick bite fever (ATBF), caused by Rickettsia africae, using different experimental approaches. Several significant findings were revealed. 1) Patients with ATBF (n = 15) had increased serum levels of soluble CD40 ligand (sCD40L), which decreased during follow-up. 2) These enhanced sCD40L levels seem to reflect both direct and indirect (through endothelial cell activation involving CX3CL1-related mechanisms) effects of R. africae on platelets. 3) In combination with sCD40L, R. africae promoted a procoagulant state in endothelial cells by up-regulating tissue factor and down-regulating thrombomodulin expression. 4) Although the R. africae-mediated activation of platelets involved TLR2, the combined procoagulant effects of R. africae and sCD40L on endothelial cells involved TLR4. 5) Doxycycline counteracted the combined procoagulant effects of R. africae and sCD40L on endothelial cells. Our findings suggest an inflammatory interaction between platelets and endothelial cells in ATBF, involving TLR-related mechanisms. This interaction, which includes additive effects between sCD40L and R. africae, may contribute to endothelial inflammation and hypercoagulation in this disorder.

Adult↗
PubMed2006

The role of intravenous immunoglobulin in the treatment of chronic heart failure.

Chronic heart failure (HF), including both ischemic and idiopathic dilated cardiomyopathies, is accompanied by a dysregulated cytokine network characterized not only by a rise in inflammatory cytokines, but also by an inadequate elevation of anti-inflammatory mediators. This dysregulation has been implicated in the development and progression of chronic HF, and in the last decade, attempts have been made to modulate this persistent inflammation. Failure of anti-tumor necrosis factor therapy in HF has led to further interest in a more general immunomodulatory approach, directed against the inflammatory imbalance rather than one particular cytokine. Treatment with intravenous immunoglobulin (IVIg) may represent such a broad-based approach trying to restore the dysregulated cytokine network through various mechanisms such as Fc receptor blockade, neutralization of microbial antigens and superantigens and more direct anti-inflammatory effects on the cytokine network. However, although one randomized placebo-controlled study in patients with chronic HF showed that IVIg improved left ventricular ejection fraction, accompanied by anti-inflammatory net effects, IVIg had no effect in another placebo-controlled study examining the effect of this medication in recent-onset cardiomyopathy. So far, few patients have been included in clinical trials, and there is clearly a need for larger placebo-controlled mortality studies involving a diverse group of patients with regard to cause and severity of HF.

Autoantibodies↗
PubMed2006

Decreased endomyocardial RANKL expression in transplant coronary artery disease.

Transplant-associated coronary artery disease (TxCAD) appears to be initiated by endothelial cell activation and inflammation involving inflammatory cytokines and chemokines. Osteoprotegerin (OPG) and receptor activator of nuclear Factor-kappaB ligand (RANKL) have been implicated in cardiovascular disease progression and we measured the expression of these mediators in serum and myocardial biopsies taken serially during the first year after heart transplantation (HTx), relating them to the development of TxCAD. Serum OPG as well as myocardial gene expression of RANK and OPG, but not RANKL, were highest early after HTx and declined progressively. Importantly, patients who develop TxCAD or experience episodes of acute rejection showed a lower myocardial RANKL expression throughout the first year after transplantation than patients without these complications. Our findings may suggest an unrecognized role RANKL in maintaining myocardial and/or endothelial integrity and suggest that RANKL should be further investigated as a parameter that may predict development of TxCAD.

Adolescent↗
PubMed2006

Immune modulatory effects of cyclooxygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment.

OBJECTIVES: To examine the immune modulating effects of cyclooxygenase type 2 (COX-2) inhibitors (COX-2i) in HIV-infected patients on combination antiretroviral treatment (CART). DESIGN: In-depth substudy from an approved, open, controlled, randomized study comparing the immune modulating effects of CART in combination with COX-2i after 12 weeks. METHODS: Patients (n = 38) on long-term CART with stable viral load (VL) < 50,000 copies/ml and CD4+ T-cell counts > 100/microl were randomized to CART and rofecoxib 25 mg bid (n = 12) or celecoxib 400 mg bid (n = 12), or CART only without placebo (n = 14). Routine clinical chemistry, CD4+ and CD8+ counts and VL were safety parameters. Immunological parameters included C-reactive protein, beta2-microglobulin, Ig isotypes and IgG subclasses as well as several T-lymphocyte subsets. Non-parametric analyses were used throughout. RESULTS: Prestudy experiments showed higher median intracellular expression of COX-2 in CD4+ (P = 0.048) and possibly CD8+ (P = 0.09) T cells from patients on CART compared with uninfected controls. In the clinical study, increased CD4+ T-cell counts were observed only in patients on COX-2i with VL < 50 copies/ml (P = 0.02). Decreased expression of CD38+ on CD8+ T cells and subsets as well as reductions in IgA and IgM (P < 0.03) were most pronounced in patients on COX-2i who had detectable VL (n = 6). COX-2i treatment enhanced the perforin content particularly in the differentiated CD27-/CD8+ T-cell subsets compared with controls (P = 0.05). CONCLUSIONS: COX-2i together with CART improved markers for persistent immune activation, particularly in patients with viraemia, as well as enhanced perforin expression, and thereby strengthened COX-2 as a potential therapeutic target in HIV infection.

