The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts.

BACKGROUND: It is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. OBJECTIVE: This study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. METHODS: 24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. RESULTS: Compared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. CONCLUSION: IL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Macrophage-dependent IL-1ß production induces cardiac arrhythmias in diabetic mice.

Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1ß in DM mice. IL-1ß causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1ß-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1ß axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1ß as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.

Atorvastatin attenuates sympathetic hyperinnervation together with the augmentation of M2 macrophages in rats postmyocardial infarction.

OBJECTIVES: Inflammation after myocardial infarction (MI) causes cardiac nerve sprouting and consequent ventricular arrhythmias (VAs). Macrophages, as major immune cells, are involved in the entire inflammation response process and serve as a link between inflammation and sympathetic hyperinnervation by regulating nerve growth factor (NGF) expression. Accumulating evidence shows that statins possess antiarrhythmogenic properties, and the aim of this study was to explore the mechanism by which atorvastatin ameliorates cardiac sympathetic nerve sprouting via regulating macrophage polarization. METHODS: Rat models of MI were created by ligating the left coronary artery. MI-operated rats received either atorvastatin or phosphate-buffered saline for 7 days. Immunohistochemical analyses and immunofluorescence staining were used to analyze macrophage infiltration after MI and to detect the distribution and density of growth-associated protein-43 (GAP-43) and tyrosine hydroxylase (TH) in nerve fibers in peri-infarct zones after MI. The polarity of the macrophages that were obtained from the rat peritoneal cavity was examined via flow cytometry. The protein levels of NGF were detected via Western blot analysis, and the concentrations of NGF in the supernatants were determined via enzyme-linked immunosorbent assay. The mRNA levels of NGF, inducible nitric oxide synthase (iNOS), Arginase-1 (Arg1), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) were examined by quantitative real-time polymerase chain reaction. The association between VAs and MI was evaluated using programmed electrophysiological stimulation. RESULTS: Macrophages were successfully induced to the M1 (classically activated) and M2 (alternatively activated) phenotypes by stimulation with lipopolysaccharide and interferon-γ (LPS + IFN-γ) and interleukin-4 (IL-4), respectively. Atorvastatin markedly downregulated IL-1ß, TNF-α, iNOS, and NGF and upregulated Arg1, shifting the macrophage phenotype from M1 to M2. Moreover, atorvastatin significantly reduced TH levels and the density of GAP-43-positive nerve fibers and decreased inducible VAs. CONCLUSION: Atorvastatin effectively ameliorated cardiac sympathetic nerve remodeling and prevented VAs after MI by significantly downregulating the expression of NGF, IL-1ß, and TNF-α via together with the augmentation of M2 macrophage.

ß1-Adrenoceptor autoantibodies affect action potential duration and delayed rectifier potassium currents in guinea pigs.

ß1-Adrenoceptor autoantibodies (ß1-AAs) affect the action potential duration (APD) in cardiomyocytes and are related to ventricular arrhythmias. The delayed rectifier potassium current (I K) plays a crucial role in APD, but the effects of ß1-AAs on I K have not been completely illuminated. This work aimed to observe the effects of ß1-AAs on I K and APD and further explore the mechanisms of ß1-AA-mediated ventricular arrhythmias. ß1-AAs were obtained from sera of patients with coronary heart disease (CHD) and nonsustained ventricular tachycardia. With whole-cell patch clamp technique, action potentials and I K were recorded. The results illustrated 0.1 µmol/L ß1-AAs shortened APD at 50 % (APD50) and 90 % (APD90) of the repolarization. However, at 0.01 µmol/L, ß1-AAs had no effects on either APD90 or APD50 (P > 0.05). At 0.001 µmol/L, ß1-AAs significantly prolonged APD90 and APD50. Moreover, ß1-AAs (0.001, 0.01, 0.1 µmol/L) dose-dependently increased the rapidly activating delayed rectifier potassium current (I Kr), but similarly decreased the slowly activating delayed rectifier potassium current (I Ks) and increased L-type calcium currents at the different concentrations. Taken together, the IKr increase induced by high ß1-AA concentrations is responsible for a significant APD reduction which would contribute to repolarization changes and trigger the malignant ventricular arrhythmias in CHD patients.

