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Lars Christian Haugli Bråten,1 Elisabeth Gjefsen,1,2 Kristina Gervin,1 Are Hugo Pripp,3 Jan Sture Skouen,4 Elina Schistad,5 Linda Margareth Pedersen,1 Monica Wigemyr,1 Kaja Kristine Selmer,1 Hans Christian Dalsbotten Aass,6 Guro Goll,7 Jens Ivar Brox,5 Ansgar Espeland,8,9 Lars Grøvle,10 John-Anker Zwart,1,2 Kjersti Storheim1,11 On behalf of The AIM-study group1Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital HF, Oslo, Norway; 2Faculty of Medicine, University of Oslo, Oslo, Norway; 3Oslo Centre of Biostatistics and Epidemiology Research Support Services, Oslo University Hospital Ulleval, Oslo, Norway; 4Department of Physical Medicine and Rehabilitation, Haukeland University Hospital, Bergen, Norway; 5Department of Physical Medicine and Rehabilitation, Oslo University Hospital HF, Oslo, Norway; 6Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway; 7Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Oslo, Norway; 8Department of Radiology, Haukeland University Hospital, Bergen, Norway; 9Department of Clinical Medicine, University of Bergen, Bergen, Norway; 10Department of Rheumatology, Østfold Hospital Trust, Grålum, Norway; 11Oslo Metropolitan University, Department of Physiotherapy, Oslo, NorwayCorrespondence: Lars Christian Haugli Bråten, Tel +4722117769, Email l.c.h.braten@studmed.uio.noObjective: Randomized trials testing the effect of antibiotics for chronic low back pain (LBP) with vertebral bone marrow changes on MRI (Modic changes) report inconsistent results. A proposed explanation is subgroups with low grade discitis where antibiotics are effective, but there is currently no method to identify such subgroups. The objective of the present study was to evaluate whether distinct patterns of serum cytokine levels predict any treatment effect of oral amoxicillin at one-year follow-up in patients with chronic low back pain and Modic changes at the level of a previous lumbar disc herniation.Design: We used data from an overpowered, randomized, placebo-controlled trial (the AIM study) that tested 100 days of oral 750 mg amoxicillin vs placebo three times daily in hospital outpatients with chronic (> 6 months) LBP with pain intensity ≥ 5 on a 0– 10 numerical rating scale and Modic changes type 1 (oedema type) or 2 (fatty type). We measured serum levels of 40 inflammatory cytokines at baseline and analysed six predefined potential predictors of treatment effect based on cytokine patterns in 78 randomized patients; three analyses with recursive partitioning, one based on cluster analysis and two based on principal component analyses. The primary outcome was the Roland–Morris Disability Questionnaire score at one-year follow-up in the intention to treat population. The methodology and overall results of the AIM study were published previously.Results: The 78 patients were 25– 62 years old and 47 (60%) were women. None of the three recursive partitioning analyses resulted in any suggested subgroups. Of all main analyses, the largest effect estimate (mean difference between antibiotic and placebo groups) was seen in a subgroup not predefined as of main interest (Cluster category 3+4; − 2.0, 95% CI: − 5.2– 1.3, RMDQ points; p-value for interaction 0.54).Conclusion: Patterns of inflammatory serum cytokine levels did not predict treatment effect of amoxicillin in patients with chronic LBP and Modic changes.Clinical Trial Registration Number: ClinicalTrials.gov (identifier: NCT02323412).Keywords: low back pain, Modic changes, infection, cytokines, inflammation

Aims Radiofrequency catheter ablation of atrial flutter and fibrillation may be favoured by large, elongated lesions. We compared bipolar ablation with unipolar ablation from one or two electrodes in the porcine heart. Methods and Results In vitro, confluent lesions were reliably created by a ‘dielectrode’ catheter (energy delivered simultaneously (in parallel) from two 4mm electrodes spaced 1mm apart, towards an indifferent electrode), and a ‘bipolar’ catheter (energy delivered (in series) between two 4mm electrodes spaced 5mm apart). Sixteen anaesthetized pigs were randomized to standard unipolar (4), dielectrode (6) or bipolar (6) ablation. Two radiofrequency current deliveries of 30s duration (70°C) were administered to the inferior vena cava–tricuspid valve isthmus and two to the right atrial free wall in all animals. After 4h, the lesions were examined macroscopically and histologically. Mean (SD) endocardial lesion length×width×depth measured 7·4 (2·4)×5·4 (2·2)×2·8 (0·8)mm in the standard unipolar mode, 10·2 (1·4)×6·3 (0·7)×3·3 (1·1)mm in the dielectrode mode and 14·0 (3·6)×6·0 (1·7)×3·8 (1·2)mm in the bipolar mode. Thus lesion length increased significantly through the three groups (P<0·001), while width and depth did not. Conclusion Both dielectrode and bipolar ablation were feasible in porcine right atrial ablation, and created longer lesions than the standard unipolar mode. By allowing a larger interelectrode distance, bipolar ablation created the longest lesions and may be favourable when linear lesions are necessary. [ABSTRACT FROM PUBLISHER]

