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European Journal of Heart Failure 2006 8(8):816-825; doi:10.1016/j.ejheart.2006.02.010
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© 2006 European Society of Cardiology

Familial inflammatory dilated cardiomyopathy

Irene Portiga,*, Andreas Wilkea,1, Matthias Freylanda,2, Markus-Joachim Wolfb,3, Anette Richtera, Volker Rupperta, Sabine Pankuweita and Bernhard Maischa

a Philipps-University Hospital, Department of Internal Medicine and Cardiology Baldingerstrasse, 35033 Marburg, Germany
b Department of Pneumology, Philipps-University Hospital Marburg, Germany

* Corresponding author. Tel.: +49 6421 2866462; fax: +49 6421 2868954. E-mail address: portig{at}med.uni-marburg.de


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Systematic family screening has recently identified dilated cardiomyopathy as an inherited disorder in up to 30% of cases. Mutations in genes encoding proteins responsible for myocardial architecture have been identified, but additional pathophysiological mechanisms including inflammatory reactions have been proposed.

Aims: Identification and characterization of familial DCM, where at least one affected family member fulfils the criteria for inflammatory DCM may lead to a better understanding of the aetiology and pathogenesis of (inflammatory) DCM.

Methods and results: Ten families were examined. In six families, clinical characteristics and mode of inheritance were compatible with pure fDCM, fDCM with conduction defect and autosomal recessive fDCM. In four families, (auto-)immune features were diagnosed in affected and non-affected family members.

Conclusions: Familial DCM with an inflammatory component was identified as a specific subgroup of familial DCM. In most cases, the inflammatory process seems to modify, i.e. aggravate, the "classic, cytoskeletopathic" familial DCM, but in some, especially when taking clinical and genetic aspects into account, inflammatory (auto-)immune features can be addressed as the leading pathogenetic principle. Further elucidation of these families may provide a better insight into pathophysiologic processes and may aid in the development of specific therapeutic strategies.

Key Words: Dilated cardiomyopathy • Familial dilated cardiomyopathy • Inflammatory DCM

Received July 22, 2005; Revised November 22, 2005; Accepted February 8, 2006


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Pathogenesis of idiopathic dilated cardiomyopathy (DCM) is as yet largely unknown. Aetiological factors that have been proposed include genetics, microbial infection and autoimmune reactions, but most likely all three contribute to disease manifestation. Since research in DCM is hampered by the fact that symptoms develop relatively late, i.e. physicians are most often confronted with the scarring end-stage, heritable forms of DCM may provide insight into the pathogenetic mechanisms through close follow-up of as yet clinically unaffected family members. This approach might not only aid in the understanding of DCM but also in the identification of patients likely to respond to specific therapies.

In familial forms of DCM (fDCM), comprising up to 30% of cases, mutations in cytoskeletal (dystrophin, desmin, taffazzin, β- and {delta}-sarcoglycan) [1-7], sarcomeric (actin, β-myosin heavy chain, troponin I and T, P-tropomyosin) [8-12], nuclear envelope proteins (lamin A/C, emerin) [13-15] and others (EYA4, phospholamban) [16,17] have been identified. Additional genetic loci have been mapped, as yet without identification of the corresponding gene (reviewed in [18]). Mutations in most of the above mentioned genes, albeit at different sites, cause congenital myopathies and congenital muscular dystrophies, where mode of inheritance is, in contrast to fDCM, usually autosomal recessive and cardiac involvement the rule.