Induced KCNQ1 autoimmunity accelerates cardiac repolarization in rabbits: potential significance in arrhythmogenesis and antiarrhythmic therapy.

BACKGROUND: Autoantibodies directed against various cardiac receptors have been implicated in cardiomyopathy and heart rhythm disturbances. In a previous study among patients with dilated cardiomyopathy, autoantibodies targeting the cardiac voltage-gated KCNQ1 K(+) channel were associated with shortened corrected QT intervals (QTc). However, the electrophysiologic actions of KCNQ1 autoimmunity have not been assessed experimentally in a direct fashion. OBJECTIVE: The purpose of this study was to investigate the cardiac electrophysiologic effects of KCNQ1 autoantibody production induced by vaccination in a rabbit model. METHODS: Rabbits were immunized with KCNQ1 channel peptide. ECG recordings were obtained during a 1-month follow-up period. Rabbits then underwent in vivo electrophysiologic study, after which cardiomyocytes were isolated for analysis of slow delayed rectifier current (IKs) and action potential properties via patch-clamp. RESULTS: KCNQ1-immunized rabbits exhibited shortening of QTc compared to sham-immunized controls. Reduced ventricular effective refractory periods and increased susceptibility to ventricular tachyarrhythmia induction were noted in KCNQ1-immunized rabbits upon programmed ventricular stimulation. Action potential durations were shortened in cardiomyocytes isolated from KCNQ1-immunized rabbits compared to the sham group. IKs step and tail current densities were enhanced after KCNQ1 immunization. Functional and structural changes of the heart were not observed. The potential therapeutic significance of KCNQ1 immunization was then explored in a dofetilide-induced long QT rabbit model. KCNQ1 immunization prevented dofetilide-induced QTc prolongation and attenuated long QT-related arrhythmias. CONCLUSION: Induction of KCNQ1 autoimmunity accelerates cardiac repolarization and increases susceptibility to ventricular tachyarrhythmia induction through IKs enhancement. On the other hand, vaccination against KCNQ1 ameliorates drug-induced QTc prolongation and might be useful therapeutically to enhance repolarization reserve in long QT syndrome.

T-cell-mediated inflammatory activity in the stellate ganglia of patients with ion-channel disease and severe ventricular arrhythmias.

BACKGROUND: Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are electric diseases characterized by catecholamine-induced ventricular arrhythmias. Unbalanced autonomic innervation of the heart may trigger arrhythmic events and stellectomy is a treatment option for patients who are resistant to pharmacological drugs. We analyzed left stellectomy specimens of LQTS and CPVT patients for signs of inflammatory activity. METHODS AND RESULTS: Stellate ganglia were retrieved from 12 consecutive patients (8F; 4 mol/L; mean age, 23.4±17 years) with either LQTS (n=8) or CPVT (n=4) and serious arrhythmias. Control stellate ganglia were obtained from 10 accidently deceased patients (6F; 4 mol/L; mean age, 35±17.6 years). Sections were immunostained with antibodies against T cells (CD3, CD4, CD8, CD20, Granzyme B), CD68 (macrophages), and HLA-DR (human leukocyte antigen-DR) antigens (activation marker). Immunopositive cells were quantified as cells/mm2. Polymerase chain reaction (PCR) and reverse transcription PCR were performed to screen for herpes virus DNA. Stellate ganglia of all 12 LQTS/CPVT patients revealed mild but distinct inflammatory infiltrates composed of T lymphocytes and macrophages, which were diffusely spread, but also clustered in small foci opposed to ganglion cells, interpreted as T-cell-mediated ganglionitis. Morphometric analysis showed that CD3+ and CD8+ T cells/mm2 were significantly higher in the ganglia of LQTS/CPVT cases than in healthy controls (P=0.0018 and P=0.0009, respectively). Molecular analyses were negative for neurotropic viruses. CONCLUSIONS: T-cell-mediated cytotoxicity toward ganglion cells may boost adrenergic activity as to trigger or enhance electric instability in LQTS/CPVT patients who are already genetically predisposed to arrhythmias.

