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Biomedical subjects

L Gullestad

Publications and source records attributed to L Gullestad.

At least 19 recordsLinked to original sources
PubMed2006

Clopidogrel increases expression of chemokines in peripheral blood mononuclear cells in patients with coronary artery disease: results of a double-blind placebo-controlled study.

BACKGROUND: Chemokines and platelet activation are both important in atherogenesis. Platelet inhibitors are widely used in coronary artery disease (CAD), and we hypothesized that the platelet inhibitor clopidogrel could modify chemokines in CAD patients. OBJECTIVES: We sought to investigate the effect of clopidogrel on the expression of chemokines and chemokine receptors in peripheral blood mononuclear cells (PBMC) in CAD patients. PATIENTS/METHODS: Thirty-seven patients with stable angina were randomized to clopidogrel (n = 18) or placebo (n = 19). PBMC, blood platelets and plasma were collected at baseline and after 7-10 days in the patients, and in 10 healthy controls. mRNA levels of chemokines and chemokine receptors in PBMC were analyzed by ribonuclease protection assays and real-time reverse transcriptase polymerase chain reaction. Platelet activation was studied by flow cytometry. RESULTS: (i) At baseline, the gene expression of the regulated on activation normally T-cell expressed and secreted (RANTES) chemokines and macrophage inflammatory peptide (MIP)-1beta in PBMC, the expression of CD62P and CD63 on platelets and the levels of platelet-derived microparticles (PMP) were elevated in angina patients comparing healthy controls; (ii) markers of platelet activation were either reduced (CD63) or unchanged (CD62P, PMP, beta-thromboglobulin) during clopidogrel therapy; (iii) in contrast, clopidogrel significantly up-regulated the gene expression of RANTES and MIP-1beta in PBMC, while no changes were found in the placebo group; (iv) a stable adenosine 5'-diphosphate metabolite attenuated the release of MIP-1beta, but not of RANTES, from activated PBMC in vitro. CONCLUSIONS: Even if we do not argue against a beneficial role for clopidogrel in CAD, our findings may suggest potential inflammatory effects of clopidogrel in CAD.

Aged↗
PubMed2006

Increased inflammatory markers in children with familial hypercholesterolaemia.

BACKGROUND: While data are abundant on increased levels of inflammatory markers in adult patients with hypercholesterolaemia, such data in children are limited. Therefore, we sought to investigate the degree and character of inflammation in children with heterozygous familial hypercholesterolaemia (FH) by measuring levels of neopterin, high-sensitivity C-reactive protein (hsCRP), and soluble CD40 ligand (sCD40L). MATERIALS AND METHODS: In the present study, we compared the concentration of inflammatory markers in children suffering from heterozygous FH (n = 207) with those in unaffected siblings (n = 84). Furthermore, we investigated the effect of 2-year treatment with pravastatin (20-40 mg qd) or placebo on plasma levels of those markers. RESULTS: Our main finding was that serum levels of neopterin and hsCRP were significantly higher in FH children compared with healthy siblings, whereas sCD40L was not. Body mass index and high-density lipoprotein cholesterol levels were significant independent predictors of hsCRP and neopterin. Furthermore, pravastatin therapy decreased neopterin, but not hsCRP and sCD40L, in the FH children, but these changes were not different from the placebo group. CONCLUSION: These findings indicate low-grade monocyte/macrophage hyperactivity in the early stages of atherogenesis, but our findings also suggest that inflammation as well as anti-inflammatory effects of statins are less prominent features of atherosclerosis in FH children than in FH adults.

Adolescent↗
PubMed2006

Undiagnosed dysglycaemia and inflammation in cardiovascular disease.