ADP-ribosyl Cyclase 1↗
PubMed2006

Thalidomide attenuates the development of fibrosis during post-infarction myocardial remodelling in rats.

BACKGROUND: Inflammation plays a pathogenic role in the development of heart failure (HF). The aim of this study was to examine the effect of treatment with the immunomodulating drug thalidomide in a rat model for post-myocardial infarction (MI) HF. METHODS: Rats were subjected to MI by left coronary artery ligation or sham-operated. Seven days after surgical intervention rats were randomised to treatment with thalidomide or vehicle for 8 weeks. RESULTS: Our main findings were: (i) thalidomide treatment did not affect cardiac function or the hypertrophic response, as determined by haemodynamic measurements and heart chamber weights, respectively. (ii) HF rats treated with thalidomide had a minor reduction in septum and relative wall thickness (p<0.05), indicating an anti-remodelling effect. (iii) Thalidomide appeared to have immunostimulatory effects on the myocardium as evident by increased MIP-1alpha gene expression (p<0.05). (iv) Treating HF rats with thalidomide reduced myocardial collagen content, as assessed by markedly decreased levels of hydroxyproline ( approximately 40% reduction; p<0.05), accompanied by lower TGF-beta(1) gene expression (p<0.05). CONCLUSION: Although thalidomide had no effect on cardiac function, our results suggest that intervention with thalidomide may have beneficial effects in post-MI HF by attenuating collagen accumulation and development of myocardial fibrosis.

Animals↗
PubMed2006

Enhanced T-cell expression of RANK ligand in acute coronary syndrome: possible role in plaque destabilization.

OBJECTIVE: Based on its role in inflammation and matrix degradation, we hypothesized a role for osteoprotegerin (OPG), RANK, and RANK ligand (RANKL) in coronary artery disease. METHODS AND RESULTS: We examined the expression of various members of the OPG/RANKL/RANK axis in patients with stable and unstable angina and in the atherosclerotic lesions of apolipoprotein E-deficient (apoE(-/-)) mice. Our findings were: (1) Serum levels of OPG were raised in patients with unstable angina (n=40), but not in those with stable angina (n=40), comparing controls (n=20); (2) mRNA levels of RANKL were increased in T-cells in unstable angina patients accompanied by increased expression of RANK in monocytes; (3) strong immunostaining of OPG/RANKL/RANK was seen within thrombus material obtained at the site of plaque rupture during acute myocardial infarction; (4) OPG/RANKL/RANK was expressed in the atherosclerotic plaques of apoE(-/-) mice, with RANKL located specifically to the plaques; and (5) RANKL enhanced the release of monocyte chemoattractant peptide-1 in mononuclear cells from unstable angina patients, and promoted matrix metalloproteinase (MMP) activity in vascular smooth muscle cells. CONCLUSIONS: We show enhanced expression of the OPG/RANKL/RANK system both in clinical and experimental atherosclerosis, with enhanced T-cell expression of RANKL as an important feature of unstable disease.

Adult↗
PubMed2006

Mannose binding lectin and soluble Toll-like receptor 2 in heart failure following acute myocardial infarction.

BACKGROUND: To determine the relationship between markers of innate immunity and clinical outcomes in patients with heart failure (HF) after acute myocardial infarction (AMI). Atherogenesis and HF is associated with the altered control of inflammation by innate immune defenses that include pattern-recognition molecules such as Toll-like receptors (TLRs) and mannose-binding lectin (MBL). METHODS AND RESULTS: We assessed circulating levels, and relationships with adverse outcomes of MBL and sTLR2 levels in 234 patients with AMI complicated with HF. Blood was sampled at baseline (median 3 days after AMI), 1 month, 1 year, and 2 years. For comparison, we also measured MBL and sTLR2 levels in 20 age- and sex-matched healthy controls. Patients with post-MI HF had markedly decreased serum levels of sTLR2 at baseline that increased during follow-up, but did not reach the concentrations present in healthy controls. In contrast, serum MBL levels were initially normal in patients with post-MI HF, but decreased during follow-up, and MBL levels measured 1 month after the index infarct were inversely associated with a higher incidence of reinfarction. CONCLUSION: These findings suggest that circulating levels of MBL and sTLR2 may reflect different aspects of the innate immune response and further suggest the involvement of innate immunity responses in the pathogenesis of post-MI HF.

