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Biomedical subjects

H Aass

Publications and source records attributed to H Aass.

At least 19 recordsLinked to original sources
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

[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

Differential effects of cocaine on the positive inotropic effect of noradrenaline mediated by alpha1- and beta-adrenoceptors in failing human myocardium.

Electrically driven (1 Hz) ventricular trabeculae from explanted failing human myocardium were indirectly examined for the localization of the alpha1-adrenoceptor population and the beta-adrenoceptor population in relation to sympathetic nerve endings. We examined the influence of neuronal uptake blockade by cocaine upon the horizontal position of the concentration-response curves for the inotropic effects exerted by noradrenaline in the presence and absence of appropriate adrenoceptor antagonists. Cocaine shifted the concentration-response curve for alpha1-adrenoceptor stimulation, but not that for beta-adrenoceptor stimulation, to lower concentrations of noradrenaline in a parallel manner. The concentration-response curve for combined adrenoceptor stimulation was shifted by cocaine to lower concentrations of noradrenaline in a nonparallel manner. In explanted allograft heart, cocaine had no effect upon the position of the concentration-response curve to alpha1-adrenoceptor stimulation. The data indicate that in the explanted native hearts the alpha1-adrenoceptor population is located close to or within the synaptic cleft, while the beta-adrenoceptor population remaining in the failing myocardium is located more distantly to the neuronal release sites.

Adult↗
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

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

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↗
PubMed2001

When should heparin preferably be administered during radiofrequency catheter ablation?

RF catheter ablation is complicated by thromboembolism in about 1% of patients. Limited knowledge exists concerning when and how to use anticoagulation or antithrombotic treatment. We studied the activation of coagulation (prothrombin fragment 1 + 2 [PF1 + 2] and D-dimer), platelets (beta-thromboglobulin [beta-TG]) and fibrinolysis (plasmin-antiplasmin complexes [PAP]) during RF ablation of accessory pathways in 30 patients. They were randomized to receive heparin (100 IU/kg, intravenously) (1) immediately after introduction of the femoral venous sheaths (group I) or (2) after the initial electrophysiological study, prior to the delivery of RF current (groups II and III). Group II additionally received saline irrigation of all femoral sheaths. After the initial bolus, 1,000 IU of heparin was supplied hourly in all groups. Within groups II and III, median plasma values of PF1 + 2 and beta-TG more than tripled (P < or = 0.007) during the diagnostic study and gradually declined during heparin administration despite RF current delivery. Median D-dimer tripled (P = 0.005) and PAP doubled (NS) before heparin administration; then both remained around the upper reference values. In the early heparin group, however, PF1 + 2, D-dimer, and PAP did not rise at all, and beta-TG showed only a slight increase towards the end of the procedure. The differences between group I versus groups II and III were statistically significant prior to the first RF current delivery (PF1 + 2, D-dimer, and beta-TG) and by the end of the procedure (PF1 + 2, D-dimer, and PAP). In conclusion, "late" heparin administration allows hemostatic activation during the initial catheterization and diagnostic study. By administering intravenous heparin immediately after introduction of the venous sheaths, hemostatic activation is significantly decreased. Saline irrigation of the venous sheaths added nothing to late heparin administration.

Adult↗
PubMed2000

[Cardiac manifestations in Fabry disease].

BACKGROUND: Fabry's disease is an X-linked inborn error of metabolism. The patients lack or have very low activity of the enzyme alpha-galactosidase A. This results in deposition of sphingolipids in endothelial cells and vascular smooth muscle cells; thus the disease can affect nearly every organ in the body. Renal failure is the most common cause of death, but cardiac involvement is frequent. MATERIAL AND METHODS: We describe two brothers with Fabry's disease and provide a review of the literature in the field. RESULTS: Both patients had extensive electro- and echocardiographic findings. INTERPRETATION: Fabry's disease should be suspected in men with unexplained electro- and/or echocardiographic signs of left ventricular hypertrophy and a short PQ interval in the ECG.