BACKGROUND: Cardiovascular (CV) disease is associated with increased levels of glucose, but the prevalence of dysglycaemia in CV diseases is not fully known. The study examined the prevalence of unknown dysglycaemia and its association with inflammation in Caucasian patients with ischaemic vascular complications, i.e. coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral artery disease (PAD). MATERIALS AND METHODS: This case-controlled study involved 149 patients (mean age 68 years) hospitalized for CAD, PAD or CVD and 59 control-subjects (CTR) free from CV-disease. The prevalence of dysglycaemia according to WHO/ADA criteria (impaired fasting glycaemia, impaired glucose tolerance or diabetes mellitus) was assessed by a 75-g oral glucose tolerance test. Inflammatory parameters were analyzed in fasting samples. RESULTS: Dysglycaemia was found in 49%, 55% and 57% of patients with CAD, CVD and PAD, respectively; all were significantly higher than among the controls (29%). The odds ratio (95% CI) for being dysglycaemic were 1.7 (1.04-2.77), 1.9 (1.19-3.06) and 2.0 (1.25-3.19) for CAD, CVD and PAD, respectively. Inflammatory markers (the total leucocyte count, soluble tumour necrosis factor-receptor type I, C-reactive protein) were elevated in patient groups and tended to increase with increasing blood glucose levels in all groups. The levels of the anti-inflammatory cytokine transforming growth factor-beta1 and insulin-like growth factor binding protein 3 were lowered in patients with CAD and, in patients with PAD, the former was inversely related to the levels of the blood glucose. CONCLUSIONS: Undiagnosed dysglycaemia was common in patients with ischaemic CV manifestations regardless of vascular bed involved. Inflammation was associated in a dosage-related manner to glucose levels.

Adult↗
PubMed2003

The effect of a neuropeptide Y Y1 receptor antagonist in patients with angina pectoris.

AIMS: Neuropeptide Y (NPY) is a potent vasoconstrictor released during sympathetic activation that may be involved in myocardial ischaemia. We examined the effect of a Y1 receptor antagonist on haemodynamic and ischaemic responses to exercise in patients with coronary artery disease. METHODS AND RESULTS: Eighty-two evaluable male patients were included in a randomized, double blind, two-way crossover study with a low dose (6.7 microg/kg/min; n=59)and a high dose (13.3 microg/kg/min; n=23) of the Y1 receptor antagonist AR-H040922 given as infusions for 2h or placebo. Myocardial ischaemia during a symptom-limited exercise test was monitored by conventional ST-segment analysis and heart rate (HR)-adjusted ST changes including the ST/HR slope and ST/HR recovery. Administration of the high dose AR-H040922 attenuated systolic blood pressure by 6-11 mmHg (p<0.05) during and after exercise without affecting HR. None of the two doses of AR-H040922 influenced any of the ischaemic parameters or duration of exercise, however. The maximal increase in NPY was higher during AR-H040922 (p<0.05) compared with placebo. CONCLUSIONS: Selective NPY Y1 receptor blockade attenuates the increase in blood pressure during exercise indicating a role for endogenous NPY in blood pressure regulation. Despite this effect, the Y1 receptor antagonist did not influence exercise-induced ischaemic parameters in patients with coronary artery disease.

Adult↗
PubMed2003

CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells.

CXC-chemokines may be involved in atherogenesis. Herein we examined the possible role of CXC-chemokines in the inflammatory interactions between oxidized (ox-) low-density lipoprotein (LDL), platelets and peripheral blood mononuclear cells (PBMC) in 15 patients with coronary artery disease (CAD) without 'traditional' risk factors and 15 carefully matched controls. Our main findings were: (a) ox-LDL stimulated the release of the CXC-chemokines interleukin (IL)-8, ENA-78 and GRO-alpha from PBMC, particularly in CAD. (b) In platelets, ox-LDL induced release of ENA-78 and, when combined with SFLLRN, also of GRO-alpha, with significantly higher response in CAD. (c) Platelet-rich plasma, especially when costimulated with ox-LDL, enhanced the release of IL-8 from PBMC, particularly in CAD patients. (d) Freshly isolated PBMC showed markedly increased IL-8 mRNA expression in CAD patients. Our findings suggest enhanced inflammatory interactions between ox-LDL, platelets and PBMC in CAD patients involving CXC-chemokine related mechanisms, possible contributing to atherogenesis in these and other CAD patients.

