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Antibodies against cholinergic and adrenergic receptors (adrenoceptors) are frequent in serum of patients with chronic heart failure. Their prevalence is associated with Chagas' disease, idiopathic dilated cardiomyopathy (DCM), and ischaemic heart disease. Among the epitopes targeted are first and second extracellular loops of the β-adrenergic (β-adrenoceptor) and M2 muscarinic receptor. β(1)-adrenoceptor autoantibodies affect radioligand binding and cardiomyocyte function similar to agonists. Corresponding rodent immunizations induce symptoms compatible with chronic heart failure that are reversible upon removal of the antibodies, transferable via the serum and abrogated by adrenergic antagonists. In DCM patients, prevalence and stimulatory efficacy of β(1)-adrenoceptor autoantibodies are correlated to the decline in cardiac function, ventricular arrhythmia and higher incidence of cardiac death. In conclusion, such autoantibodies seem to cause or promote chronic human left ventricular dysfunction by acting on their receptor targets in a drug-like fashion. However, the pharmacology of this interaction is poorly understood. It is unclear how the autoantibodies trigger changes in receptor activity and second messenger coupling and how that is related to the pathogenesis and severity of the associated diseases. Here, we summarize the available evidence regarding these issues and discuss these findings in the light of recent knowledge about the conformational activation of the human β(2)-adrenoceptor and the properties of bona fide cardiopathogenic autoantibodies derived from immune-adsorption therapy of DCM patients. These considerations might contribute to the conception of therapy regimen aimed at counteracting or neutralizing cardiopathogenic receptor autoantibodies. [ABSTRACT FROM AUTHOR]

Background: In patients suffering from dilated cardiomyopathy (DCM), immunoadsorption with subsequent IgG substitution (IA/IgG) leads to an acute and prolonged improvement of hemodynamics and heart failure symptoms. However, some patients receiving IA/IgG experience recurrence of heart failure after an initial benefit. The aim of this study was to investigate whether a second IA/IgG treatment episode improves left ventricular systolic function and further mitigates heart failure symptoms in these patients., Methods: We retrospectively analyzed 15 DCM patients who experienced a significant improvement of LVEF (≥ 5% absolute or ≥ 20% relative) and heart failure symptoms (≥ 1 NYHA functional class) but a subsequent deterioration (decline in LVEF ≥ 5% absolute or ≥ 20% relative and NYHA worsening ≥1 class) after the first IA/IgG. These patients underwent a second IA/IgG treatment 41.7 ± 27.4 months after the first cycle. Follow up data were acquired 3-6 months after both IA/IgG treatments., Results: The first IA/IgG induced an improvement of LVEF from 33 ± 6.4% to 43.2 ± 7.9% (P < 0.001) and of mean NYHA functional class from 2.9 ± 0.26 to 1.8 ± 0.56 (P < 0.001). The second treatment was associated with a significant improvement in LVEF (from 29.7 ± 4.6% to 34.9 ± 8.3%, P = 0.013) and NYHA functional class (2.87 ± 0.64 to 2.33 ± 0.72; P = 0.02). This improvement was less pronounced compared to the first treatment with respect to both, LVEF (P = 0.09) and NYHA improvement (P = 0.04)., Conclusion: In DCM patients, who experience a significant improvement of LVEF and heart failure symptoms after IA/IgG but a subsequent relapse during follow up, repeated IA/IgG may be considered., (© 2014 Wiley Periodicals, Inc.)