Adult↗
PubMed2000

Management of atrial flutter.

Typical atrial flutter is a macroreentrant arrhythmia of the right atrium. The isthmus area between the tricuspid annulus, the inferior vena cava, and the ostium of the coronary sinus is a critical zone of the reentry circle. Atrial flutter has been treated with class I and III antiarrhytmic drugs to maintain sinus rhythm, with moderate success. Catheter ablation has been highly successful in treating atrial flutter. A contiguous line of bidirectional electrical block is created in the isthmus area between the tricuspid annulus and the inferior vena cava by application of radiofrequency energy. In patients with both atrial flutter and atrial fibrillation, ablation of the atrial flutter circuit may make the atrial fibrillation more easy to control. Quality of life assessments show improvement after ablation of atrial flutter. With a probability of success of 90%, a recurrence rate of 5% to 15%, and few complications, catheter ablation emerges as the best treatment of recurrent, symptomatic flutter.

Animals↗
PubMed2000

Myocardial expression of CC- and CXC-chemokines and their receptors in human end-stage heart failure.

OBJECTIVES: Chemokines regulate several biological processes, such as chemotaxis, collagen turnover, angiogenesis and apoptosis. Based on the persistent immune activation with elevated circulating levels of chemokines in patients with congestive heart failure (CHF), we have hypothesised a pathogenic role for chemokines in the development of CHF. The objective of this study was to examine mRNA levels and cellular localisation of chemokines and chemokine receptors in human CHF. METHODS: We examined explanted hearts from ten patients with end-stage heart failure (all chambers) and in ten organ donors using an RNase protection assays and immunohistochemical techniques. RESULTS: Our main findings were: (i) expression of eight chemokine and nine chemokine receptor genes in both failing and nonfailing myocardium, (ii) particularly high mRNA levels of monocyte chemoattractant protein (MCP)-1 and CXC-chemokine receptor 4 (CXCR4), in both chronic failing and nonfailing myocardium, (iii) decreased mRNA levels of MCP-1 and interleukin (IL)-8 in the failing left ventricles compared to failing left atria, (iv) decreased chemokine (e.g., MCP-1 and IL-8) and increased chemokine receptor (e.g., CCR2, CXCR1) mRNA levels in failing left ventricles and failing left atria compared to corresponding chambers in the nonfailing hearts and (v) immunolocalisation of MCP-1, IL-8 and CXCR4 to cardiomyocytes. CONCLUSION: The present study demonstrates for the first time chemokine and chemokine receptor gene expression and protein localisation in the human myocardium, introducing a new family of mediators with potentially important effects on the myocardium. The observation of chemokine dysregulation in human end-stage heart failure may represent a previously unknown mechanism involved in progression of chronic heart failure.

Adult↗
PubMed1999

Possible role of proinflammatory cytokines in heart allograft coronary artery disease.

Transplant coronary artery disease (Tx-CAD) is the main determinant of long-term prognosis after heart transplantation. Immunologic processes may play a central role in the development of Tx-CAD, but the pathogenesis has not been fully clarified. We examined plasma levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL)-1beta and IL-6, and the CC-chemokine macrophage chemoattractant protein-1 (MCP-1) in 62 cardiac allograft recipients undergoing yearly heart catherization with coronary angiography for evaluation of graft disease. In this cross-sectional study, we found significantly increased levels of IL-1beta, IL-6, TNF-alpha, and MCP-1 compared with healthy controls even several years (median 7 years) after transplantation in periods with no intercurrent illness. Although no significant differences were found in plasma levels of IL-1beta and TNF-alpha between patients with (n = 25) and without (n = 37) Tx-CAD, the Tx-CAD group had significantly increased levels of IL-6 and MCP-1 compared with both controls and transplant recipients without Tx-CAD. Increased IL-6 levels compared with controls were found only in patients with Tx-CAD. Finally, while there was no significant relation between Tx-CAD and altered lipid status, the combination of high plasma concentrations of IL-6 or MCP-1 and high low-density lipoprotein cholesterol was strongly associated with increased occurrence of Tx-CAD. These findings indicate that cardiac allograft recipients have a persistent immune activation long term after transplantation. This activation, as particularly reflected in increased MCP-1 and IL-6 levels, may be related to the development of Tx-CAD.