Certain phenotypic features have been associated with single mutations although they are not specific: one group shows conduction system disease (lamin A/C) (reviewed in [18]) and others have been associated with sensorineural hearing loss [19] or retinitis pigmentosa [20]. Genotype-phenotype correlation is highly variable prompting the view that modifier or susceptibility genes, i.e. genes encoding proteins relevant to energy metabolism, contractility or myocardial perfusion, might contribute to the development of DCM. But inflammatory infiltrates, e.g. in response to viral infection, may well have a share and have been described in endomyocardial biopsies of index patients of fDCM by others [20]. We have therefore screened the local cardiomyopathy/myocarditis registry for patients with inflammatory DCM (iDCM) according to either the Dallas criteria [21] or the classification of the World Heart Federation Council on Cardiomyopathies [22,23] and attempted to identify and characterize families with a heritable form of inflammatory DCM.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study design
All patients presenting with inflammatory DCM according to WHO criteria [24] between 1989 and 2001 were included in the analysis. Patients with inflammatory DCM were identified in our database, which is kept abreast by active follow up. Medical records, coronary angiograms, levographies and endomyocardial biopsies of all patients with inflammatory DCM were analysed. The study, which complied with the Declaration of Helsinki, was approved by the local ethics committee and written informed consent was obtained from patients included in the study.

208 patients with inflammatory DCM were sent a questionnaire asking for heart disease in relatives (symptoms of heart insufficiency, sudden death, diagnosis of heart disease), 124 (60%) of these were returned. Using the questionnaires, 19 families were identified where familial preponderance was at least probable, i.e. if at least one 1st degree relative had symptoms of heart insufficiency, a family member had died suddenly, or was already diagnosed of having an enlarged left ventricle or reduced left ventricular ejection fraction and no primary heart disease. Further evaluation led to exclusion of nine families, since secondary causes of heart disease had already been diagnosed. In the remaining 10 families, index patients and all available family members were invited for clinical examination, electro- and echocardiography, and blood sampling. Family history was taken and a detailed two to four generation pedigree constructed.

2.2. Definitions and clinical follow-up
Patients had to fulfill WHO criteria established for the diagnosis of inflammatory DCM: enlarged left ventricle (left ventricular end-diastolic diameter≥117% of the predicted value [25], i.e. 2SD+5% above mean [26]) with reduced ejection fraction (<45%) in the absence of any primary heart disease [24], but histologic evidence of myocarditis in endomyocardial biopsies obtained during routine diagnostic procedures according to the Dallas criteria [21] or the more recent classification by the World Heart Federation Council on Cardiomyopathies [22]. The WHF criteria introduce immunohistochemical techniques for further characterization of infiltrating cells and their localization. Dallas and WHF criteria for the diagnosis of active myocarditis are closely related, the WHF Council on Cardiomyopathies have introduced diagnostic criteria for chronic myocarditis [22] to account for postulated chronic inflammatory processes. Snap-frozen biopsies were subjected to immunohistochemical staining. For the detection of infiltrating cells, monoclonal antibodies against CD2, CD3, CD4, CD8, CD11c, CD14, CD45RO, CD54 and CD56 (Dako Diagnostics, Hamburg, Germany) were used (minimum requirement for immunohistochemistry on cryostat sections is a T-cell marker (e.g. CD2 or CD3) to clearly identify T lymphocytes and a marker for endothelial cells (e.g. EN4). Markers for the characterization of T subtypes (CD4, CD8), B cells (e.g. CD79a) or activated macrophages (e.g. CD11c, CD14) are considered optional). An avidin-biotin double sandwich technique (Vectastain Elite ABC Kit; Vector Laboratories, Burlingame, CA, USA) was used in combination with a monoclonal antibody against the endothelial antigen EN4 (Sanbio, Am Uden, The Netherlands).

Morphological diagnosis of active myocarditis: presence of a clear-cut inflammatory infiltrate (diffuse, focal, or confluent). Number of infiltrating cells was recorded. Infiltrating cells were subclassified as lymphocytic, granulocytic (neutrophilic, eosinophilic, mast cell), granulomatous, consisting of macrophages or giant cells. Necrosis or myocytolysis were compulsory; fibrosis was graded if present.