Auto-antibodies against cardiac proteins have been described in patients with dilated cardiomyopathy. Antibodies against the C-terminal part of KChIP2 (anti-KChIP2 [C-12]) enhance cell death of rat cardiomyocytes. The underlying mechanisms are not fully understood. Therefore, we wanted to explore the mechanisms responsible for anti-KChIP2-mediated cell death. Rat cardiomyocytes were treated with anti-KChIP2 (C-12). KChIP2 RNA and protein expressions, nuclear NF-κB, mitochondrial membrane potential Δψm, caspase-3 and -9 activities, necrotic and apoptotic cells, total Ca(2+) and K(+) concentrations, and the effects on L-type Ca(2+) channels were quantified. Anti-KChIP2 (C-12) induced nuclear translocation of NF-κB. Anti-KChIP2 (C-12)-treatment for 2 h significantly reduced KChIP2 mRNA and protein expression. Anti-KChIP2 (C-12) induced nuclear translocation of NF-κB after 1 h. After 6 h, Δψm and caspase-3 and -9 activities were not significantly changed. After 24 h, anti-KChIP2 (C-12)-treated cells were 75 ± 3% necrotic, 2 ± 1% apoptotic, and 13 ± 2% viable. Eighty-six ± 1% of experimental buffer-treated cells were viable. Anti-KChIP2 (C-12) induced significant increases in total Ca(2+) (plus 11 ± 2%) and K(+) (plus 18 ± 2%) concentrations after 5 min. Anti-KChIP2 (C-12) resulted in an increased Ca(2+) influx through L-type Ca(2+) channels. In conclusion, our results suggest that anti-KChIP2 (C-12) enhances cell death of rat cardiomyocytes probably due to necrosis., (© 2013 Wiley Periodicals, Inc.)

Background: The impact of white blood cell count (WBCc) on the outcome of patients with non-ischemic left ventricular (LV) dysfunction is unknown. In the present study we investigated the influence of WBCc on mortality and cardiac inflammation in patients with reduced LV systolic function in the absence of ischemic or valvular etiology., Methods and Results: We included 381 patients with reduced left ventricular (LV) ejection fraction (LVEF ≤ 45%) quantified by two-dimensional echocardiography. Coronary artery disease and valvular diseases were excluded by angiography and echo, respectively, in all patients. WBCc was quantified routinely upon first hospital admission. In 291 patients, endomyocardial biopsies from the right ventricle were performed upon first hospital admission for assessment of cardiac inflammation. Follow-up was up to 5.5 years (median 2.93 [1.7;4.0]). Information on vital status of patients was obtained from official resident data files. WBCc >11 Gpt/l was associated with significantly increased mortality in patients with severe LV dilation (end-diastolic diameter (LVEDD) >70 mm quantified by echocardiography) in comparison to patients showing WBCc ≤ 11 Gpt/l (41.7% vs 13.6%, p=0.02). Multivariable Cox regression analysis showed that WBCc predicts mortality independently of other cardiovascular risk factors and LVEF (hazard ratio 1.14; p=0.04). Doses of heart failure medication did not differ significantly in patients with LVEDD >70 mm and WBCc >11 Gpt/l when compared to LVEDD >70 mm and WBCc ≤ 11 Gpt/l (percent of maximum doses: ß-blockers p=0.51, ACE inhibitors p=0.56, AT1 antagonists p=0.77, aldosterone antagonists p=0.35). WBCc including its subpopulations (monocytes, lymphocytes and granulocytes) did not show a significant correlation with cardiac amounts of CD3(+)-lymphocytes (r=0.02, p=0.78) or CD68(+)-macrophages (r=1.0, p=0.09) (n=291)., Conclusion: WBCc at first hospital admission predicts long term-mortality in patients with dilated cardiomyopathy independently of cardiovascular risk factors., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Dilated cardiomyopathy (DCM) is one of the main causes for heart failure in younger adults. Although genetic disposition and exposition to toxic substances are known causes for this disease in about one third of the patients, the origin of DCM remains largely unclear. In a substantial number of these patients, autoantibodies against cardiac epitopes have been detected and are suspected to play a pivotal role in the onset and progression of the disease. The importance of cardiac autoantibodies is underlined by a hemodynamic improvement observed in DCM patients after elimination of autoantibodies by immunoadsorption. A variety of specific antigens have already been identified and antibodies against these targets may be detected by immunoassays. However, these assays cannot discriminate between stimulating (and therefore functionally effective) and blocking autoantibodies. There is increasing evidence that this distinction is crucial. It can also be assumed that the targets for a number of cardiotropic antibodies are still unidentified and therefore cannot be detected by immunoassays. Therefore, we established a method for the detection of functionally active cardiotropic antibodies, independent of their respective antigen. The background for the method is the high homology usually observed for functional regions of cardiac proteins in between mammals. This suggests that cardiac antibodies directed against human antigens will cross-react with non-human target cells, which allows testing of IgG from DCM patients on adult rat cardiomyocytes. Our method consists of 3 steps: first, IgG is isolated from patient plasma using sepharose coupled anti-IgG antibodies obtained from immunoadsorption columns (PlasmaSelect, Teterow, Germany). Second, adult cardiomyocytes are isolated by collagenase perfusion in a Langendorff perfusion apparatus using a protocol modified from previous works. The obtained cardiomyocytes are attached to laminin-coated chambered coverglasses and stained with Fura-2, a calcium-selective fluorescent dye which can be easily brought into the cell to observe intracellular calcium (Ca(2+)) contents. In the last step, the effect of patient IgG on the cell shortening and Ca(2+) transients of field stimulated cardiomyocytes is monitored online using a commercial myocyte calcium and contractility monitoring system (IonOptix, Milton, MA, USA) connected to a standard inverse fluorescent microscope.

