Inflammatory / Familial Dilated Cardiomyopathy: Is there a Link to Autoimmune Diseases? (IKARIUS-Study) - Project description
Background
Diseases originating primarily from cardiac muscle (the myocardium) – the cardiomyopathies – are the third most common cause of heart failure. The most common form of cardiomyopathy is dilated cardiomyopathy (DCM), in which the cardiac cavities are enlarged and there is a loss of systolic and often also of diastolic function. A multifacetted combination of genetic, autoimmune and viral factors is suspected as the cause of DCM, but the involvement of modifier genes and environmental factors is also under discussion. Familial forms appear to account for DCM in up to 40 % of cases. Some of these patients may have an autoimmune disorder or dysregulation or a predisposition for infections. In individuals, this can apparently lead to symptoms of inflammatory DCM, triggered by a particular vulnerability of the myocardium, resulting for example from an infection with cardiotropic viruses or from environmental factors.
Objective
The purpose of this subproject is to improve the understanding of the pathogenesis of DCM by answering the following questions. Therefore a detailed family history, which includes the family tree, will be taken. In the second phase of the project all family members will be included, as far as this is possible. Particular questions include the following:
- In families with DCM, is there a genetic association with autoimmune diseases or with infections?
- In addition to a genetic association or predisposition, is there a change in the regulation of the expression of responsible genes?
Implementation
The first milestone of the project was to record as many patients with DCM as possible. This group of DCM patients was checked to find out what proportion of the patients had familial or sporadic DCM. Their etiology was reviewed to find out how many became ill with an idiopathic, inflammatory or virus-induced form of DCM. This was done by using comprehensive diagnostics, analysis of questionnaires and family trees for the family history as well as the examination of endomyocardial biopsies. The second milestone of the project was the molecular biological examination of the blood of patients and family members within the identified families.
Up to now, 323 patients with DCM and 117 family members were enrolled. So far, we identified 65 families (21%) with a minimum of two affected family members. The underlying etiologies were distributed as follows: In total we were able to identify an inflammatory DCM in 21% of the index patients and in 20% of the index patients a viral heart disease. In 54% of all patients’ families we detected a history of autoimmune diseases. Genetic analysis of the patients resulted so far in identification of a lamin A/C mutation in two patients, a new phopholamban mutation and a myopalladin and a N-cadherin mutation in one patient each. The CD 45 polymorphismus 77C>G probably associated with autoimmune diseases was detected in 5 patients.
Using DNA-based testing methods, new mutations in particular genes such as CARP, lamin A/C or melusin were identified, partially in collaboration with SP 3 and SP 5. With the help of microchip technology, a changed expression of genes involved in the development and regulation of autoimmune reactions as well as polymorphism clusters in HLA class II and CTLA4 genes were found in patients with DCM.