Mid-regional proatrial natriuretic peptide for predicting prognosis in hypertrophic cardiomyopathy.

OBJECTIVES: N-terminal probrain natriuretic peptide (NT-proBNP) predicts mortality and the development of heart failure in hypertrophic cardiomyopathy (HCM). Mid-regional proatrial natriuretic peptide (MR-proANP) is a stable by-product of production of atrial natriuretic peptide. We sought to compare the prognostic value of MR-proANP and NT-proBNP in HCM. METHODS: We prospectively enrolled a cohort of patients with HCM from different European centres and followed them. All patients had clinical, ECG and echocardiographic evaluation and measurement of MR-proANP and NT-proBNP at inclusion. RESULTS: Of 357 patients enrolled, the median age was 52 (IQR: 36-65) years. MR-proANP and NT-proBNP were both independently associated with age, weight, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), wall thickness and left atrial dimension. During a median follow-up of 23 months, 32 patients had a primary end point defined as death (n=6), heart transplantation (n=8), left ventricular assist device implantation (n=1) or heart failure hospitalisation (n=17). Both NT-proBNP and MR-proANP (p<10-4) were strongly associated with the primary endpoint, and the areas under the receiver operating characteristic (ROC) curves for both peptides were not significantly different. However, in a multiple stepwise regression analysis, the best model for predicting outcome was NYHA 1-2 vs 3-4 (HR=0.35, 95% CI 0.16 to 0.77, p<0.01), LVEF (HR=0.96, 95% CI 0.94 to 0.98, p=0.0005) and MR-proANP (HR=3.77, 95% CI 2.01 to 7.08, p<0.0001). CONCLUSIONS: MR-proANP emerges as a valuable biomarker for the prediction of death and heart failure related events in patients with HCM.

Galectin-3 as a Predictor of Left Ventricular Reverse Remodeling in Recent-Onset Dilated Cardiomyopathy.

OBJECTIVES: Studies have evaluated the association of galectin-3 and outcome in patients with heart failure. However, there is still scarce evidence concerning the clinical usefulness and predictive value of galectin-3 for left ventricular reverse remodeling (LVRR) in patients with recent-onset dilated cardiomyopathy (RODCM). PATIENTS AND METHODS: Baseline galectin-3 was measured in 57 patients with RODCM. All patients were followed for at least 12 months. The study end point was LVRR at 12 months, defined as an absolute improvement of the left ventricular ejection fraction of ≥10% to a final value of ≥35%, accompanied by a decrease in the left ventricular end diastolic diameter of at least 10%, as assessed by echocardiography. In receiver operating characteristic curve analysis, the optimum cut-off value for baseline galectin-3 with the highest Youden index was 59 ng/ml. RESULTS: Overall, LVRR at 12 months was observed in 38 patients (66%). In a univariate analysis, NYHA functional class and baseline galectin-3 levels were associated with LVRR. After adjustment for covariates, galectin-3 remained an independent predictor for LVRR. CONCLUSIONS: Our study suggests that baseline galectin-3 is an independent predictor of LVRR. Low levels of galectin-3 may be regarded a useful biomarker of favorable ventricular remodeling in patients with RODCM.

The prognostic value of sST2 and galectin-3 considering different aetiologies in non-ischaemic heart failure.

Objective: Several studies indicate a prognostic value of sST2 and galectin-3 in heart failure (HF). While previous studies focused on ischaemic cause of HF, we investigated the role of sST2 and galectin-3 in patients with non-ischaemic dilated cardiomyopathy (DCM). Methods: sST2 and galectin-3 serum concentrations were measured in 262 subjects with DCM. Survival rates were determined for all-cause mortality (ACM) and cardiac mortality (CM). Results: In a univariate model, sST2 as a continuous variable was a predictor of ACM (HR 1.05; 95% CI 1.03 to 1.07, P<0.001) and CM (HR 1.03; 95% CI 1.00 to 1.06, P=0.040). In the subgroup of patients with inflammatory and/or viral DCM (DCMi⋎viral), the endpoints ACM (HR 1.10; 95% CI 1.05 to 1.17, P<0.001) and CM (HR 1.10; 95% CI 1.02 to 1.18, P=0.013) were significant. In the subgroup of patients with idiopathic DCM, the endpoint ACM (HR 1.04; 95% CI 1.01 to 1.07, P=0.019) was significant. In a multivariate model, the prognostic value of the sST2 main group remained intact for ACM (HR 1.04; 95% CI 1.02 to 1.07, P=0.003).Univariate and multivariate analysis of galectin-3 as continuous variable did not show any significant result. However, in a quartile model, intermediate values of galectin-3 were significantly associated with a lower event rate of ACM and CM. Conclusion: The study revealed that sST2 predicts ACM and CM in patients with non-ischaemic HF and could be useful especially in patients with inflammatory background. Our findings that intermediate levels of galectin-3 allow for better prognosis were new and different to other investigations. Trial registration number: NCT03090425; Results.