Adult↗
PubMed2002

Inflammatory imbalance between IL-10 and TNFalpha in unstable angina potential plaque stabilizing effects of IL-10.

BACKGROUND: The pathogenesis of atherosclerosis and acute coronary syndromes involves inflammation and immunological mechanisms. We hypothesized that patients with unstable angina may have an imbalance between inflammatory and anti-inflammatory cytokines. DESIGN: Plasma levels of tumour necrosis factor (TNF)alpha and interleukin (IL)-10 were analyzed in 44 patients with stable angina, 29 patients with unstable angina and 20 controls. mRNA levels of these cytokines were analyzed in peripheral blood mononuclear cells (PBMC). We also studied the in vitro effects of IL-10 in PBMC from unstable angina patients. RESULTS: Our main findings were: (1) the angina patients and particularly those with unstable disease had significantly raised TNFalpha in comparison with the controls, both at the protein and mRNA level; (2) in contrast, the levels of IL-10 were not different in the angina patients in comparison with the healthy controls, resulting in a markedly enhanced TNFalpha:IL-10 ratio, particularly in the unstable angina patients; (3) while exogenously added IL-10 markedly inhibited the release of TNFalpha, IL-8 and tissue factor as well as impairing the gelatinolytic activity and mRNA production of matrix metalloproteinase-9, it enhanced the tissue inhibitor of this metalloproteinase (i.e. TIMP-1) in PBMC from the unstable angina patients. CONCLUSION: Patients with unstable angina appear to have an imbalance between TNFalpha and IL-10, possibly favouring inflammatory net effects. IL-10 may have beneficial effects on mechanisms that are important in plaque rupture and thrombus formation.

Adult↗
PubMed2001

Complement activation in patients with congestive heart failure: effect of high-dose intravenous immunoglobulin treatment.

BACKGROUND: Increasing evidence implicates innate immunity in the pathogenesis of congestive heart failure (CHF). In the present study, we examined the possible role of complement, an important part of innate immunity, in CHF. METHODS AND RESULTS: Complement activation was analyzed in systemic and coronary circulation in 39 patients with CHF and 20 healthy control subjects. In a double-blind, placebo-controlled study, we have recently reported that high-dose intravenous immunoglobulin (IVIG) improves left ventricular ejection fraction (LVEF) in these patients. To examine if this improvement was related to IVIG-induced effects on complement, we also examined complement activation during induction (first week) and maintenance therapy (6 months) with IVIG or placebo. Our main findings were: (1) We found enhanced systemic complement activation involving classic, alternative, as well as terminal pathway in patients with CHF compared with healthy control subjects. (2) Particularly enhanced complement activation was found in coronary sinus, representing venous drainage from the heart. (3) The systemic complement activation was further enhanced during IVIG but not during placebo therapy, particularly during induction therapy. (4) Although IVIG improved LVEF in patients with CHF, the degree of IVIG-mediated complement activation was negatively correlated with this improvement of LVEF. CONCLUSIONS: This study further supports the involvement of innate immunity in the pathogenesis of CHF. Our findings suggest that complement may be added to the list of possible therapeutic targets in CHF and that future studies with specific complement inhibitors may be of interest in this disorder.

C-Reactive Protein↗
PubMed2001

Omega-3 fatty acids enhance tumor necrosis factor-alpha levels in heart transplant recipients.