Aims: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG., Methods and Results: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (≥20 relative and ≥5% absolute) 6 months after IA/IgG were considered responders. Compared with non-responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin-proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only., Conclusion: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention.

Aims: Autoantibodies against second extracellular loops of β(1)-adrenergic receptors frequent in dilated cardiomyopathy confer myocardial dysfunction presumably via cAMP stimulation. Here, we investigate the autoantibody impact on receptor conformation and function., Methods and Results: IgG was prepared from patients with dilated cardiomyopathy, matched healthy donors (10 each) or commercial IgG preparations (2). IgG binding to β(1)-adrenergic receptor peptides was detected in 5 of 10 patients and 2 of 10 controls. IgG colocalization with the native receptor was detected in 8 of 10 patients and 1 of 10 controls (10 of 10 patients and 7 of 10 controls at >30 mg IgG/L). All IgGs exhibiting receptor colocalization triggered changes in receptor conformation (determined with fluorescent sensors) not stringently correlated to cAMP stimulation, suggesting the induction of more or less active receptor conformations. Receptor-activating IgG was detected in 8 of 10 patients but only 1 of 10 controls. In addition, IgG from 8 of 10 patients and 3 of 10 controls attenuated receptor internalization (measured by total internal reflection fluorescence microscopy). IgG-inducing inactive receptor conformations had no effect on subsequent cAMP stimulation by isoproterenol. IgG-inducing active receptor conformations dampened or augmented subsequent cAMP stimulation by isoproterenol, depending on whether receptor internalization was attenuated or not. Corresponding IgG effects on the basal beating rate and chronotropic isoproterenol response of embryonic human cardiomyocytes were observed., Conclusions: (i) Autoantibodies trigger conformation changes in the β(1)-adrenergic receptor molecule. (ii) Some also attenuate receptor internalization. (iii) Combinations thereof increase the basal beating rate of cardiomyocytes and optionally entail dampening of their chronotropic catecholamine responses. (iv) The latter effects seem specific for patient autoantibodies, which also have higher levels.

The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.