The role of Interleukin-6, its -174 G>C polymorphism and C-reactive protein in idiopathic cardiac arrhythmias in children.

UNLABELLED: ABSTRACT Purpose: Knowledge about the role of inflammation in the pathogenesis of arrhythmias in children is limited. Several studies have suggested a relationship between plasma IL-6 levels and/or the -174G>C IL-6 gene polymorphism and atrial fibrillation in adults. Our present study was performed to investigate whether serum IL-6, -174G>C IL-6 polymorphism and C-reactive protein (CRP) are associated with arrhythmias of unknown origin in children. METHODS: The study included 126 children diagnosed with supraventricular or ventricular arrhythmia. Patients with congenital heart defects as well as arrhythmias of known origin were excluded from the study. The control group comprised 37 healthy children. The 24 hour Holter electrocardiography monitoring was performed. Serum IL-6, -174 GC IL-6 polymorphism and CRP concentrations were measured on admission. RESULTS: There were no differences in IL-6, CRP and -174 G>C IL-6 genotype distribution between the control and patient groups. No significant differences in IL-6, CRP and -174 G>C IL-6 genotypes were observed between children with supraventricular or ventricular arrhythmias. The severity of arrhythmias showed also no associations with IL-6, CRP or -174 G>C IL-6 genotypes. CONCLUSION: The results suggest that idiopathic cardiac arrhythmias of unknown origin in children are not associated with selected pro-inflammatory markers of infections i.e. elevated IL-6, CRP or -174 G>C IL-6 polymorphism. This new information can effectively reduce the total financial cost of unnecessary diagnosis and treatment of children affected by cardiac arrhythmias.

Combined cardiac magnetic resonance imaging and C-reactive protein levels identify a cohort at low risk for defibrillator firings and death.

BACKGROUND: Annually, ≈80,000 Americans receive guideline-based primary prevention implantable cardioverter-defibrillators (ICDs), but appropriate firing rates are low. Current selection criteria for ICDs rely on left ventricular ejection fraction, which lacks sensitivity and specificity. Because scar-related myocardial tissue heterogeneity is a substrate for life-threatening arrhythmias, we hypothesized that cardiac magnetic resonance identification of myocardial heterogeneity improves risk stratification through (1) its association with adverse cardiac events independent of clinical factors and biomarker levels and (2) its ability to identify particularly high- and low-risk subgroups. METHODS AND RESULTS: In 235 patients with chronic ischemic and nonischemic cardiomyopathy with a left ventricular ejection fraction of ≤35% undergoing clinically indicated primary prevention ICD implantation, gadolinium-enhanced cardiac magnetic resonance was prospectively performed to quantify the amount of heterogeneous myocardial tissue (gray zone [GZ]) and dense core scar. Serum high-sensitivity C-reactive protein (hsCRP) and other biomarkers were assayed. The primary end point was appropriate ICD shock for ventricular tachycardia/fibrillation or cardiac death, which occurred in 45 (19%) patients at a 3.6-year median follow-up. On univariable analysis, only diuretics, hsCRP, GZ, and core scar were associated with outcome. After multivariable adjustment, GZ and hsCRP remained independently associated with outcome (P<0.001). Patients in the lowest tertile for both GZ and hsCRP (n=42) were at particularly low risk (0.7% per year event rate), whereas those in the highest tertile for both GZ and hsCRP (n=32) had an event rate of 16.1% per year, P<0.001. CONCLUSIONS: In a cohort of primary prevention ICD candidates, combining a myocardial heterogeneity index with an inflammatory biomarker identified a subgroup with a very low risk for adverse cardiac events, including ventricular arrhythmias. This novel approach warrants further investigation to confirm its value as a clinical risk stratification tool. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00181233.

Arrhythmogenic autoantibodies against calcium channel lead to sudden death in idiopathic dilated cardiomyopathy.

