Overview of the Research Fields of SFB Transregio 19

A. Elucidation of structural determinants of DCMi at the cellular and molecular level.

B. Characterization of virus-host interactions and their relevance for the clinical course of the DCMi.

C. Development of new experimental and clinical therapies building upon new insights into a molecular pathogenesis of the disease, such as obtained in project areas A and B.

A general goal of SFB Transregio 19 is the improvement of the differential diagnosis and the differential therapy of the frequent and prognostically adverse cardiac disorder DCMi. This shall be achieved by close interdisciplinary cooperation between the participating institutions. A characteristic feature of SFB/TR 19 is the investigation of basic aspects of DCMi in close connection with clinical questions, taking methodological advantage e.g. from the exchange of clinical materials such as endomyocardial biopsies.

Clinical Importance and Complexity of DCMi Pathogenesis

DCM is a heart muscle disease of younger patients with a peak of manifestation in the third to fifth decade of life. The prevalence of DCM in Germany is estimated about 500.000 patients. Despite progress in heart failure therapy the prognosis of this disease is adverse with a 5-years-mortality above 50 %. In 1999 the average hospitalisation time of DCM patients was 12 days per year including 3.6 days on a intensive care unit. Patients were hospitalized at a mean rate of 2.3 times per year. This results in costs for stationary treatment alone between 2 to 4 billion Euro per year. The costs for ambulant heart failure therapy are iin a similar range. The total economic damage caused by this disease is far higher, however, since the generally young patients are taken out of the economic process 10-30 years before they reach the retirement normal age. HTX which is available in Germany as a palliative therapeutic option for about 250 DCM patients per year adds costs of 0.5 billion Euro over a time period of 5 years. Despite the frequency of the disease and the resulting importance for health economy there are still no generally accepted diagnostic and therapeutic guidelines, in contrast to other frequent cardiovascular disorders. This results in profound deficiencies in the diagnosis and therapy of these patients.

It needs to be emphasized that due to the lack of established diagnostic procedures most patients with suspected DCM are not comprehensively investigated according to the WHO Guidelines (both nationally and internationally). Therefore a large number of unreported disease cases must be suspected. Although the first diagnosis is often not made before the middle decades of life, since symptoms occur rather late during the course of the disease, the disease process occurs far earlier according to current research. At the time of clinical diagnosis there is often already irreversible damage to the heart and prognosis is serious.

Several studies suggest that viral etiologies play a key role in DCMi which constitutes a sub-entity of DCM. In addition to classical myocarditis viruses (coxsackieviruses and adenoviruses) detected in 15 to 20 % of DCM cases other viruses ( e.g. parvovirus B19, human herpes virus-6) can not only trigger myocarditis, but also persist in the myocardium. Most recent data show cardiac virus persistence in up to 70 % of DCM patients, an unexpected finding to be further investigated by SFB/TR 19 with respect to its therapeutic implications. Since the currently available epidemiological data are insufficient, the incidence and prevalence of DCMi are most probably grossly underestimated. As one consequence there are no reliable data on the natural cause of the disease, dependent on etiologic virus and/or other factors such as inflammation. SFB/TR 19 shall create a solid data basis for later risk-stratified application of novel differential therapeutic procedures under development by research groups of the SFB.

Long Term Goals of SFB Transregio 19

Based on a first 4-years funding period and the combined scientific potential of the SFB groups a number of fundamental problems can be tackled which may promote the whole research field in its basic and clinical aspects. Building upon many years of preparatory work from the participating groups significant progress may be expected. One final goal is the clinical establishment of improved diagnostic procedures and novel causal therapies derived from a better pathogenic understanding of DCMi. It is hoped that molecular genetic, virological and immunological analyses will allow risk stratification at an early time point and initiation of highly efficient, causal therapies before grave organ damage has occurred. Specific long term goals are:

1. Comprehensive elucidation of exogenous and genetic determinants of the highly variable individual susceptibilities and disease courses. Such knowledge would then allow early detection and protection/therapy of endangered individuals at an early stage of the disease.

2. Detailed understanding of the often rapid and potentially reversible “remodeling” of the myocardium during acute and chronic viral infections and/or autoimmune processes. Modulation of this phenomenon may have therapeutic potential.

3. Elucidations of the immune mechanisms which dependent on virus- and host-specific pathogenicity determinants influence the course of disease (rapid virus elimination, chronical virus persistence, or chronic autoimmunity).

4. The research groups shall develop, analyse and finally establish novel experimental and clinical therapies for DCMi including antiviral and immunmodulatory therapies and mechanical heart assist devices. They have in part already been evaluated by SFB groups within the framework of controlled clinical trials. It is hoped for the future that better understanding of the molecular mechanisms underlying these therapies will lead to improved, highly efficient differential therapies of DCMi.

Position of SFB Transregio 19 in Cardiovascular Research

SFB/TR 19 investigates the molecular pathomechanisms and innovative therapies for DCMi within the framework of an intensive interdisciplinary cooperation (internal medicine- cardiology- cardiosurgery- molecular pathology- virology- immunology- biochemistry- genetics- pharmacology- physiology- epidemiology- biometry). The genetic, structural and immunological determinants of DCMi are currently only incompletely understood, resulting in empirical treatments without sufficient database or pathomechanistic foundations. Thus, generally accepted guidelines for differential diagnosis and therapy are lacking.

Not only the endogenous (genetic, structural, immunological) determinants of DCMi are largely unknown, but also their exogenous triggers ( e.g. viruses) and their interaction with the host are only partly known.

In particular, there are rather no animal models which adequately reflect the observed clinical phenomena. The development of such animal models is therefore one important objective of SFB/TR 19. The novel (recombinant and conventional) animal models shall be useful for further analyses of complex clinical phenomena ( e.g. cardiac remodeling, vascular endothelial dysfunction, susceptibility for cardiac viral infections). On the clinical side, experimental data obtained in a number of projects shall be examined with respect to their clinical relevance by using innovative methods ( e.g. novel human myocardial biopsy studies and cardiovascular functional tests).