Objectives: To explore serum cytokine levels over time in patients with chronic low back pain (cLBP) and Modic changes (MCs), difference in change between treatment groups in the Antibiotics in Modic Changes (AIM) study and associations between change in cytokines and low back pain., Methods: Serum concentrations of 39 cytokines were measured at baseline and 1 year from 73 participants in the AIM study; 30 randomized to placebo, 43 to Amoxicillin. Low back pain intensity was measured by numeric rating scale. Change in cytokine levels over time were assessed by paired t-tests. Difference in change in cytokine levels between treatment groups and associations between changes in LBP and cytokine levels were assessed by linear regression models. Networks of cytokine changes in each treatment groups were explored by Pearson's correlations., Results: Five cytokines changed from baseline to 1 year, (mean change, log transformed values with CI) C-X-C motif chemokine ligand (CXCL) 10 (IP-10) (0.11 (0.01-0.20)), CXCL13 (0.61 (0.00-0.12)), C-C motif chemokine ligand (CCL)26 (0.05 (0.01-0.1)), granulocyte macrophage-colony stimulating factor (GM-CSF) (-0.12 (-0.23 to 0.00)) and CXCL11 (0.12 (0.03-0.22)). Treatment group only influenced change in CCL21 (β 0.07 (0.01-0.12)), and IL-6 (β -0.17 (-0.30 to -0.03)). Change in CXCL13 (β 2.43 (0.49-4.38)), CCL27 (β 3.07 (0.46-5.69)), IL-8 (β 1.83 (0.08-3.58)) and CCL19 (β 3.10 (0.86-5.43)) were associated with change in LBP. The correlation networks of cytokine changes demonstrate small differences between treatment groups., Conclusions: Cytokine levels are relatively stable over time in our sample, with little difference between treatment groups. Some cytokines may be associated with LBP intensity. The differences between the correlation networks suggest that long-term Amoxicillin-treatment may have longstanding effects to be further explored., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) is an established treatment modality for advanced heart failure (HF) but 20-30% of patients treated with CRT do not experience clinical improvement. Hence, in this study we aimed to investigate whether baseline cardiopulmonary exercise testing (CPX) can help improve the prediction of a positive functional CRT response., Methods: This prospective observational study included 76 HF patients undergoing elective CRT implantation and clinical CPX and echocardiographic assessment were performed at baseline, 6, and 12 months., Results: Peak VO2 increased from 11.0±2.5 ml/min/kg to 12.0±4.1 ml/min/kg and 12.2±3.5 ml/min/kg at 6 and 12 months after CRT, respectively. The number of patients classified as "CRT-responders" (Δ peak VO2≥1 ml/kg/min) was 33 (46%) and 36 (52%) at 6 and 12 months after CRT, respectively. Patients with baseline peak VO2<40% of predicted (lowest tertile) demonstrated a 68% and 69% response rate at 6 and 12 months, respectively, as compared to a 35% and 42% response rate among patients with baseline peak VO2≥40% of predicted (p=0.01 and p=0.02, respectively). In multivariate analysis patients with baseline peak VO2<40% of predicted had an adjusted odds ratio of 4.4 (95% CI 1.6-12.5; p<0.01) and 3.1 (95% CI 1.1-8.8; p=0.03) for positive CRT response at 6 and 12 months, respectively., Conclusions: Treatment with CRT improves exercise capacity but this increase is most substantial among patients with a lower baseline peak VO2 (% of predicted). Baseline CPX can, therefore, be utilized to identify patients more likely to exhibit a functional improvement after CRT., (Copyright © 2012 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce., Methods: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed., Results: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61-1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37-0.76; p=0.0005)., Conclusion: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