AIMS: Calcium channel plays an important role in the autoimmune pathogenesis of idiopathic dilated cardiomyopathy (DCM). Autoantibodies have emerged as a new upstream target of sudden death in DCM. We sought to validate the hypothesis that autoantibodies against l-type calcium channel (CC-AAbs) are arrhythmogenic and lead to sudden death in patients with DCM. METHODS AND RESULTS: We investigated sudden death and ventricular arrhythmias in 80 patients with DCM in a prospective, case follow-up survey. During a follow-up of 32 (SD 8) months, CC-AAbs-positive patients not only had a higher incidence of ventricular tachycardia (VT) but also a higher incidence of sudden death than CC-AAbs-negative patients (for VT: 59.0 vs. 24.4%, P = 0.002 and for sudden death: 20.5 vs. 4.9%, P = 0.045). Further univariate and multivariate analyses showed that the occurrence of CC-AAbs was the strongest independent predictor for sudden death (odds ratio: 10.20, 95% confidence interval: 2.43-36.78, P = 0.0027). Experimental studies in ex vivo systems using affinity-purified CC-AAbs from patients demonstrated that CC-AAbs were able to induce VT by prolongation of action potential duration (APD) and triggered activity by early afterdepolarization (EAD). CONCLUSION: Our results demonstrate for the first time to our knowledge that there is a high incidence of sudden death and VT in CC-AAbs-positive patients with DCM. Furthermore, experimental data from ex vivo systems suggest that CC-AAbs might induce VT by prolongation of APD and triggered activity by EAD.

Role of proinflammatory markers and NT-proBNP in patients with an implantable cardioverter-defibrillator and an electrical storm.

BACKGROUND: Several studies have attempted to identify risk factors for the development of an electrical storm (ES), which is defined as 3 separate ventricular tachyarrhythmic (VT/VF) events, but in the majority of studies no triggers have been found. However, little is known about the role of inflammation and NT-proBNP in patients with ES. The aim of this study was therefore to assess the relationship of Interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP) and NT-proBNP serum concentrations in ICD-patients with or without single spontaneous ventricular tachyarrhythmic events (VT/VF) and in ES. METHODS: Markers were determined in 51 patients without ICD-intervention, in 15 ICD-patients with single VT/VF-episodes during 9-months follow-up and in 20 ICD-patients with ES (blood sampling performed within 60min after fulfilling ES criteria). VT/VF-episodes were analysed by stored ICD-electrograms. RESULTS: All patients had idiopathic dilated cardiomyopathy (n=23) or coronary artery disease (n=63). Patients with ES revealed significantly higher mean serum concentrations of all markers (IL-6 15.19+/-10.34 pg/mL, hs-CRP 20.12+/-14.4 mg/L, NT-proBNP 4799+/-4596 pg/mL) compared to baseline values of patients with single VT/VF-events during follow-up (IL-6 8.37+/-5.8 pg/mL (p=0.03), hs-CRP 4.7+/-5.3 mg/dL (p<0.001), NT-proBNP 1913+/-2665pg/mL (p=0.04)) and compared to baseline values of ICD-patients without device intervention (IL-6 4.62+/-3.66 pg/mL (p<0.001), hs-CRP 4.1+/-3.4 mg/L (p<0.001), NT-proBNP 1461+/-2281pg/mL (p<0.001)). In 9/20 patients presenting with ES (45%) baseline values were available. All markers were significantly higher during ES compared to event-free determination (IL-6 14.54+/-10.43 vs. 7.03+/-2.83 pg/mL (p=0.04), hs-CRP 19.07+/-16.07 vs. 6.5+/-3.9 mg/L (p=0.02), NT-proBNP 4218+/-2561 vs. 2099+/-1279 pg/mL (p=0.03)). CONCLUSIONS: Electrical storm is associated with significantly elevated IL-6, hs-CRP and NT-proBNP serum concentrations in ICD-patients with structural heart disease. Thus, ES may be triggered by proinflammatory activity. Combined intraindividual elevation of determined markers might help to identify patients at risk of impending electrical storm.

High serum tryptase value in massive acute myocardial infarction with ventricular arrhythmia exortion in a cocaine abuser.