BACKGROUND: Proinflammatory cytokines may contribute to clinical complications in heart transplant (HTx) recipients. Previous studies have shown immunomodulating effects of omega-3 fatty acids, but the results are somewhat conflicting. In this study, we examined plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL) 10, and their relations to antioxidant vitamins in 45 HTx recipients before and after treatment with omega-3 fatty acids or placebo. METHODS: The patients were long-time survivors of heart transplantation, randomized in a double-blind fashion to receive omega-3 fatty acids (3.4 g/day) or placebo for 1 year. Plasma levels of cytokines were measured by enzyme immunoassays and vitamin A, vitamin E, and beta-carotene by high-performance liquid chromatography. RESULTS: In the omega-3, but not in the placebo group, there was a rise in the proinflammatory cytokine TNF-alpha (P<0.05), a decrease in the anti-inflammatory cytokine IL-10 (P=0.07), and a rise in TNF/IL-10 ratio (P<0.05) after 12 months, suggesting a proinflammatory net effect. In the omega-3 group, the increase in TNF-alpha was associated with an increase in eicosapentaenoic acid in plasma (r=0.58, P<0.02). During omega-3 fatty-acid treatment, but not during placebo, there was a decrease in vitamin E (P<0.05) and beta-carotene (P<0.05) levels, and the decrease in vitamin E was inversely correlated with the increase in TNF-alpha (r= -0.56, P<0.01). The rise in TNF-alpha levels during omega-3 fatty acids treatment was most pronounced in those patients with transplant coronary artery disease (P<0.04). CONCLUSION: Our data suggest that omega-3 fatty acids in HTx recipients may change the balance between proinflammatory and anti-inflammatory cytokines in an inflammatory direction, possibly related to prooxidative effects of these fatty acids.

Double-Blind Method↗
PubMed2001

[Immunomodulating treatment in advanced heart failure--effect of intravenous immunoglobulin].

BACKGROUND: Congestive heart failure is characterised by enhanced immune activation. Immune-mediated mechanisms may play a pathogenic role, hence the growing interest in therapeutic regimens that could modulate the immune response in heart failure. MATERIAL AND METHODS: In the present report we discuss the pathogenic role of immunological and inflammatory mediators in the pathophysiology of heart failure and discuss different treatment modalities with focus on our recent study with intravenous immunoglobulin. In that study 40 patients with symptomatic chronic heart failure and left ventricular ejection fraction (LVEF) < 40% were randomised in a double-blind fashion to receive therapy with immunoglobulin or placebo for a total period of 26 weeks. RESULTS: We found that intravenous immunoglobulin, but not placebo, shifted the cytokine balance in an anti-inflammatory direction, and that such a shift was associated with improvement in LVEF by 5 EF units. Functional capacity and haemodynamic variables also improved. INTERPRETATION: Our study supports the hypothesis that immunological variables might be of significant importance in the pathogenesis of heart failure and it suggests a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in such patients. These issues are further discussed in the present article.

Adjuvants, Immunologic↗
PubMed2001

Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients.

Statins appear to have several biologic effects beyond those of lipid metabolism, and we hypothesized that immunomodulating effects of statins are important for the beneficial effects of these medications after heart transplantation. Our findings suggest that pravastatin treatment reduces plasma markers of inflammation and improves peripheral endothelial function in heart transplant recipients, possibly contributing to the observed clinical benefits of statin treatment in these patients.

Cell Adhesion Molecules↗
PubMed2001

Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure.