Organic cation transporters (OCT1-3 and OCTN1/2) facilitate cardiac uptake of endogenous compounds and numerous drugs. Genetic variants of OCTN2, for example, reduce uptake of carnitine, leading to heart failure. Whether expression and function of OCTs and OCTNs are altered by disease has not been explored in detail. We therefore studied cardiac expression, heart failure-dependent regulation, and affinity to cardiovascular drugs of these transporters. Cardiac transporter mRNA levels were OCTN2>OCT3>OCTN1>OCT1 (OCT2 was not detected). Proteins were localized in vascular structures (OCT3/OCTN2/OCTN1) and cardiomyocytes (OCT1/OCTN1). Functional studies revealed a specific drug-interaction profile with pronounced inhibition of OCT1 function, for example, carvedilol [half maximal inhibitory concentration (IC₅₀), 1.4 μmol/L], diltiazem (IC₅₀, 1.7 μmol/L), or propafenone (IC₅₀, 1.0 μmol/L). With use of the cardiomyopathy model of coxsackievirus-infected mice, Octn2mRNA expression was significantly reduced (56% of controls, 8 days after infection). Accordingly, in endomyocardial biopsy specimens OCTN2 expression was significantly reduced in patients with dilated cardiomyopathy, whereas the expression of OCT1-3 and OCTN1 was not affected. For OCTN2 we observed a significant correlation between expression and left ventricular ejection fraction (r = 0.53, P < 0.0001) and the presence of cardiac CD3⁺ T cells (r = -0.45, P < 0.05), respectively. OCT1, OCT3, OCTN1, and OCTN2 are expressed in the human heart and interact with cardiovascular drugs. OCTN2 expression is selectively reduced in dilated cardiomyopathy patients and predicts the impairment of cardiac function., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Arachidonic acid and related cardioprotective eicosanoids are released in myocardial ischemia/reperfusion injury. The present study analyzes the effects of the eicosapentaenoic acid derived 17,18-epoxyeicostetraenoic acid on isolated cardiomyocytes and investigates whether 17,18-epoxyeicostetraenoic acid serves as a potential factor in the cardio-depressant postischemic effluent., Basic Procedures: After 10 minutes of global ex vivo stop-flow ischemia, adult rat hearts were reperfused and coronary postischemic effluent was collected over a period of 30 seconds. Nonischemic effluent was collected prior to ischemia. The effects of 17,18-epoxyeicostetraenoic acid on calcium (Ca(2+)) metabolism and contraction frequency of isolated neonatal rat cardiomyocytes were tested and compared with the effects of prior collected postischemic and nonischemic effluents. Isolated neonatal cardiomyocytes were preincubated with selective (NS-398, SC-560) and nonselective cyclooxygenase inhibitors (indomethacin) to determine whether cardio-depressive effects are mediated by cyclooxygenase., Findings: In contrast to the nonischemic effluent, both 17,18-epoxyeicostetraenoic acid and the postischemic effluent induced a comparable decrease of the Ca(2+) transient and the contraction frequency (P < .05 vs control). The cardio-depressive effects of 17,18-epoxyeicostetraenoic acid and the postischemic effluent were significantly attenuated after preincubation with the unselective cyclooxygenase inhibitor indomethacin and the selective cyclooxygenase-2 inhibitor NS-398 (P < .05 vs control). Selective cyclooxygenase-1 inhibition with SC-560 did not influence the effect of 17,18-epoxyeicostetraenoic acid and the postischemic effluent., Conclusions: Our data show that the cardio-depressive effects of 17,18-epoxyeicostetraenoic acid are comparable with the postischemic effluent and are mediated by cyclooxygenase-2. Our results suggest a potential cardioprotective role of the eicosanoid 17,18-epoxyeicostetraenoic acid in heart ischemia/reperfusion injury., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dilated cardiomyopathy (DCM) is characterized by contractile dysfunction leading to heart failure. The molecular changes in the human heart associated with this disease have so far mostly been addressed at the gene expression level and only a few studies have analyzed global changes in the myocardial proteome. Therefore, our objective was to investigate the changes in the proteome in patients suffering from inflammatory DCM (iDCM) and chronic viral infection by a comprehensive quantitative approach. Comparative proteomic profiling of endomyocardial biopsies (EMB) from 10 patients with iDCM (left ventricular ejection fraction <40%, symptoms of heart failure) as well as 7 controls with normal left ventricular function and histology was performed by label-free proteome analysis (LC-MS/MS). Mass spectrometric data were analyzed with the Rosetta Elucidator software package. The analysis covered a total of 485 proteins. Among the 174 proteins displaying at least a 1.3-fold change in intensity (p < 0.05), major changes were observed for mitochondrial and cytoskeletal proteins, but also metabolic pathways were affected in iDCM compared to controls. In iDCM patients, we observed decreased levels of mitochondrial proteins involved in oxidative phosphorylation and tricarboxylic acid cycle. Furthermore, deregulation of proteins of carbohydrate metabolism, the actin cytoskeleton, and extracellular matrix remodeling was observed. Proteomic observations were confirmed by gene expression data and immunohistochemistry (e.g. collagen I and VI). This study demonstrates that label-free, mass spectrometry-centered approaches can identify disease dependent alterations in the proteome from small tissue samples such as endomyocardial biopsies. Thus, this technique might allow better disease characterization and may be a valuable tool in potential clinical proteomic studies.