A 38-year-old cocaine abuser was admitted to the Emergency Department with a one hour history of precordial chest pain associated with shortness of breath and extreme discomfort. On admission his blood pressure was 90/60 mmHg, the resting 12-lead ECG showed ventricular tachycardia at about 300 beats per minute, and oxygen saturation was 86 percent in room air. After electrical cardioversion, the 12-lead ECG revealed sinusal rhythm and a significative ST segment elevation in leads I, aVL and V1-V6, that was about 0.5 mV in leads I and aVL and more than 1 mV in leads V2, V3 and V4. Laboratory determinations showed elevated creatine-chinase MB (CK-MB) and troponin I. An emergency coronary angiogram was normal. Cocaine use is a major cause of acute myocardial infarction in patients with normal epicardial coronary arteries but the exact mechanism still remains unclear. We hypothesize a non-IgE mediated mast-cell activation, with a direct action played by cocaine, and consequent massive expression of several factors effecting the microcirculatory system, including pro-inflammatory cytokines and chemokines. Our hypothesis is supported by an elevated serum tryptase levels in the patient.

Relationship between amiodarone-induced subclinical lung toxicity and Th1/Th2 balance.

BACKGROUND: Although amiodarone is a potent antiarrhythmic agent, its clinical use is limited by serious lung toxicity. This study investigated the mechanisms of amiodarone-induced lung toxicity from an immunological perspective. Because interferon gamma (IFN-gamma: Th1 cytokine) inhibits pulmonary fibroblast proliferation whereas interleukin-4 (IL-4: Th2 cytokine) augments fibroblast growth and collagen production, we hypothesized that amiodarone lung toxicity is related to Th1/Th2 balance. METHODS: Twenty-six consecutive Japanese patients with ventricular arrhythmias treated with amiodarone were enrolled in this study and were divided into two groups. Group A contained patients demonstrating amiodarone lung toxicity diagnosed by chest X-ray, KL-6 or D(LCO) (n=6), whereas group B included patients treated without any adverse effects (n=20). Th1/Th2 balance was investigated by the ratio of IFN-gamma and IL-4 produced by activated peripheral CD4(+) T cells. RESULTS: Clinical baseline characteristics prior to oral amiodarone did not show any differences between group A and group B except for D(LCO) (82.0+/-5.2% vs. 90.8+/-9.0%, p=0.032) and Th1/Th2 balance (7.98+/-1.68 vs. 13.34+/-5.10, p=0.020). This balance was not altered three months after withdrawal of amiodarone in group A and under continued treatment in group B, suggesting patient-specific rather than amiodarone-induced. After starting amiodarone, serum concentration of desethylamiodarone was greater in group A than in group B (p=0.009) and was inversely proportional to Th1/Th2 ratio (p=0.013). Multilogistic regression analysis indicated that Th1/Th2 balance was the most powerful indicator of amiodarone lung toxicity (p=0.046, odds ratio of 0.424). CONCLUSIONS: Although large cohort is required, the present study indicates that Th1/Th2 balance may influence amiodarone metabolism and may be a powerful indicator of amiodarone-induced subclinical lung toxicity at least in Japanese.

Autoimmunity against the second extracellular loop of beta(1)-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits.

OBJECTIVES: We sought to define the electrophysiologic property of the rabbit heart associated with autoimmunity against the second extracellular loop of the beta(1)-adrenergic receptor. BACKGROUND: Sudden death of patients with cardiomyopathy, probably due to lethal ventricular arrhythmias, can be predicted by the presence of autoantibodies against the second extracellular loop of the beta(1)-adrenergic receptor. METHODS: Rabbits were immunized by repetitive subcutaneous administration of a synthetic peptide corresponding to the second extracellular loop of beta(1)-adrenergic receptors (beta group; n = 30) for a mean of 4.2 months. Control rabbits received only vehicle (control group; n = 30). RESULTS: One of the rabbits in the beta group died suddenly during the observation period, but none of the control animals died. The prevalence of sustained ventricular tachycardia was significantly higher in the beta group (beta: 4 of 27 vs. control: 0 of 30), and a standard microelectrode experiment revealed prolongation of the action potential duration (APD) in the right ventricular papillary muscle (beta: 156 +/- 5 ms vs. control: 131 +/- 4 ms; p < 0.05). Early afterdepolarization (EAD) was observed in one rabbit in the beta group (1 of 26), but not in any animals in the control group (0 of 17). A dose of 100 nmol/l of E-4031 induced EAD in the beta group (10 of 10), but not in the control group, except for one rabbit (1 of 10). The whole-cell, patch-clamp experiment on left ventricular M cells showed significant decreases in transient outward current (I(to1)) (-43%) and slowly activated delayed rectifier current (I(Ks)) densities (-33%), whereas the inward-rectifying K current (I(K1)) and rapidly activated delayed rectifier current (I(Kr)) densities remained unchanged. CONCLUSIONS: Long-term immunization against the second extracellular loop of the beta(1)-adrenergic receptor caused EAD and APD prolongation and decreased the K-channel density, suggesting that an arrhythmic substrate via autoimmune mechanisms is present in cardiomyopathic patients who have autoantibodies directed against the receptors.