Adult↗
PubMed1999

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.

Adult↗
PubMed1999

Temperature-controlled radiofrequency catheter ablation with a 10-mm tip electrode creates larger lesions without charring in the porcine heart.

BACKGROUND: Radiofrequency catheter ablation of atrial flutter, atrial fibrillation or ventricular tachycardia may be favoured by large lesions. We compared lesions created in unipolar mode using 10-mm/8 F electrodes with those of 4-mm/7 F catheters. METHODS: Ablations were first performed in porcine hearts in vitro (70 degrees C, 60 s, tangential catheter tip-tissue orientation). Anaesthetized pigs were thereafter ablated with 10- or 4-mm catheters in the right atrial free wall (RAFW), inferior vena cava-tricuspid valve (IVC-TV) isthmus and left ventricle (LV). RESULTS: In vitro, lesion length doubled and lesion volume tripled using the 10-mm catheter. Average power supply was 69 (SD12) (10-mm tip) versus 26 (SD7) W (4-mm tip). In vivo, lesion length increased by 50% and lesion volume fivefold. Charring at the lesion surface or sudden impedance rises were not observed in vivo. Histologically, coagulation necrosis and minor haemorrhages were found. One RAFW lesion (10-mm) showed a dissection approaching the epicardium. Fibrinous platelet clots or overt thromboses covered the endocardial surface in half of all lesions. Three 10-mm electrode isthmus lesions extended to the right descending posterior artery and one LV lesion to the left anterior descending artery, but there was no damage to the arterial walls. Following six ablations with the 10-mm electrode and two with the 4-mm tip, injury to the adjacent lung tissue of 0.5 to 6.0 mm depth was found (p = 0.22). CONCLUSION: RF ablation using 10-mm/8 F electrodes created significantly larger lesions. 10-mm electrodes appeared safe in the porcine IVC-TV isthmus and LV, but not in the RAFW.

Animals↗
PubMed1999

The activation of platelet function, coagulation, and fibrinolysis during radiofrequency catheter ablation in heparinized patients.

INTRODUCTION: Catheter ablation may be complicated by clinical thromboembolism in about 1% of patients. METHODS AND RESULTS: We studied the activation of coagulation (prothrombin fragment 1+2 [PF1+2]), platelets (beta-thromboglobulin [beta-TG])) and fibrinolysis (plasmin-antiplasmin complexes [PAP] and D-dimer) during radiofrequency (RF) ablation in 13 patients. They received heparin 100 U/kg intravenously after the initial electrophysiologic study, prior to the delivery of RF current; thereafter 1,000 U/hour throughout the procedure. PF1+2 increased fourfold (P < 0.001) during the diagnostic study, but gradually declined to upper reference value during heparin administration. There was a strong correlation between procedure duration prior to heparin bolus (range 39 to 173 min); and (a) the maximal rise of PF1+2 (r = 0.83, P < 0.001) and (b) the increase of PF1+2 from baseline to end of the procedure (r = 0.74, P = 0.004). There was no correlation between postheparin changes of PF1+2 and (a) postheparin procedure duration (range 40 to 317 min), (b) number of RF pulses (range 1 to 16), or (c) RF current duration (range 46 to 687 sec). Plasma beta-TG concentration showed similar trends. Fibrinolytic activity increased moderately from baseline until heparin administration; then remained around the upper reference values. PAP at the end of procedure and D-dimer at the time of heparin administration both correlated with preheparin procedure duration (r = 0.70, P = 0.007 and r = 0.69, P = 0.01, respectively). All parameters were normal the next morning. CONCLUSION: Procedure duration prior to heparin administration, and not the delivery of RF current per se, determines activation of hemostasis and fibrinolysis during RF ablation.

