Reza Mobini

Hemodynamic improvement and removal of autoantibodies against β1-adrenergic receptor by immunoadsorption therapy in dilated cardiomyopathy

The removal of beta(1)-adrenergic receptor (beta(1)AR) autoantibodies by immunoadsorption (IA) has been proposed as a potential mechanism for the improvement of the left ventricular function in dilated cardiomyopathy (DCM). In the present study, the possible association between removal of the autoantibodies against the human beta(1)AR with the hemodynamic improvement induced by IA was investigated.IA was performed in 22 DCM patients (n=22; NYHA III-IV, EF<30%, stable medication). The beta(1)AR autoantibodies from column eluents (CE) were detected by enzyme-linked immunosorbent assay (ELISA) and BIAcore methods. CE of 32% (7/22) of the patients was found to be antibody-positive with ELISA or BIAcore. In addition, a bioassay system was also used for the detection of this autoantibody. Seventy-three percent (16/22) of the patients were found to be antibody-positive by this method. However, independent of the beta(1)AR antibody detection method, both antibody-positive and antibody-negative groups showed similar acute and prolonged hemodynamic improvements during IA therapy. Furthermore, antibody-positive and -negative groups received a comparable improvement of left ventricular ejection fraction. These results suggest that different mechanisms are involved in the hemodynamic improvement induced by IA. The beneficial hemodynamic effects induced by IA are not directly associated with the removal of beta(1)AR autoantibodies.

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n 5 7), MI rats treated with GH (MI 1 GH; n 5 11; 3 mg/kgzday), and sham-operated rats (sham; n 5 8). All rats were investigated with 31 P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI 5 1.69 6 0.09 vs. MI 1 GH 5 2.42 6 0.05, P , 0.001; sham 5 2.34 6 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P , 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham 5 124.1 6 8.4; MI 5 203.9 6 34.7; MI 1 GH 5 118.3 6 8.4 ng/ml; P , 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling. (Endocrinology 141: 4592‐ 4599, 2000)

β1-adrenoceptor antibodies induce positive inotropic response in isolated cardiomyocytes

beta(1)-Adrenoceptor autoantibodies are present in approximately 30% of patients suffering from dilated cardiomyopathy. The inotropic effects mediated by these antibodies remain to be studied. Monoclonal antibodies were raised against a peptide corresponding to the second extracellular loop of the human beta(1)-adrenoceptor in balb/C mouse (n=6), and were characterized by enzyme immunoassay after purification by protein A. Purified immunoglobulin G from non-immunized animals (controls) did not influence Ca(2+) transient and cell shortening of rat cardiomyocytes measured by confocal-laser-scanning-microscopy. beta(1)-adrenoceptor antibodies caused a dose-related increase in Ca(2+) transient (dilution 1:2: +35.3+/-5.1%), and in cell shortening (dilution 1:2: +40.5+/-6.3%) (P<0.01 vs. controls). The effect of the beta(1)-adrenoceptor antibodies was blocked by the antigenic peptide and by the antagonist metoprolol. In addition, beta(1)-adrenoceptor antibodies induced a dose-dependent increase of the cyclic adenosine monophosphate. The inotropic response induced by isoproterenol was attenuated by the beta(1)-adrenoceptor antibody. beta(1)-adrenoceptor antibodies as partial agonists induce a specific positive inotropic effect via the protein-kinase-A-cascade.

A Monoclonal Antibody Directed Against an Autoimmune Epitope on the Human β1-Adrenergic Receptor Recognized in Idiopathic Dilated Cardiomyopathy

A monoclonal antibody (MAb M16) was obtained by immunizing Balb/C mice with free peptide H26R, corresponding to the second extracellular loop of the human beta1-adrenergic receptor (beta1AR), against which functional autoantibodies have been detected in patients with idiopathic dilated cardiomyopathy. The MAb was found to be of IgG2b type and directed against a conformational epitope, encompassing the sequence recognized by the human autoantibodies. BIAcore measurements yielded an equilibrium constant of 6.5 X 10(7) M1 with an association rate constant (kon) of 6.5 X 10(4) M(-1) sec(-1) and a dissociation rate constant (koff) of 1.0 X 10(-3) sec(-1). It immunoprecipitated only poorly the solubilized beta1AR of Sf9 cell membranes. Functionally, the MAb was capable of not only reducing the number of the maximal binding sites to the beta1-adrenergic receptor of transfected Sf9 cell membranes, but also of displaying a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These properties, which the MAb shares with the human autoantibodies, makes it an interesting tool for passive transfer studies in mice.