Background: Disturbances of humoral immunity have been described in dilated cardiomyopathy (DCM), and a number of antibodies against cardiac cell proteins have been identified. Previous studies showed that immunoadsorption therapy with subsequent IgG substitution (IA/IgG) enhances cardiac function, and that removal of cardiodepressant antibodies may represent one essential mechanism of this therapy. The long-term effect of IA/IgG on the level of cardiodepressant antibodies remains to be elucidated., Methods: A total of 17 patients with DCM were observed up to 12 months after IA/IgG. Echocardiographic measurements were performed at baseline, 3, 6 and 12 months after therapy. Cardiodepressant antibodies were detected by incubation of rat cardiomyocytes with purified patients' IgG and recording of contractility and Ca(2+) ratio., Results: In contrast to patients without cardiodepressant antibodies before IA/IgG, patients with negative inotropic antibodies showed an improvement of left ventricular ejection fraction (LVEF) from 33.8 +/- 1.7% to 44.7 +/- 2.7%; 44.5 +/- 2.3% and 51.8 +/- 1.7% after 3, 6 and 12 months (P < 0.001 vs. baseline, P < 0.05 vs. LVEF of non-cardiodepressant group). Immediately after IA/IgG therapy, no cardiodepressant effects of patients' IgG on isolated cardiomyocytes were detectable, and this effect remained diminished until 6 months after IA/IgG (P < 0.001 for contractility and Ca(2+) ratio). Compared with the levels after 3 and 6 months, cardiodepressant antibodies reoccured after 12 months (P = 0.067 for contractility, P < 0.05 for Ca(2+) ratio vs. 6 months after IA/IgG). However, the negative inotropic reaction is still diminished compared with the reaction before IA/IgG., Conclusion: IA/IgG therapy induces long-term reduction of negative inotropic antibodies. After 12 months, however, re-increase of negative inotropic antibodies cannot be excluded.