Aged↗
PubMed2005

Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study.

BACKGROUND: Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD). METHODS AND RESULTS: Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-alpha, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage. CONCLUSIONS: Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

Aged↗
PubMed2005

Plasma levels of soluble tumor necrosis factor receptor type I during the acute phase following complicated myocardial infarction predicts survival in high-risk patients.

OBJECTIVES: We sought to determine the relationship between circulating cytokine levels and clinical outcomes in patients with heart failure (HF) following acute myocardial infarction (AMI). BACKGROUND: Persistent inflammation plays a role in the development of HF, and various inflammatory cytokines predict cardiovascular events in acute coronary syndromes. METHODS: We measured plasma levels of interleukin (IL)-6, monocyte chemotractant protein 1, IL-10, and soluble tumor necrosis factor receptor type 1 (sTNFR1) during longitudinal testing over a period of two years in 234 patients with HF following AMI recruited for participation in the OPTIMAAL trial, focusing on the possible prognostic value of circulating cytokine levels in these patients. RESULTS: Measurement of sTNFR1 at baseline predicted all-cause mortality and cardiovascular death in patients with post-MI HF after adjustment for other biomarkers that have been shown to give prognostic information in HF patients, such as N-terminal B-type natriuretic peptide. CONCLUSIONS: Assessment of sTNFR1 levels might provide important prognostic information in patients who develop HF during the acute phase following AMI.

Aged↗
PubMed2005

Chemokines in children with heterozygous familiar hypercholesterolemia: selective upregulation of RANTES.

OBJECTIVE: Increasing data support the involvement of chemokines in atherogenesis. However, although several studies have shown increased chemokine levels in adult patients, the literature is virtually devoid of data on chemokines in children with hypercholesterolemia. METHODS AND RESULTS: We examined the gene expression of chemokines in peripheral blood mononuclear cells (PBMCs) from clinically healthy children with and without heterozygous familial hypercholesterolemia (FH). Our main findings were: (1) compared with healthy controls, PBMCs from FH children showed significantly higher mRNA levels of RANTES, but not of the other examined chemokines; (2) an opposite pattern was seen in adult FH subjects, with markedly enhanced expression of macrophage inflammatory peptide-1alpha, but not of RANTES; (3) this increased gene expression of RANTES in PBMCs from FH children seemed to reflect enhanced RANTES expression in monocytes but not in T cells; (4) FH children also had raised serum levels of neopterin, additionally suggesting monocyte/macrophage activation in these children; and (5) PBMCs from both FH children and controls showed enhanced release of interleukin 8 on RANTES stimulation in vitro. CONCLUSIONS: Our findings support a role of inflammation also in the early stages of atherogenesis possibly involving monocyte-derived RANTES as an important mediator.

Adolescent↗
PubMed2005

Enhanced plasma levels of LIGHT in unstable angina: possible pathogenic role in foam cell formation and thrombosis.

BACKGROUND: Numerous studies have demonstrated the ability of oxidized LDL [(ox)LDL] to promote an inflammatory response in macrophages. Several inflammatory mediators have been reported to increase after oxLDL stimulation of such cells, but their relative importance is still unknown. In the present study, we used microarrays to identify genes in THP-1 macrophages that were upregulated by oxLDL. METHODS AND RESULTS: Our main findings were as follows. In a microarray screening experiment, we identified LIGHT, a ligand in the tumor necrosis factor superfamily, as one of the genes that were markedly upregulated in oxLDL-stimulated THP-1 macrophages. We showed significantly raised plasma levels of LIGHT in patients with stable angina (n=40) and particularly in those with unstable angina (n=40) compared with healthy controls (n=20), which underscores the clinical relevance of the in vitro finding. We also showed that LIGHT enhanced lipid accumulation in oxLDL-stimulated THP-1 macrophages, possibly through upregulation of class A scavenger receptor (SR-A). This increased lipid accumulation was accompanied by enhanced expression of tissue factor and plasminogen activator inhibitor-1, as well as enhanced thrombin formation, transforming macrophages into a prothrombotic phenotype. The LIGHT-mediated increase in SR-A, tissue factor, and plasminogen activator inhibitor-1 was also seen in human monocyte-derived macrophages. Finally, the LIGHT-mediated enhancement of SR-A and TF expression appears to involve nuclear factor-kappaB activation. CONCLUSIONS: These findings suggest that LIGHT could serve as a molecular link between lipid metabolism, inflammation, and thrombus formation, which are all features of atherosclerotic plaques.