Beneficial effect on cardiac function by intravenous immunoglobulin treatment in patients with dilated cardiomyopathy is not due to neutralization of anti-receptor autoantibody.

Anti-β1-adrenoceptor (β1AR) autoantibodies have been shown to be pathophysiologically important in idiopathic dilated cardiomyopathy (DCM). Treatment with intravenous immunoglobulin (IVIG) has shown beneficial effects in both DCM and ischemic cardiomyopathy. However, the underlying mechanism has not been clarified. In the present study, we therefore examined whether the improvement of cardiac function was due to neutralization of functional β1AR autoantibodies by anti-idiotypic antibodies. Autoantibodies against the β1AR was analysed in sera from patients with DCM (n=16) and coronary artery disease (CAD) (n=21) treated with IVIG or placebo before, 6 and 12 months. Six month after treatment, DCM patients showed increase in β1AR autoantibodies, mostly in IgG1 and IgG2, whereas in CAD patients mostly in IgG2. No changes in β1AR autoantibodies after 12 months were detected. In summary, our results indicate that improvement of cardiac function by IVIG is not due to neutralization of β1AR autoantibodies.

Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the imidazoline I1-receptor agonist moxonidine

Although beta-adrenergic blockade is beneficial in heart failure, inhibition of central sympathetic outflow using moxonidine has been associated with increased mortality. In the present study, we studied the acute effects of the imidazoline-receptor agonist moxonidine on haemodynamics, NA (noradrenaline) kinetics and myocardial metabolism. Fifteen patients with CHF (chronic heart failure) were randomized to a single dose of 0.6 mg of sustained-release moxonidine or matching placebo. Haemodynamics, NA kinetics and myocardial metabolism were studied over a 2.5 h time period. There was a significant reduction in pulmonary and systemic arterial pressures, together with a decrease in cardiac index in the moxonidine group. Furthermore, there was a simultaneous reduction in systemic and cardiac net spillover of NA in the moxonidine group. Analysis of myocardial consumption of substrates in the moxonidine group showed a significant increase in non-esterified fatty acid consumption and a possible trend towards an increase in myocardial oxygen consumption compared with the placebo group (P=0.16). We conclude that a single dose of moxonidine (0.6 mg) in patients already treated with a beta-blocker reduced cardiac and overall sympathetic activity. The finding of increased lipid consumption without decreased myocardial oxygen consumption indicates a lack of positive effects on myocardial metabolism under these conditions. We suggest this might be a reason for the failure of moxonidine to prevent deaths in long-term studies in CHF.

The effects of hypoxia and hypercapnia on renal and heart function, haemodynamics and plasma hormone levels in stable COPD patients*

Background:  Fluid retention with oedema is an important clinical problem in advanced chronic obstructive pulmonary disease (COPD).

Who are the enemies? Inflammation and autoimmune mechanisms

Inflammation and autoimmune mechanisms are involved in the development of clinical myocarditis and dilated cardio- myopathy, and may also play a role in the progression of congestive heart failure, regardless of aetiology. New molecular biological and immunohistological methods have confirmed the persistence of viral infection in patients with myocarditis as well as in those with a diagnosis of idiopathic dilated cardio- myopathy. A causal link between viral myocarditis and the development of dilated cardiomyopathy has been proposed but remains to be confirmed. This may have prognostic implications and lead to new therapies such as immunosuppression, immuno- modulation and antiviral therapies in cardiomyopathy and myocarditis. More recently it has been found that inflammatory reactions are also involved in the progression of congestive heart failure, regardless of aetiology. (Eur Heart J Supplements 2002; 4 (Suppl G): G27-G32)