BACKGROUND: Congestive heart failure (CHF) is characterized by enhanced immune activation, and immune-mediated mechanisms may play a pathogenic role in this disorder. Based on the immunomodulatory effects of intravenous immunoglobulin (IVIG), we hypothesized that IVIG could downregulate inflammatory responses in CHF patients and have potential beneficial effects on the left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Forty patients with chronic symptomatic CHF and LVEF of <40%, stratified according to cause (ie, ischemic and idiopathic dilated cardiomyopathy), were randomized in a double-blind fashion to receive therapy with IVIG or placebo for a total period of 26 weeks. Our main findings were that (1) IVIG, but not placebo, induced a marked rise in plasma levels of the anti-inflammatory mediators interleukin (IL)-10, IL-1 receptor antagonist, and soluble tumor necrosis factor receptors; (2) significantly correlated with these anti-inflammatory effects, IVIG, but not placebo, induced a significant increase in LVEF from 26+/-2% to 31+/-3% (P:<0.01), and this was found independent of the cause of heart failure; and (3) N-terminal pro-atrial natriuretic peptide decreased significantly after induction therapy and continued to decrease toward the end of study during IVIG therapy (P:<0.001) but remained unchanged during placebo. CONCLUSIONS: We demonstrated an IVIG-induced change in the balance between inflammatory and anti-inflammatory cytokines that favored an anti-inflammatory net effect in CHF. This effect was significantly correlated with an improvement in LVEF, suggesting a potential for immunomodulating therapy in addition to optimal conventional cardiovascular treatment regimens in CHF patients.

Adjuvants, Immunologic↗
PubMed2001

Monocyte chemoattractant protein-1 enhances and interleukin-10 suppresses the production of inflammatory cytokines in adult rat cardiomyocytes.

OBJECTIVE: Chemokines control the migration of leukocytes to inflamed tissue, and in particular monocyte chemoattractant protein (MCP)-1 has been implicated in the pathogenesis of several cardiovascular disorders such as chronic heart failure (CHF) and myocarditis. We hypothesised that MCP-1 may directly contribute to an inflammatory response in the cardiomyocytes, and in the present study we examined in adult rat cardiomyocytes: (i) the effect of tumour necrosis factor (TNF)alpha on MCP-1 production, (ii) the effect of MCP-1 on production of other inflammatory cytokines, and (iii) if the anti-inflammatory cytokine interleukin (IL)-10 could suppress any TNFalpha-induced MCP- 1 production. METHODS: We used enzyme immunoassays, RNase protection assays and slot blot analysis to measure protein and mRNA levels of various cytokines in adult rat cardiomyocyte cultures. RESULTS: (i) We found a approximately 6.4-fold increase of the MCP-1 level accompanied by an increase in MCP-1 mRNA accumulation in cardiomyocyte cultures after TNFalpha stimulation. (ii) In contrast, TNFalpha had no effect on IL-10 and only a modest effect on IL-1beta and IL-6 levels in these cells. (iii) Importantly, MCP-1 stimulated inflammatory response in cardiomyocytes by enhancing IL- 1beta and IL-6 levels in these cells as found at both the protein and mRNA level. (iv) Co-stim-ulation with IL-10 resulted in a approximately 55% reduction in TNFalpha-stimulated MCP-1 levels in cardiomyocyte culture supernatants. CONCLUSION: The present study demonstrates for the first time that MCP- 1 can directly affect cardiomyocytes, and we introduce MCP-1 as a potential enhancer and IL- 10 as a potential suppresser of inflammatory responses within the myocardium.

Animals↗
PubMed2001

Effect of folic acid treatment on endothelium-dependent vasodilation and nitric oxide-derived end products in hyperhomocysteinemic subjects.