Morphological diagnosis of chronic myocarditis: presence of an inflammatory infiltrate (diffuse, focal or confluent) of ≥14 lymphocytes/mm2 (up to five macrophages may be included). Infiltrating lymphocytes were subclassified as B/T lymphocytes, CD4+/CD8+ T cells or activated T cells. CD4 to CD8 or lymphocyte to macrophage ratios were determined and have been used to distinguish acute from subacute and chronic forms of myocarditis [27]. Localization of the infiltrate (interstitially or perivascularly) was recorded. Necrosis or myocytolysis was absent; fibrosis was graded if present.

To exclude skeletal muscle involvement creatinine kinase levels were measured and if elevated or symptoms suggestive of skeletal muscle involvement were present, neurological examination including EMG was performed in two index patients (resulting in myopathic changes in one index patient and no abnormal findings in the other).

FiDCM was diagnosed when at least one 1st degree family member met one of the following criteria:

  • diagnosis (inflammatory) DCM is already established
  • unexplained sudden death or stroke before the age of 30
  • two major echocardiographic criteria: LVEDD≥117% of predicted value and FS<25%
  • three minor echocardiographic and/or electrocardiographic criteria: LVEDD>112% of predicted value, FS<28%, pericardial effusion; unexplained conduction defects such as II° or III° AV block, bundle branch block or unexplained (supra-)ventricular arrhythmia before the age of 50.

Family members were classified as affected, if two major, one major (LVEDD>117% of predicted value) and one minor criterion or three minor echocardiographic criteria, and probably affected if only one or two minor echocardiographic criteria applied.

These criteria correspond closely to those established for the diagnosis of familial DCM as outlined previously [26].

2.2.1. Immunohistochemical and molecular biological analysis of endomyocardial biopsies and blood samples
Formalin-fixed endomycardial samples had been sent as part of routine diagnostic procedures to the local department of pathology and the Department of Pathology, University Hospital, London, for conventional histopathological staining. Snap-frozen biopsies were subjected to immunohistochemical staining as described elsewhere [28]. In addition, biopsies from each patient were subjected to PCR-analysis and Southern blot hybridization for the detection of microbial genome as described elsewhere [28].

Analysis of candidate genes (cardiac actin, myosin heavy chain, myosin light chain, P-tropomyosin, troponin I and T, lamin A/C, {delta}-sarcoglycan and desmin) via dideoxy fingerprinting was performed using standard techniques described in detail elsewhere [29].


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Of 124 consecutive patients with inflammatory DCM, 10 were chosen for further evaluation since at least one 1st degree relative fulfilled the criteria outlined in the preceding paragraphs: in two families inflammatory DCM, in two families myocarditis (not histologically proven), in three families left ventricular dilatation and reduced ejection fraction (non-invasively), in one family inflammatory DCM and in one family peripartum cardiomyopathy had already been diagnosed in 1st degree relatives; in three families, a history of heart failure in 1st degree relatives and, in two families, a history of sudden death could be established.

3.1. Index patients
Age at onset of symptoms was 37 years and female to male ratio was 1:1.5. Mean of Henry Index was 131%, mean of fractional shortening 20% on echocardiographic evaluation (in one index patient data not available). Active myocarditis according to Dallas criteria was found in five, chronic myocarditis according to WHF criteria (of which two also showed borderline myocarditis according to Dallas criteria) in seven cases. Inflammatory infiltrates were lymphomonocytic in nature. Microbial genome was not found in endomyocardial biopsies of index patients. To date, dideoxy fingerprinting has not revealed missense mutations in candidate genes (specified in Section 2) analysed.

3.2. Characterization of index families
Eighty-seven 1st and 2nd degree relatives older than 18 years of age were further evaluated either in person (42 [48.3%]) or through medical records available for deceased relatives (9 [10.3%]) or relatives not willing or able to visit our outpatient clinic (36 [41.4%]). Sixteen relatives (18%) had clinical or autopsy established DCM, inflammatory DCM or myocarditis. The median number of relatives examined per family was 7 (range, 4 to 21). Noninvasive screening revealed a further three (probably affected) relatives from two families.