Aged↗
PubMed2005

Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure.

BACKGROUND: Persistent inflammation appears to play a role in the development of heart failure (HF). Osteoprotegerin (OPG), the receptor activator of nuclear factor-kappaB (RANK), and RANK ligand (RANKL) are newly discovered members of the tumor necrosis factor superfamily that are critical regulators in bone metabolism but appear also to be involved in immune responses. We hypothesized that the OPG/RANK/RANKL axis could be involved in the pathogenesis of heart failure (HF), and this hypothesis was investigated in both experimental and clinical studies. METHODS AND RESULTS: Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue. (2) Enhanced myocardial protein levels of OPG, RANK, and RANKL, in particular, were also seen in human HF, and using immunohistochemistry, we localized these mediators to cardiomyocytes within the LV in both experimental and clinical HF. (3) In human HF, we also found increased systemic expression of RANKL (T cells and serum) and OPG (serum), with increasing levels according to functional, hemodynamic, and neurohormonal disease severity. (4) RANKL increased total matrix metalloproteinase activity in human fibroblasts, which indicates a matrix-degrading net effect and suggests a potential mechanism by which enhanced RANKL expression in HF may contribute to LV dysfunction. CONCLUSIONS: These findings suggest a potential role for known mediators of bone homeostasis in the pathogenesis of HF and possibly represents new targets for therapeutic intervention in this disorder.

Adult↗
PubMed2005

Coping, quality of life, and hope in adults with primary antibody deficiencies.

BACKGROUND: Living with a chronic disease, such as primary antibody deficiency, will often have consequences for quality of life. Previous quality-of-life studies in primary antibody deficiency patients have been limited to different treatment methods. We wanted to study how adults with primary antibody deficiencies manage their conditions and to identify factors that are conducive to coping, good quality of life and hope. METHODS: Questionnaires were sent to all patients > or =20 years of age with primary antibody deficiencies who were served by Rikshospitalet University Hospital. The questionnaires consisted of several standardized scales: Ferrans and Powers Quality of Life Index (QLI), Short Form-36 (SF-36), Jalowiec Coping Scale (JCS), Nowotny Hope Scale (NHS), and one scale we devised with questions about resources and pressures in the past. Of a total of 91, 55 patients (aged 23-76 years) answered the questionnaires. The questionnaire study were supplemented with selected interviews of ten extreme cases, five with low and five with high quality of life scores. RESULTS: Among the 55 patients, low quality of life scores were related to unemployment, infections in more than four organs, more than two additional diseases, or more than two specific occurrences of stress in the last 2-3 months. Persons with selective IgA deficiency had significantly higher QLI scores than those with other antibody deficiencies. An optimistic coping style was most frequent used, and hope values were moderately high. Based on the interviews, the patients could be divided into three groups: 1) low QLI scores, low hope values, and reduced coping, 2) low QLI scores, moderate hope values, and good coping, and 3) high QLI scores, moderate to strong hope values, and good coping. Coping was related to the patients' sense of closeness and competence. CONCLUSION: Low quality of life scores in adults with primary antibody deficiencies were linked to unemployment and disease-related strains. Closeness and competence were preconditions for coping, quality of life and hope. The results are valuable in planning care for this patient group.

Activities of Daily Living↗
PubMed2005

Soluble CD40 ligand in acute and chronic heart failure.

AIMS: Inflammatory cytokines may play a pathogenic role in heart failure (HF). CD40-CD40 ligand (CD40L) interactions are important in atherogenesis and based on its role in inflammation we sought to evaluate the role of CD40L in human HF. METHODS AND RESULTS: Serum levels of soluble (s) CD40L were measured in 236 patients with acute HF following myocardial infarction, treated with either angiotensin-converting enzyme (ACE)-inhibition or angiotensin II blockade and followed for 2 years, and in 116 patients with chronic HF. Our main findings were: (i) patients with acute HF had increased sCD40L levels, particularly those with severe HF, diabetes, or hypertension; (ii) when these patients were followed longitudinally, persistently raised sCD40L levels were found throughout the observation period with no effect of captopril or losartan; (iii) the increase in sCD40L during follow-up was not seen in patients receiving warfarin therapy; (iv) patients with chronic HF also had raised sCD40L, significantly correlated with clinical severity, neurohormonal dysregulation, and left ventricular dysfunction; (v) studies from different blood compartments suggest that the vasculature of lower extremities and the failing myocardium itself may produce and secrete sCD40L in chronic HF. CONCLUSION: Our findings may suggest a pathogenic role for enhanced CD40-CD40L interactions in human HF.

Acute Disease↗