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Underlying Mechanisms

Underlying Mechanisms


Excerpt from the publication: Staudt et al. J Am Coll Cardiol 2007;49:1684-92


Dilated cardiomyopathy (DCM) is a frequently occurring myocardial disease with poor prognosis that is characterized by progressive depression of myocardial contractile function and by ventricular dilatation. DCM can be triggered by autoantibodies. We have recently shown that antibodies from DCM patients induce an acute negative inotropic effect in isolated rat cardiomyocytes through depression of calcium transients. These autoantibodies also induce cardiac dysfunction in animal models similar to that seen in human DCM patients. Removal of these antibodies from patient's plasma by therapeutic immunoadsorption improves cardiac function in patients with heart failure due to DCM.

We studied the role of the effector part of these negative inotropic antibodies and could recently show the existence of Fcg receptors on cardiomyocytes. The newly detected Fcg receptors IIa can induce an activating signal via its cytoplasmic membrane and provide an explanation of why antibodies directed against different antigens on cardiomyocytes can induce the same functional effects. Whereas intact IgG of DCM patients induce negative inotropic effects their respective F(ab')2 fragments do not (see figure below). In accordance to previously performed in vitro experiments we were able to measure the improvement in cardiac function of DCM patients during immunoadsorption therapy only if antibodies belonging to the IgG-3 subclass were also effectively depleted, but not IgG-1, IgG-2 or IgG-4. This might indicate that the Fc part of IgG-3 has enhanced affinity for the involved Fc receptor, as is the case for the Fcg receptor IIa, or it might indicate a large spatial distance between the antigens involved in DCM and the Fcg receptor that could be bridged only by the longer Fc part of IgG-3. We assume that antigens on cardiomyocytes allow binding of several antibodies in close proximity to each other. These clustered antibodies then crosslink the Fcg receptor IIa via their Fc part, thereby causing clustering and activation.

The present study has parallel implications with respect to another severe immune-mediated disorder in cardiovascular medicine: heparin-induced thrombocytopenia. In heparin-induced thrombocytopenia, antibodies are generated against the self-protein, platelet factor 4, when platelet factor 4 forms multimolecular complexes with heparin. This results in immune complexes, which activate platelets by cross-linking their Fcg receptors IIa. Intravascular activation of platelets results in enhanced thrombin generation and can lead to catastrophic thromboembolic complications.

We hypothesize that a similar mechanism is basically involved in DCM (i.e., autoantibodies bind to their antigen via the Fab part and then induce cardiac dysfunction by activating Fcg receptors IIa on cardiomyocytes). This model might also be potentially applied for other antibody-mediated degenerative autoimmune disorders.


Intact immunoglobulin (Ig)G of dilated cardiomyopathy (DCM) patients induced negative inotropic effects by binding via their Fab part to the antigenic epitope on cardiomyocytes and then via their Fc part to the Fcg receptor IIa (FcgR) (A).
The F(ab')2 fragments of these antibodies inhibited the effect of intact DCM IgG (B), as did Fc fragments of normal IgG (C).
Reconstitution of Fc parts by sequential incubation of cardiomyocytes with DCM F(ab')2 fragments and goat-anti-human F(ab')2 IgG induced a negative inotropic effect (D) comparable to findings for intact DCM IgG.