Different clinical features and different patterns of genetic transmission were observed. The following compilation as well as Tables 1 and 2 give an overview of the clinical and histopathologic features of each index patient and their affected relatives.


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  		Table 1 Clinical features of affected family members and those with heart disease, index patient is underlined, affected members are in bold and probably affected in italic letters

 


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  		Table 2 Clinical and immunohistochemical characteristics of affected family members

 
3.2.1. Families with AV-conduction defects
Two families were identified, where affected members developed AV-conduction defects with the need of permanent pacing early in disease.

Family 1: In the index patient, active myocarditis according to Dallas criteria was diagnosed at autopsy. Two siblings and a nephew were found to have myocarditis according to clinical, echocardiographic and electrocardiographic signs. During acute illness, brother and sister developed III° AV block with the need for permanent pacing. At that time, left ventricular function was only mildly compromised.

In family 2 (see Fig. 1), III° AV block was accompanied by sustained ventricular tachycardia in two affected family members. Heart muscle biopsies of the index patient revealed chronic myocarditis according to WHF criteria (lymphomonocytic infiltrate, CD4+ plus CD8+ cells exceeding 10 cells, 4 CD11c positive cells/mm2). His sister received a pacemaker in her early 40s; at that time, she had only slight left ventricular dilatation. Their mother died of heart failure aged 48, further medical records were not available.


Figure 1
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  		Fig. 1 Pedigrees of families with inflammatory dilated cardiomyopathy. Pedigrees of families 2, 5, 7 and 9 are shown. Squares indicate male, circles female family members, symbols with a slash members who have died, solid symbols affected, open symbols unaffected family members and shaded symbols members with unknown clinical status.

 
3.2.2. Families without additional features compatible with "classic" fDCM
Family 3: Heart muscle biopsies of the index patient showed borderline myocarditis according to Dallas criteria. His mother has asymptomatic left ventricular dilatation with markedly reduced ejection fraction and his brother died after heart transplantation (pre-transplant diagnosis: DCM) aged 32.

Family 4: The index patient suffered from active myocarditis according to Dallas criteria. The diagnosis was made histologically in 1990 on an H&E staining. His son (aged 39) is affected; biopsies showed chronic myocarditis according to WHF criteria (more than 10 CD2 positive cells plus 4 CD14 positive cells/mm2).

Family 5 (see Fig. 1): The index patient, aged 56, demonstrated borderline myocarditis according to Dallas criteria. Of her five children, the eldest son received a heart transplantation due to active myocarditis according to Dallas criteria. The index patient had a twin brother, who suffered from spina bifida and died shortly after birth, and seven more siblings: a triplet was stillborn, another brother died of sudden infant's death at the age of 6 months, a sister died aged 2 allegedly having had diphtheria and another sister died in a car accident aged 25, a third sister is healthy.

3.2.3. Families without additional features compatible with AR fDCM
Family 6: The index patient had severe acute myocarditis (consisting of 11 CD4+ and 8 CD8+ T cells/mm2 and 18 CD11c+ cells/mm2) according to Dallas and WHF criteria (Fig. 2) aged 16 with evidence of sustained ventricular tachycardia during acute disease. The parents immigrated from Pakistan in the early 1990s and are both healthy. Her younger sister is affected with asymptomatic left ventricular dilatation and reduced ejection fraction. Four (three female and one male) of seven children of the index patient's aunt (father's side) died suddenly at an early age, further medical records are not available.


Figure 2
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  		Fig. 2 Histopathological findings in endomyocardial biopsies in patients with inflammatory dilated cardiomyopathy. Immunostaining with monoclonal antibodies against CD3 revealed lymphocytic cells in the inflammatory infiltrate (I) among cardiomyocytes (M) (magnification x630). Binding of anti-CD3 was visualized using an avidin-biotin double sandwich technique resulting in brown, anti-EN4 antibody binds endothelial cells resulting in blue staining.