PURPOSE: An elevated plasma homocysteine concentration is an independent risk factor for cardiovascular diseases. In this study, we tested the hypothesis that hyperhomocysteinemia induces endothelial dysfunction mediated, at least in part, through nitric oxide-dependent mechanisms and that folic acid supplementation improves endothelial function in hyperhomocysteinemic subjects. SUBJECTS AND METHODS: Endothelial function was evaluated in healthy controls and hyperhomocysteinemic subjects by measuring plasma levels of the nitric oxide-derived end products nitrite and nitrate and by assessing vasodilatory responses in the skin microcirculation and forearm vasculature. In the subjects with hyperhomocysteinemia, these measurements were repeated after 6 weeks and 12 months of folic acid supplementation. RESULTS: Compared with healthy controls, hyperhomocysteinemic subjects had significantly lower median plasma levels of nitric oxide-derived end products (12.1 microM [range 4.4 to 41.8] versus 24.6 microM [13.6 to 53.2]; P <0.001), a significantly lower endothelium-dependent vasodilatory response to acetylcholine (P <0.01), hyperemic response in the microcirculation (P <0.01), and total forearm blood flow during reactive hyperemia (P = 0.01). There was no significant difference in the endothelium-independent response. Folic acid treatment for 12 months increased the plasma level of nitric oxide-derived end products by 121% (95% confidence interval [CI], 72% to 170%), the vasodilatory response to acetylcholine by 124% (95% CI, 36% to 212%), and the ischemia-mediated hyperemic responses in the microcirculation by 60% (95% CI, 25% to 96%) and in the forearm vasculature by 47% (95% CI, 21% to 73%). CONCLUSIONS: Homocysteine appears to induce its atherogenic effect, at least in part, by depressing endothelial function, possibly through nitric oxide-dependent mechanisms. This effect can be reversed by folic acid supplementation.

Adult↗
PubMed2001

Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes.

OBJECTIVES: We sought to study the relationships between chemokines and oxidative stress in acute coronary syndrome. BACKGROUND: In view of existing knowledge on the participation of leukocytes and oxidative stress in the pathogenesis of acute coronary syndrome, we hypothesized that chemokines may play a role in recruiting and activating leukocytes in this disorder. METHODS: The levels of chemokines and oxidative stress were studied in 38 patients with stable and 38 with unstable angina and in 20 controls. In separate in vitro experiments the effect of chemokines on reactive oxygen species in monocytes and the effect of antioxidants on chemokine levels in these cells were also studied. RESULTS: 1) Angina patients had raised serum levels of chemokines in both cross-sectional and longitudinal testing, with particularly high levels of interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory peptide (MIP)-1-alpha in unstable disease. 2) T cells, and particularly monocytes, seem to contribute to the raised IL-8, MCP-1 and MIP-1-alpha levels in unstable angina. 3) Concomitantly, and significantly correlated with MCP-1 and IL-8 levels, stable and particularly unstable angina patients had decreased plasma levels of antioxidants and increased lipid peroxidation, suggesting enhanced oxidative stress. 4) Monocyte chemoattractant protein-1 enhanced the generation of O2- in monocytes from unstable angina patients, and the antioxidant glutathione-monoethyl ester suppressed the production of IL-8 and MCP-1 in these cells. CONCLUSIONS: Our findings suggest an interaction between chemokines and oxidative stress in unstable angina. This interaction may represent a vicious circle involved in the pathogenesis of acute coronary syndromes.

Adult↗
PubMed2001

Enhanced gene expression of chemokines and their corresponding receptors in mononuclear blood cells in chronic heart failure--modulatory effect of intravenous immunoglobulin.

OBJECTIVES: We sought to study the gene expression of chemokines and their corresponding receptors in mononuclear blood cells (MNCs) from patients with chronic heart failure (CHF), both of which were cross-sectional and longitudinal studies during therapy with intravenous immunoglobulin (IVIg). BACKGROUND: We have recently demonstrated that IVIg improves left ventricular ejection fraction (LVEF) in patients with CHF. Based on the potential pathogenic role of chemokines in CHF, we hypothesized that the beneficial effect of IVIg may be related to a modulatory, effect on the expression of chemokines and their receptors in MNCs. METHODS: We examined: 1) the gene expression of C, CC and CXC chemokines and their receptors in MNCs from 20 patients with CHF and 10 healthy blood donors; and 2) the expression of these genes in MNCs from 20 patients with CHF randomized in a double-blind fashion to therapy with IVIg or placebo for 26 weeks. RESULTS: Our main findings in CHF were: 1) markedly raised gene expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and interleukin (IL)-8; 2) enhanced gene expression of their corresponding receptors; 3) modulation in a normal direction of this abnormal chemokine and chemokine receptor gene expression during IVIg, but not during placebo therapy; 4) down-regulation of MIP-1alpha, MIP-1beta and IL-8 during IVIg at the protein level in plasma; and 5) a correlation between down-regulation of MIP-1alpha gene expression and improved LVEF during IVIg therapy. CONCLUSIONS: Our results further support a pathogenic role for chemokines in CHF and suggest that IVIg may represent a novel therapeutic approach, with the potential to improve LVEF in patients with CHF, possibly by modulatory effects on the chemokine network.