Clinical predictors of outcome in patients with inflammatory dilated cardiomyopathy.

OBJECTIVES: The study objectives were to identify predictors of outcome in patients with inflammatory dilated cardiomyopathy (DCMi). METHODS: From 2004 to 2008, 55 patients with biopsy-proven DCMi were identified and followed up for 58.2±19.8 months. Predictors of outcome were identified in a multivariable analysis with a Cox proportional hazards analysis. The primary endpoint was a composite of death, heart transplantation and hospitalization for heart failure or ventricular arrhythmias. RESULTS: For the primary endpoint, a QTc interval >440msec (HR 2.84; 95% CI 1.03-7.87; p = 0.044), a glomerular filtration rate (GFR) <60ml/min/1.73m2 (HR 3.19; 95% CI 1.35-7.51; p = 0.008) and worsening of NYHA classification during follow-up (HR 2.48; 95% CI 1.01-6.10; p = 0.048) were univariate predictors, whereas left ventricular ejection fraction at baseline, NYHA class at entry, atrial fibrillation, treatment with digitalis or viral genome detection were not significantly related to outcome. After multivariable analysis, a GFR <60ml/min/1.73m2 (HR 3.04; 95% CI 1.21-7.66; p = 0.018) remained a predictor of adverse outcome. CONCLUSIONS: In patients with DCMi, a prolonged QTc interval >440msec, a GFR<60ml/min/1.73m2 and worsening of NYHA classification during follow-up were univariate predictors of adverse prognosis. In contrast, NYHA classification at baseline, left ventricular ejection fraction, atrial fibrillation, treatment with digitalis or viral genome detection were not related to outcome. After multivariable analysis, a GFR <60ml/min/1.73m2 remained independently associated with adverse outcome.

Biventricular unloading in patients with refractory cardiogenic shock.

BACKGROUND: Cardiogenic shock remains a clinical challenge with high mortality rate. Mechanical circulatory support (MCS) devices have become an integral component of the therapeutic armamentarium expanding the treatment options for refractory cardiogenic shock (RCS). METHODS: We included all consecutive patients with biventricular unloading with Impella-2.5 and VA-ECMO admitted for RCS between October 2013 and March 2015. Outcome data included survival to discharge, bridging to VAD and 28-day mortality. RESULTS: A total of 17 patients were included. Mean age was 63.3±10.5 and 15 (88%) patients were male. RCS resulted from acute myocardial infarction in 14 (82%), acute myocarditis in 1 (6%) dilated cardiomyopathy in 2 (12%) patients. Mean SAPS II and SOFA score on admission was 74.7±16.86 and 11.16±1.79, respectively. Vasopressor doses and lactate levels were significantly decreased within 72h on biventricular support (p=0.025 for norepinephrine and p=0.005 for lactate). Nine (53%) patients died while on support. Of the remaining 8 patients, 5 (29%) patients were weaned successfully and discharged in cardiac rehabilitation and 3 (18%) patients were successfully bridged to VAD. All 5 patients who were discharged to rehabilitation survived at day 28 after discharge, while 1 of 3 VAD patients died after VAD implantation, corresponding to an overall 28-day survival rate of 41%. CONCLUSIONS: Biventricular support with Impella-2.5 and VA-ECMO in patients with RCS is feasible and led to significant hemodynamic improvement and reduction of lactate levels. Despite high severity scores, ICU- and 28-day mortality rates were better than predicted.

Long-term outcome and predictors of outcome in patients with non-ischemic dilated cardiomyopathy.

