Common goal of the six projects of project area C is the development of novel experimental and clinical therapeutic approaches based also on new pathomechanistic insights derived from project areas A and B. In particular the clinical approaches of area C are closely interconnected with the core project Z1.
The therapeutic approaches may be classified as follows:
I. Antiviral strategies (TP C1, C4, C5)
II. Immunoadsorption procedures (TP C2, C3)
III. Mechanical unloading using heart assist devices (TP C6)
Beyond their direct relevance for DCMi several projects of area C may gain broader impact relevance in cardiovascular and infectious medicine. The majority of myocarditis cases are triggered by viral infections. In human DCMi hearts numerous molecular biological studies have detected viral persistence of entero- and adenoviruses and more recently other potentially cardiotropic viruses (parvovirus B19, HHV6, EBV, CMV). A recent pilot study has shown, that antiviral therapy with interferon-ß leads to effective elimination of cardiac entero- and adenoviral genomes, in conjunction with reduced cardiac inflammation and improved hemodynamic function of the heart. This approach is currently further evaluated in an international, randomized, double-blind, placebo-controlled clinical trial (BICC Trial).
In addition, various novel nucleic acid-based strategies are developed and evaluated in area C ( e.g. RNA interference approaches and gene therapy approaches). From a pharmacological point of view, transmembrane transport proteins may play an important role in all drug-based therapies of DCMi. These proteins are involved both in the cellular elimination of antiviral drug and the transport of endogenous substances (cGMP, cAMP) and possibly dysregulated in DCMi hearts. Expression, location, and function of these cardiac transporters are therefore investigated in project C4.
It is well known that in DCM patients various humoral antibodies exist which are directed against different cardiac structures. For part of these antibodies molecular mimicri is a possible induction mechanism. Various experimental approaches have shown that the induction of autoantibodies results in a DCM-like phenotype. Consistent with these results first clinical studies have shown, that immunoadsorption leads to reduced cardiac inflammation and functional improvement in severely ill DCM patients Based on these pilot studies projects C2 and C3 try to better understand the mechanisms of immunoadsorption by identifiation and characterisation of cardiodepressant autoantibodies.
A further therapeutic approach in terminally failing DCMi patients are the mechanical assist devices. Surprisingly it has been possible in a significant fraction of such patients to remove the assist devices after some time, since mechanical unloading lead to a significant improvement and stabilization of cardiac function. The mechanisms of recovery are as yet completely unknown and subject of project C6. |