Adolescent↗
PubMed1998

Neuropeptide Y receptor 1 (NPY-Y1) expression in human heart failure and heart transplantation.

Neuropeptide Y (NPY) is a neurotransmitter released from cardiac sympathetic nerve terminals along with catecholamines. It influences vascular tone and cardiac function, probably through the receptor subtype Y1. The present study examined the expression of Y1 in patients with end-stage heart failure and in heart transplant recipients. Y1 mRNA was analyzed in right ventricular endomyocardial biopsies taken from 12 donor hearts prior to implantation (controls), 15 patients with end stage heart failure at time of transplantation, and 16 patients more than 1 year after transplantation. RT-PCR (reverse transcription polymerase chain reaction) was used to detect mRNA for the Y1 receptor, the beta1-adrenergic-receptor, and beta-actin. Y1 mRNA was present in biopsies of all donor hearts, but was observed significantly less frequently in the two patient groups; only 5 out of 15 (P < 0.01) heart failure and 9 out of 16 (P < 0.05) transplant recipients demonstrated visible PCR product. In contrast, mRNA for the beta1-adrenergic receptor and beta-actin were detected by RT-PCR in all samples. Our results provide the first evidence for altered regulation of the neuropeptide Y1 receptor in heart failure and transplant patients, and suggests that loss of signal transduction by this receptor may be adaptive in both groups.

Actins↗
PubMed1998

Angiotensin II receptor subtype AT1 and AT2 expression after heart transplantation.

OBJECTIVE: Cardiac hypertrophy appears early after heart transplantation, and may represent a myocardial response to injury. Recent evidence suggests that angiotensin II (Ang II) may promote growth through the AT1 and inhibit growth through the AT2 receptor subtypes. We therefore asked whether hypertrophy after heart transplantation is characterized by alterations in Ang II receptor gene expression. METHODS: The expression of Ang II receptor subtypes. AT1 and AT2, was analyzed in right ventricular endomyocardial biopsies taken from 10 human donor hearts prior to implantation (controls) and from 17 heart transplant recipients, 11 studied during annual evaluation (> 1 year after transplantation) and 6 one week after transplantation. Competitive reverse transcription polymerase chain reaction (RT-PCR) was performed using synthetic RNA internal standards for both receptor subtypes. RESULTS: AT1 and AT2 receptor mRNAs were detected in all samples. AT1 receptor mRNA decreased 4.5 fold (p < 0.01) and AT2 receptor mRNA 4.2 fold (p < 0.001) in transplant patients compared with controls. In the subgroup of patients examined one week after surgery AT1 was reduced relative to AT2 receptor mRNA, resulting in an altered ratio of AT1 to AT2 early after transplantation. There was no correlation between Ang II receptor levels and left ventricular wall thickness, and the decrease in receptor level did not correlate with any hemodynamic parameters, cyclosporine blood levels, or plasma renin, Ang II or pANP, except for a negative correlation between AT2 mRNA and plasma renin (r = -0.49, p = 0.05). CONCLUSIONS: Contrary to our expectations, mRNA for both Ang II receptors was downregulated after heart transplantation. The cause of myocardial hypertrophy after heart transplantation is still unclear, but the hypertrophy does not appear to be driven by increased transcription of the AT1 receptor.

Adult↗
PubMed1998

Radiofrequency catheter ablation of two right Mahaïm-like accessory pathways in a patient with Ebstein's anomaly.

A 17-year-old woman with Ebstein's anomaly and recurrent episodes of antidromic tachycardia with two distinct morphologies is described. The tachycardias were produced by two separate Mahaïm-like accessory pathways. These were localized by their activation potentials at the anterolateral ventricular margin of the tricuspid annulus and ablated in a single session using radiofrequency current.

Adolescent↗