 
3.2.4. Families with specific additional features
The index patient of family 7 (see Fig. 1) had a severe, acute lymphomonocytic myocarditis according to Dallas criteria (immunohistochemistry showed staining with antibodies directed mainly against CD45RO), which resolved completely upon symptomatic treatment, ejection fraction improved from 20% to 86%. In the following 5 years, left ventricular end-diastolic diameter and ejection fraction remained within normal limits, but gradually deteriorated thereafter. In parallel, a Werlhof's thrombocytopenia was diagnosed, a disease known to be caused by autoantibodies against blood platelets. The index patient's brother died suddenly at the age of 46 waiting for further diagnostic procedures because of exertional dyspnoea and left ventricular dilatation, and her younger daughter developed left ventricular dilatation with reduced ejection fraction during her second pregnancy.

In family 8, the index patient had borderline myocarditis according to Dallas criteria. His brother had a congenital heart disease comprising a ventricular septal defect, an aortic arch obstruction and had suffered of the Dandy-Walker malformation. Both the index patient and his father had had asthma from an early age. Their coronary angiogram showed vessel wall abnormalities without significant stenoses and left ventriculography diffusely reduced ejection fractions.

In family 9 (see Fig. 1), the index patient had chronic myocarditis according to WHF criteria (11 CD4+ and CD8+ T cells/mm2 and 4 CD14+ cells). One brother had marked left ventricular dilatation and a reduced ejection fraction; he suffers from biopsy-proven mesangial proliferative glomerulonephritis. Another brother died suddenly aged 21. A nephew received a bone marrow transplantation because of chronic myelogenous leukemia.

In family 10, the index patient died of heart failure aged 32 awaiting heart transplantation. Upon autopsy, the heart was found to be hypertrophied with signs of chronic myocarditis according to WHF criteria (comprising more than 10 CD2 positive cells and 4 CD14 positive cells). His father and aunt had suffered from rheumatoid arthritis and both died of heart failure at the age of 60.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this study, 10 families were identified and characterized with the index patient fulfilling the criteria for diagnosis of inflammatory DCM and at least one affected 1st degree relative.

Strict echocardiographic criteria were chosen for diagnosis of affected and probably affected family members conferring higher specificity as has been recommended by Mestroni et al. [26]. A recent prospective family study on familial DCM was able to show progression to DCM in only 10% of probands initially classified as probably affected by using a threshold of 112% of the predicted value [30], which is in keeping with the cut-offs defined for our study. Nevertheless, classification of family members as affected or healthy in studies dealing with fDCM has always been an issue, e.g. due to age-related and often incomplete penetrance.

In two families, AV-conduction system disease with the need for permanent pacing early in the course of disease and in three families DCM without additional clinical features were present. Both mode of inheritance (autosomal dominant) and clinical presentation (see Table 1) are compatible with familial DCM (fDCM) associated with cardiac conduction system disease (CDDC) and pure DCM as described by others before. In one family, mode of inheritance is probably autosomal recessive, since both parents are not affected.

4.1. Disease loci for CDDC
Disease loci for CDDC were mapped to chromosomes 1p1-q21 [31], 2q14-q22 [32], 2q35 [2], 3p22-p25 [33] and 6q23 [34] or are unknown [35]. On chromosome 2q35 desmin and on chromosome 1p1-q21, nuclear envelope proteins are encoded; missense mutations were characterized in the lamin A/C gene [13-15,36] and in the desmin gene [2]. Desmin-related myopathy is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmia and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. Lamin A/C gene mutations have been reported to cause Emery-Dreifuss muscular dystrophy, where skeletal muscle weakness and wasting is often associated with conduction defects and myocardial dysfunction [37]. More recently, an additional mutation was identified in a family exhibiting three different phenotypes: pure DCM, DCM with mild limb-girdle muscular dystrophy and DCM with Emery-Dreifuss muscular dystrophy [36].

In our families with AV-conduction defects, neither skeletal muscle involvement nor restrictive heart failure nor intracytoplasmic deposits could be detected. A desminopathy is thus unlikely. Moreover, mutations in the lamin A/C gene could not be detected in either of these families.