Background: The objective of the present study was to use gene expression profiling, functional annotations and classification to identify aetiology-specific biological processes and potential molecular markers for different aetiologies of end-stage heart failure., Methods and Results: Individual left ventricular myocardial samples from eleven coronary artery disease and nine dilated cardiomyopathy transplant patients were co-hybridized with pooled RNA from four non-failing hearts on custom-made arrays of 7000 human genes. Significance analysis identified differential expression of 153 and 147 genes, respectively, in coronary artery disease or dilated cardiomyopathy versus non-failing hearts. Analysis of Gene Ontology biological process annotations indicated aetiology-specific patterns, primarily related to genes involved in catabolism and in regulation of protein kinase activity. Gene expression classifiers were obtained and used for class prediction of random samples of coronary artery diseased and dilated cardiomyopathic hearts. Best classifiers frequently included matrix metalloproteinase 3, fibulin 1, ATP-binding cassette, sub-family B member 1 and iroquois homeobox protein 5., Conclusion: Combining functional annotation from microarray data and classification analysis constitutes a potent strategy to identify disease-specific biological processes and gene expression markers in e.g. end-stage coronary artery disease and dilated cardiomyopathy.

The possible involvement of different kinases in the alpha(1)-adrenoreceptor (AR)-mediated positive inotropic effect (PIE) was investigated in rat papillary muscle and compared with beta-AR-, endothelin receptor- and phorbol ester-induced changes in contractility. The alpha(1)-AR-induced PIE was not reduced by the inhibitors of protein kinase C (PKC), MAPK (ERK and p38), phosphatidyl inositol 3-kinase, or calmodulin kinase II. However, PKC inhibition attenuated the effect of phorbol 12-myristate 13-acetate (PMA) on contractility. alpha(1)-AR-induced PIE was reduced by approximately 90% during inhibition of myosin light chain kinase (MLCK) by 1-(5-chloronaphthalene-1-sulfonyl)1H-hexahydro-1,4-diazepine (ML-9). Endothelin-induced PIE was also reduced by ML-9, but ML-9 had no effect on beta-AR-induced PIE. The Rho kinase inhibitor Y-27632 also reduced the alpha(1)-AR-induced PIE. The alpha(1)-AR-induced PIE in muscle strips from explanted failing human hearts was also sensitive to MLCK inhibition. alpha(1)-AR induced a modest increase in (32)P incorporation into myosin light chain in isolated rat cardiomyocytes. This effect was eliminated by ML-9. The PIE of alpha(1)-AR stimulation seems to be dependent on MLCK phosphorylation.

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.

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.

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.

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.

Aims: Radiofrequency catheter ablation of atrial flutter and fibrillation may be favoured by large, elongated lesions. We compared bipolar ablation with unipolar ablation from one or two electrodes in the porcine heart., Methods and Results: In vitro, confluent lesions were reliably created by a 'dielectrode' catheter (energy delivered simultaneously (in parallel) from two 4 mm electrodes spaced 1 mm apart, towards an indifferent electrode), and a 'bipolar' catheter (energy delivered (in series) between two 4 mm electrodes spaced 5 mm apart). Sixteen anaesthetized pigs were randomized to standard unipolar (4), dielectrode (6) or bipolar (6) ablation. Two radiofrequency current deliveries of 30 s duration (70 degrees C) were administered to the inferior vena cava-tricuspid valve isthmus and two to the right atrial free wall in all animals. After 4 h, the lesions were examined macroscopically and histologically. Mean (SD) endocardial lesion length x width x depth measured 7.4 (2.4) x 5.4 (2.2) x 2.8 (0.8) mm in the standard unipolar mode, 10.2 (1.4) x 6.3 (0.7) x 3.3 (1.1) mm in the dielectrode mode and 14.0 (3.6) x 6.0 (1.7) x 3.8 (1.2) mm in the bipolar mode. Thus lesion length increased significantly through the three groups (P < 0.001), while width and depth did not., Conclusion: Both dielectrode and bipolar ablation were feasible in porcine right atrial ablation, and created longer lesions than the standard unipolar mode. By allowing a larger interelectrode distance, bipolar ablation created the longest lesions and may be favourable when linear lesions are necessary.

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.