Aged↗
PubMed2001

Effect of metoprolol CR/XL on exercise tolerance in chronic heart failure - a substudy to the MERIT-HF trial.

BACKGROUND: Beta-blockade usually causes a slight reduction in exercise capacity among healthy subjects, while more variable results have been observed in chronic heart failure (CHF), probably related to patients studied, methods and agent used. The effect of metoprolol controlled release/extended release (CR/XL) on peak oxygen uptake (peak VO(2)) in this patient population has not previously been investigated. AIMS: We examined the effect of long-term treatment with the selective beta(1)-receptor blocker metoprolol CR/XL once daily on exercise capacity in patients with CHF. METHODS: Ninety-four patients (70 males and 24 females; mean age 63.6+/-10.6 years) with chronic symptomatic heart failure in New York Heart Association (NYHA) functional class II-IV, and with ejection fraction <or=40%, stabilized on optimum standard therapy were randomized to metoprolol CR/XL or placebo in a double-blind trial. Exercise capacity was evaluated by peak VO(2) at baseline, after 3 months and at the end of study (mean follow-up 11.4+/-0.4 months). RESULTS: Compared with placebo metoprolol CR/XL produced a significant decrease in heart rate by 11 beats/min at rest and 18 beats/min at peak exercise. There was a tendency for a temporal decline in peak VO(2) after 3 months of therapy in both groups, but altogether peak VO(2) remained unchanged from baseline with no difference between the groups at 1 year. CONCLUSIONS: In patients with moderate to severe CHF, 11.4 months of beta(1)-blockade with metoprolol CR/XL had no effect on exercise capacity when compared with placebo or baseline.

Aged↗
PubMed2001

Myocardial gene expression of leukaemia inhibitory factor, interleukin-6 and glycoprotein 130 in end-stage human heart failure.

BACKGROUND: Studies in different animal models and plasma analyses in humans suggest that members of the interleukin-6 (IL-6) cytokine family may be involved in the pathogenesis of congestive heart failure (CHF). Accordingly, we have examined IL-6-related cytokines in chronic CHF in humans by analysing gene and protein expression in myocardium derived from patients with end-stage heart failure and donor hearts. METHODS: Gene expression of cytokines/receptors of the IL-6 family was documented in myocardial samples using cDNA array hybridization and RNase protection assays. Immunohistochemistry was used to detect leukaemia inhibitory factor (LIF), IL-6 and glycoprotein 130 (gp130) in myocardial tissues. RESULTS: Myocardial gene activity was documented for the majority of IL-6 family cytokines and their receptors. Immunohistochemical analysis localized IL-6, LIF and their common receptor subunit gp130 to myocytes and vascular smooth muscle cells. LIF mRNA levels were enhanced in the left ventricles of CHF patients relative to the left ventricles of donor hearts (patients 4.6 +/- 4.7 vs. donors 0.3 +/- 0.3, P < 0.005). Myocardial IL-6 and gp130 mRNA levels were not statistically different between patients and donors, but in contrast to LIF mRNA expression in heart explants, gp130 mRNA levels were significantly higher in left atrium compared with left ventricle in both patients and donors. CONCLUSIONS: Both mRNA and proteins of gp130 and its ligands IL-6 and LIF are expressed in both nonfailing and failing human myocardium. The elevated LIF mRNA levels in left ventricles from patients with end-stage heart failure suggest a role for LIF in the pathogenesis of CHF.

Adult↗