Background: Recent data indicate that cardiac antibodies play an active role in the pathogenesis of dilated cardiomyopathy (DCM) and may contribute to cardiac dysfunction in patients with DCM. The present study investigated the influence of immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) on cardiopulmonary exercise capacity in patients with DCM., Methods: Sixty patients with DCM (New York Heart Association II-IV, left ventricular ejection fraction < or =45%) were included in this single-center university hospital-based case-control study. Patients either were treated with IA/IgG (n = 30) or were followed without IA/IgG (n = 30). At baseline and after 3 months, we compared echocardiographic assessment of left ventricular function and spiroergometric exercise parameters., Results: In contrast to controls, left ventricular ejection fraction improved significantly in the IA/IgG group from 33.0% +/- 1.2% to 40.1% +/- 1.5% (P < .001). In the control group, spiroergometric exercise parameters did not change during follow-up. After 3 months, maximum achieved power increased in the treatment group from 114.2 +/- 7.4 to 141.9 +/- 7.9 W (P = .02). Total exercise time increased in the treatment group from 812 +/- 29 to 919 +/- 30 seconds (P < .05). Peak oxygen uptake (Vo(2)) increased from 17.3 +/- 0.9 to 21.8 +/- 1.0 mL min(-1) kg(-1) after IA/IgG (P < .01). Oxygen pulse (peak Vo(2)/maximum heart rate) increased in the treatment group (10.7 +/- 0.7 vs 13.6 +/- 0.7 mL beat(-1) min(-1), P < .01). The Vo(2) at the gas exchange anaerobic threshold increased after 3 months in the treatment group from 10.3 +/- 0.5 to 13.2 +/- 0.5 mL min(-1) kg(-1) (P < .001). The ventilatory response to exercise (V(E)/Vco(2) slope) decreased after IA/IgG therapy from 32.3 +/- 1.5 to 28.7 +/- 0.9 (P = .02)., Conclusions: In patients with DCM, IA/IgG therapy may induce improvement in echocardiographic and cardiopulmonary exercise parameters., (2010 Mosby, Inc. All rights reserved.)

In patients with dilated cardiomyopathy (DCM), cardiac autoantibodies are able to bind with their Fab fragment to epitopes on cardiomyocytes, but thereafter they crosslink through their Fc fragment to cardiac Fc(gamma)-receptor IIa. Polymorphic variability of the Fc(gamma)-receptor IIa is associated with modified affinity of immunoglobin G (IgG) binding and may influence therapeutic effects. In this study, 103 consecutive DCM patients were treated with immunoadsorption (IA) therapy with subsequent IgG substitution (IA/IgG). Echocardiography was performed at baseline and again at 3 and 6 months after IA/IgG. Fc(gamma)-receptor IIa polymorphism R/H131 was genotyped using a nested sequence-specific primer polymerase chain reaction (PCR). Patients with the Fc(gamma)-receptor IIa genotype R/R131 showed significantly greater improvement in left ventricular (LV) function than patients with the R/H131 or H/H131 genotypes did. Irrespective of the Fc(gamma)-receptor polymorphism, patients with shorter disease duration and a more impaired LV function responded with a greater increase in LV ejection fraction (LVEF). Therefore, the Fc(gamma)-receptor polymorphism influences the efficacy of immunomodulatory therapy involving IA/IgG.

Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and progressive systolic and diastolic dysfunction. Disturbances of the cellular and humoral immune system are frequently observed in DCM. Circulating antibodies of the IgG class against diverse myocardial antigens have been identified and are thought to play a causative role in the pathogenesis of DCM. Possible mechanisms include the promotion of chronic inflammation, activation of the β1-adrenoreceptor and activation of Fc(γ)-receptors. Various clinical studies suggest a positive effect of immunoadsorption (IA) using protein A columns, with or without subsequent IgG substitution (IA/IgG) on symptoms, myocardial function and the hemodynamic situation of these patients. Decreased myocardial inflammation was also observed in DCM patients treated with IA/IgG. In addition to conservative medical treatment, IA/IgG may therefore represent a new therapeutic option for patients with heart failure due to DCM., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Background: Growing evidence suggests participation of autoimmune mechanisms in the pathogenesis of dilated cardiomyopathy (DCM)., Methods: Patients with heart failure (left ventricular ejection fraction < or =50%) due to DCM (n = 98) or ischemic cardiomyopathy (ICM, n = 49) and controls with normal left ventricular function (n = 98) were included. Immunoglobulin G antibodies were purified from plasma by affinity chromatography and analyzed by surface plasmon resonance analysis. We analyzed the distribution of autoantibodies against Kv channel-interacting protein (KChIP) 2.6, cardiac troponin I (cTnI), and the beta1-adrenergic receptor (second extracellular loop, cardiac beta1-adrenergic receptor [SEL-beta1-AR])-two other known autoantibodies involved in heart failure. Effects of antibodies against KChIP2 on cell death of isolated rat cardiomyocytes were assessed by flow cytometry., Results: We detected autoantibodies against KChIP2.6 in 14.3% (P < .015 vs controls, P = .286 vs ICM) of the DCM samples, in 8.2% of the ICM samples (P = .304 vs controls), and in 4.1% of the control samples. Virus persistence was significantly associated with detection of autoantibodies against KChIP2.6 in DCM patients (P = .025). Antibodies against SEL-beta1-AR were more frequent in DCM samples (34.7%, P < .001 vs controls, P = .02 vs ICM) and ICM samples (16.3%, P = .083 vs control) than in control samples (7.1%). Antibodies against cTnI were more frequent in DCM samples (20.4%, P < .001 vs controls, P = .769 vs ICM) and in ICM samples (18.4%, P < .01 vs controls) than in control samples (4.1%). Antibodies against rat KChIP2 enhanced cell death in isolated rat cardiomyocytes. Immunofluorescence indicated cell surface expression of KChIP2., Conclusions: Autoantibodies against KChIP2.6, SEL-beta1-AR, and cTnI appear to be associated with DCM. Antibodies against KChIP2 may enhance cell death of rat cardiomyocytes.