[Autoantibodies against sarcolemmal Na-K-ATPase in patients with dilated cardiomyopathy: autoimmune basis for ventricular arrhythmias in patients with congestive heart failure].

BACKGROUND: Autoimmunity is one of the mechanisms of pathogenesis of idiopathic dilated cardiomyopathy (DCM) as well as virus infection and genetic predisposition. Autoantibodies against sarcolemmal Na-K-ATPase may be involved in the development of ventricular tachycardia and cardiac sudden death in patients with DCM. METHODS AND RESULTS: By using enzyme-linked immunosorbent assay, autoantibodies were detected in 26% patients with DCM and in 2% age-matched control subjects. Na-K-ATPase activity in the presence of patient IgG was lower in patients with autoantibodies than without autoantibodies, but there was no difference in the control subjects. Western blots showed that autoantibodies recognized the alpha-subunit of Na-K-ATPase, and 3H-ouabain bindings in the presence of patient IgG showed that the dissociation constant was higher in patients with autoantibodies than without autoantibodies, although maximal binding sites were similar between the two groups. No difference existed between subjects with regard to age, sex, New York Heart Association functional class, cardiac function, or neurohormone levels, except for plasma norepinephrine which was higher in patients with autoantibodies than without autoantibodies, Ventricular arrhythmias were more common in patients with autoantibodies than without autoantibodies, and multiple logistic regression analysis demonstrated that the presence of autoantibodies, but not plasma norepinephrine, was an independent predictor for the occurrence of ventricular tachycardia. Cardiac sudden death was independently predicted by the presence of autoantibodies, as well as poor systolic function. CONCLUSIONS: Patients with DCM express autoantibodies against sarcolemmal Na-K-ATPase, and these autoantibodies could be responsible for the electrical instability in some patients.

Characterization of anti-myocardial autoantibodies in Japanese patients with dilated cardiomyopathy.

Few previous reports have comprehensively screened all the anti-myocardial autoantibodies (AMCA) in relation to other clinical profiles in patients with idiopathic dilated cardiomyopathy (IDC), so the present study used both immunohistochemistry (FITC) and immunoblotting (IB) for screening patients with IDC in order to characterize the clinical significance of AMCA. Sera were collected from 100 patients with IDC and age-matched 100 healthy control subjects (CTL). For FITC, an unfixed frozen section of human myocardium was used for the standard indirect immunofluorescence; for IB, total cardiac homogenates of the same myocardium were blotted to serum at 2 sets of dilution (1:200 and 1:10,000). The positive rates of AMCA detection for each method were as follows (IDC vs CTL); 39% vs 6% for FITC, 38% vs 4% for IB (1:200), and 10% vs 0% for IB (1:10,000). Fifty-nine patients with IDC and 8 CTL were positive for AMCA by either method, and 18 patients with IDC and 2 CTL were positive for AMCA by both methods. IB-positivity at 1:200 was an independent predictor by multiple logistic regression analysis of non-sustained ventricular tachycardias as well as left ventricular end-diastolic diameter and plasma norepinephrine concentration.

Autoantibodies against the second extracellular loop of beta1-adrenergic receptors predict ventricular tachycardia and sudden death in patients with idiopathic dilated cardiomyopathy.