In contrast to pure fDCM [20,38], myocarditis in an index patient has not yet been described in families with AV-conduction defects.

4.2. Disease loci for pure DCM
Disease loci for pure DCM were mapped to chromosomes 1q32, 2q31, 2q35, 4q12, 5q33, 9q13-22, 10q21-23, 14q11, 15q2 and 15q14; seven of the relevant genes have been identified: actin (15q14), desmin (2q35), β-(4q12) and {delta}-sarcoglycan (5q33), cardiac troponin T (1q32), β-myosin heavy chain (14q11) and P-tropomyosin (15q2) (reviewed in [9]).

In the families described here, mutations in the above mentioned candidate genes could not be detected using dideoxy fingerprinting.

4.3. Disease loci for autosomal recessive DCM
Only recently, a novel TNNI3 (sarcomeric gene for cardiac troponin I) mutation in a family with recessive disease was identified; functional studies showed impairment of troponin interactions that could lead to diminished myocardial contractility [10].

As in autosomal recessive forms of fDCM described by others [20], age at onset was younger and clinical course of disease was more severe than in autosomal dominant fDCM. Myocarditis was seen in two affected family members by Mestroni et al. [20], as well.

Mutations in genes encoding proteins responsible for integrity and stability of the myocardial architecture have been associated with the deterioration of left ventricular function, whereas the mechanisms responsible for conduction system disease are unknown. As in muscular dystrophy [39], the corresponding phenotype is highly variable, which cannot only be explained by differences in expressivity and penetrance on the basis of a truly monogenic mode of inheritance. Environmental (e.g. microbial infection) and genetic factors (susceptibility or modifier genes influencing, e.g. energy metabolism) have therefore been proposed to account for these discrepancies [9,16].

We argue that myocarditis may be a causative or at least contributory factor in the materialisation of the cardiomyopathic (and electropathologic) phenotype: Inflammatory reactions in myocardium more vulnerable due to mutations in above mentioned structural proteins might contribute to the impairment of left ventricular function. Since microbial genome could not be detected in endomyocardial biopsies of index patients, on the cause of the lymphocytic infiltrate can only be speculated. One plausible explanation is an autoimmune response triggered by leakage of intracellular material functioning as danger signals (e.g. stress proteins) from vulnerable cardiomyocytes induced by physical exercise, toxins or infection [40].

4.4. Families with specific additional features
In families 7 to 10, affected and non-affected family members have a history of (auto-)immune diseases including organ-specific or systemic T cell- or autoantibody-mediated autoimmune disease (Werlhof's disease, rheumatoid arthritis, membranoproliferative glomerulonephritis), probable autoimmune disease (peripartum cardiomyopathy) [41], allergic disease involving mast cells (asthma) and lymphoproliferative disease.

In the pathogenesis of asthma, airway inflammation (comprising lymphocytes and eosinophils) in response to release of mediators from mast cells play an important role. Additionally, autoimmune phenomena have been demonstrated in patients with atopic and nonatopic asthma [42] suggesting common pathogenetic effector mechanisms for allergy and autoimmunity.

Pathogenesis of malignant lymphoproliferative diseases has been associated with autoimmune disease. Defects in the immune system, e.g. in apoptosis, or a sustained antigen drive provided by infectious agents and exo- or autoantigens have been described in B- and T-cell lymphoma [43,44], in patients with chronic myeloproliferative syndromes a variety of systemic autoimmune disorders have been reported; the nature of this link is not known [45].

Aggregation of one or more autoimmune diseases in one individual and his or her 1st or 2nd degree relatives has been reported, but only in few families genes responsible have been identified: autoimmune polyendocrine syndrome type 2 (APS-2) is a rare autosomal recessive human disorder caused by mutations in the autoimmune regulator gene (AIRE) and characterized by multiple autoimmune diseases [46,47]. Autoimmune lymphoproliferative syndrome (ALPS) is characterized by non-malignant lymphadenopathy and development of humoral autoimmune diseases, where inactivating mutations of either the Fas or the Fas-L gene lead to failure of apoptotic elimination of activated peripheral T lymphocytes [48,49].