Background: The role of melusin, a necessary component in pressure-induced left-ventricular hypertrophy (LVH) in mice, has not yet been determined in human cardiac hypertrophy. We analyzed for the first time the expression and regional distribution of melusin in human LVH due to aortic stenosis (AS) and determined AKT phosphorylation as a potential downstream effector of melusin signalling., Methods: Regional distribution of melusin was evaluated in four normal hearts. Melusin staining, gene expression and protein content were assessed in biopsies from normal and diseased hearts and melusin gene expression was correlated with LV functional changes. The pAKT/AKT ratio was determined in parallel and correlated with melusin protein content., Results: In normal hearts, melusin was found in the myocytes with a uniform regional distribution. Melusin staining, mRNA and protein were significantly decreased in human AS hearts. The reduction in melusin mRNA was significantly correlated with LVEF, LVEDD and LVESD. pAKT/AKT ratio was significantly decreased in human AS and was correlated with melusin content., Conclusion: Reduction in melusin expression parallels the functional cardiac impairment in human AS. The simultaneous decrease of melusin and AKT phosphorylation suggests a connection between the loss of melusin and the decrease in systolic function.

Background: Pressure overload leads to myocardial remodelling with collagen accumulation, left ventricular hypertrophy (LVH), neurohormonal activation and myocardial dysfunction. Prolyl 4-hydroxylases (P4H) are involved in collagen maturation. Inhibition of P4H has been shown to prevent LV remodelling and improve survival post-myocardial infarction., Aim: To evaluate the role of P4H in pressure overload-induced myocardial remodelling., Methods: Male Wistar rats underwent thoracic aortic banding (AoB) and were treated with a P4H inhibitor (P4HI) or vehicle (control). Echocardiography and haemodynamic measurements were performed after 4 weeks. Collagens, matrix metalloproteinases (MMP), tissue inhibitors of MMPs (TIMP), growth factors and neurohormonal markers were quantitated in LV samples., Results: AoB led to LVH, increased LV enddiastolic pressure (LVEDP) and decreased contractility compared to sham. P4HI reversed these effects. AoB increased collagen I and III expression, which was normalized by P4HI. AoB led to deregulation of matrix remodelling enzymes, enhanced expression of growth factors and activation of the endothelin system. P4HI partially prevented deregulation of the MMP/TIMP system, inhibited upregulation of growth factors and normalized AoB-induced ECE-1 and ETB expression., Conclusions: P4HI leads to an improvement of AoB-associated LV dysfunction and reduces imbalance of extracellular matrix turnover and hypertrophy-associated gene expression. P4H inhibition could therefore be of value in treatment of myocardial remodelling accompanying pressure overload hypertrophy.