OBJECTIVES: We sought to define the clinical and long-term prognostic implications of autoantibodies that act against the second extracellular loop of beta1-adrenergic receptors (ARs) in patients with idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Although autoantibodies directed against various domains of beta-ARs are found in patients with IDC, only a subgroup against the second extracellular domain of beta1-ARs exerts intrinsic sympathomimetic-like actions on human beta-ARs. It is suggested that the autoantibodies take part in the pathophysiology of IDC and may affect long-term prognosis of patients with this disorder. METHODS: Sera from 104 patients with IDC were screened for autoantibodies that act against the second extracellular loop of beta1-ARs by enzyme-linked immunosorbent assay, using a synthetic peptide corresponding to the domain. Relations of the autoantibodies to clinical variables and long-term prognosis were assessed by multivariate analysis. RESULTS: Autoantibodies were detected in 40 patients (38%). Multifocal ventricular premature contractions (p < 0.01) and ventricular tachycardia (VT; p < 0.01) were more common in autoantibody-positive than in autoantibody-negative patients, although no differences in cardiac function or neurohormonal levels were demonstrated. The presence of autoantibodies (p = 0.001) and a low left ventricular ejection fraction (LVEF <30%; p = 0.02) were independent predictors of VT. Sudden death was independently predicted by the presence of autoantibodies (p = 0.03), as well as by LVEF <30% (p = 0.01), whereas total mortality was predicted only by LVEF <30% (p = 0.001). CONCLUSIONS: Autoantibodies directed against the second extracellular loop of beta1-ARs were closely related to serious ventricular arrhythmias in patients with IDC, and the presence of autoantibodies independently predicted sudden death. These autoantibodies may contribute to electrical instability in patients with IDC.

[Immunosuppressive therapy for effective suppression of life threatening ventricular tachyarrhythmias in chronic myocarditis]. / Immunsuppressive Therapie zur effektiven Suppression lebensbedrohlicher ventrikulärer Tachyarrhythmien bei chronischer Myokarditis.

Chronic myocarditis predisposes to the occurrence of spontaneous ventricular arrhythmias. It is not known if an immunosuppressive treatment-as a casual therapy-leads to arrhythmia suppression. In the present study, 12 patients (four female, eight male, mean age 53 +/- 15 years) with a mean left-ventricular ejection fraction of 52 +/- 19% were included. After exclusion of coronary macroangiopathy, the presence of chronic myocarditis was demonstrated by immunohistological evaluation of right-ventricular biopsies taking the number of specific lymphocytes (CD 2-8), of activated macrophages and the degree of HLA-expression on interstitial and endothelial cells as a basis. Seven patients had a successful resuscitation due to ventricular fibrillation in their case history, three patients presented sustained monomorphic ventricular tachycardia and two syncopes with inducible tachyarrhythmias. As a "conventional" therapy ten patients received antiarrhythmic drugs and four patients an implantable cardioverter/defibrillator. After confirmation of the diagnosis by a second biopsy after 3 months, all patients underwent an immunosuppressive therapy with methylprednisolone. The initial dose of 1 mg/kg body weight was reduced by 20 mg each every 2 weeks, until a maintenance dosage of 8-12 mg/day was achieved. If the control study after 6 months still gave a positive result, a combined therapy with azathioprine, 100-150 mg/day, was carried out for a further 6 months. In nine patients (75%), the control biopsy became negative, in three patients (25%), the biopsy remained to be positive. In the group presenting negative biopsies, no tachyarrhythmia relapse occurred within a follow-up period of 49 +/- 13 months, while in the group with positive biopsies, relapses occurred in two of three patients. Complete suppression during EPS after therapy was achieved in 50% of the patients who were inducible before therapy. In addition to lymphocyte infiltration, particularly HLA expression on endothelial and interstitial cells was significantly reduced; left-ventricular ejection fraction was improved only in tendency, while left-ventricular filling pressure decreased significantly. In summary, in patients with chronic myocarditis and malignant ventricular arrhythmias, a high-dose immunosuppressive long-term therapy results in the significant reduction of inflammatory infiltrations in about 75% of the cases and, at the same time, in the effective suppression of arrhythmias.