Glomerulonephritis and immune thrombocytopenia diagnosed in members of families 7 and 9 have been described in ALPS—however, non-malignant lymphadenopathy was not present. Induction of apoptosis in lymphocytes isolated from affected and non-affected family members may reveal functional abnormalities. Using candidate gene approach, we then intend to screen for mutations in genes relevant for apoptosis including FAS.

Of note is the recurrence of asthma and rheumatoid arthritis in conjunction with impairment of left ventricular performance in families 8 and 10. The association of asthma and heart muscle disease has been made before [50]. Although bronchial hyper-responsiveness can be initiated by congestive heart failure alone, allergic and nonallergic asthma represent an independent disease entity [51]. In patients with rheumatoid arthritis evaluation of left ventricular function revealed diastolic dysfunction, end-diastolic diameter and systolic function was unimpaired [52]. Heart muscle disease on the one hand and rheumatoid arthritis/asthma on the other are thus independent and not interdependent disease entities of (auto-)immune origin.

Expansion of family screening may identify additional affected members enabling genetic linkage analysis thereby increasing the probability of identification of susceptibility loci, for example in genes affecting overall immune reactivity (CTLA-4), antigen presentation or recognition (HLA) or tissue responses to inflammation (Fc-{gamma}RIIa and Fc-{gamma}RIII) (reviewed in [53-56]).

4.5. Nature of inflammatory infiltrate
In families 1-6 (classic forms of fDCM), CD4/CD8 ratio was 1.3:1 and lymphocyte/macrophage ratio 3.5:1, whereas in families 7-10 (familial inflammatory DCM/familial autoimmunity) the inflammatory infiltrate consisted of CD4 lymphocytes exclusively and macrophages were more prevalent than lymphocytes. The first pattern is consistent with an intermediate, the second with an early type of inflammation [27]. Thus, in families 7-10, clinical course is probably more rapid leading to earlier development of symptomatic disease as is reflected by more severe impairment of left ventricular function in affected family members as compared to families 1-6.

4.6. Limitations
Possible limitations to generalization include the selected nature of the study sample due to the retrospective study design. A prospective study is currently under way. The families are small. The eldest and youngest generations were often either deceased and thus not available for examination or too young for final classification in affected or non-affected member due to age-dependent penetrance; allocations to mode of inheritance must therefore be interpreted with caution.

In conclusion, although mutations in structural proteins have been described in familial forms of dilated cardiomyopathy, these do not explain the differences in expressivity and penetrance. Since lymphomonocytic infiltrates have been detected in endomyocardial biopsies of our index patients, inflammatory reactions may contribute to the development of the clinical phenotype.

A close follow-up of as yet clinically unaffected family members may provide insight into pathogenetic mechanisms and may then aid in the development of new and specific therapeutic regimes.

Additionally, inflammatory DCM can be addressed as one organ manifestation in familial aggregation of autoimmune/allergic/lymphoproliferative diseases. A prospective study including widening of family screening may enable identification of genes responsible for the clinical phenotype.


   Acknowledgements
 
This contribution was supported by the German Heart Failure Network, which is funded by the Federal Ministry of Education and Research Germany (BMBF).


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
1 Current address: Cardiological private practice, Papenburg, Germany. Back

2 Current address: St. Georg's Hospital, Department of Cardiology, Hamburg, Germany. Back

3 Current address: Klinikum Villingen Schwenningen, teaching hospital of Freiburg, Department of Cardiology and Pneumology, Villingen-Schwenningen, Germany. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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A Luk, E Ahn, G S Soor, and J Butany
Dilated cardiomyopathy: a review
J. Clin. Pathol., March 1, 2009; 62(3): 219 - 225.
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