BACKGROUND: The study objectives were to identify predictors of outcome and to assess the long-term outcome in patients with non-ischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: From 2004 to 2008, 206 consecutive patients (age 52.1±12.6years) with non-ischemic DCM were prospectively enrolled in the study and followed up for a mean of 55.6±18.4months. Predictors of outcome were identified in a multivariable analysis with a Cox proportional hazards analysis. The primary endpoint was a composite of all-cause mortality or heart transplantation. During the follow-up period 47 patients died (22.8%) and 5 patients (2.4%) underwent heart transplantation for end-stage heart failure. For the primary end point, a systolic LVEF <35% (hazard ratio 2.56; 95% confidence interval 1.21-5.45; p=0.014), a prolonged QTc interval >440ms (hazard ratio 2.56; 95% confidence interval 1.24-3.83; p=0.007) and a GFR <60ml/min/1.73m(2) (hazard ratio 2.42; 95% confidence interval 1.36-4.29; p=0.003) were identified as independent predictors, whereas the presence of an LBBB, atrial fibrillation, mild mitral regurgitation or treatment with digitalis were not significantly related to outcome. CONCLUSIONS: In patients with non-ischemic DCM, a reduced systolic LVEF <35%, a prolonged QTc interval >440ms and an abnormal renal function with a GFR <60ml/min/1.73m(2) are independent predictors of death or need for heart transplantation.

Anticardiac Antibodies in Patients with Chronic Pericardial Effusion.

OBJECTIVES: Chronic pericardial effusion may be challenging in terms of diagnosis and treatment. Specific laboratory parameters predicting the frequency and severity of recurrences after initial drainage of pericardial effusion are lacking. MATERIALS AND METHODS: Pericardial fluid (PF) and serum (SE) samples from 30 patients with chronic pericardial effusion (PE) who underwent pericardiocentesis and pericardioscopically guided pericardial biopsy were compared with SE and PF samples from 26 control patients. The levels of antimyolemmal (AMLA) and antifibrillary antibodies (AFA) in PE and SE from patients with pericardial effusion as well as PF and SE from controls were determined and compared. RESULTS: AMLAs and AFAs in PF and SE were significantly higher in patients with chronic pericardial effusion than in the control group (AMLAs: p = 0,01 for PF and p = 0,004 for serum; AFAs: p < 0,001 for PF and p = 0,003 for serum). Patients with recurrence of PE within 3 months after pericardiocentesis had significantly higher levels of AMLAs in SE (p = 0,029) than patients without recurrence of PE. CONCLUSIONS: The identification of elevated anticardiac antibodies in PE and SE indicates increased immunological reactivity in chronic pericardial effusion. High titer serum levels of AMLAs also correlate with recurrence of pericardial effusion.

Influence of different aetiologies on clinical course and outcome in patients with dilated cardiomyopathy.

BACKGROUND: The clinical phenotype dilated cardiomyopathy is assumed to be the endstage of a multifactorial aetiopathogenetic pathophysiology which includes a not satisfactorily defined group of patients with inflammatory cardiomyopathy. METHODS: Within the German Competence Network Heart Failure patients with heart failure due to dilated cardiomyopathy of viral/inflammatory (DCMi/v) and nonviral/noninflammatory (DCM) aetiology were enrolled. After 1 year 237 patients (180 male/57 female) were re-examined including complete clinical work-up. The association of different clinical courses with the time from initial diagnosis of heart failure (newly: ≤ 1 year; late: > 1 year) was investigated. RESULTS: After 1-year-follow-up New York Heart Association (NYHA) class (by -0.48 in newly diagnosed DCM and -0.82 in newly diagnosed DCMi/v in addition to -0.24 in late diagnosed DCM and -0.17 in late diagnosed DCMi/v) as well as left ventricular ejection fraction (+14% in newly diagnosed DCM and DCMi/v and +6% in later diagnosed DCM and DCMi/v) were significantly improved in all patients. In patients with early diagnosed dilated cardiomyopathy a strong improvement of NYHA class could be demonstrated. CONCLUSIONS: This study demonstrates for the first time a significant interaction between duration of disease, NYHA class and left ventricular ejection fraction in patients with DCM. Our results clearly demonstrate that in patients with DCM an early diagnosis within 1 year after occurrence of clinical signs is associated with a strong improvement in the clinical course, whereas late diagnosis results in a loss of change in clinical course and outcome.

Detection of a large duplication mutation in the myosin-binding protein C3 gene in a case of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a cardiovascular disease with autosomal dominant inheritance caused by mutations in genes coding for sarcomeric and/or regulatory proteins expressed in cardiomyocytes. In a small cohort of HCM patients (n=8), we searched for mutations in the two most common genes responsible for HCM and found four missense mutations in the MYH7 gene encoding cardiac ß-myosin heavy chain (R204H, M493V, R719W, and R870H) and three mutations in the myosin-binding protein C3 gene (MYBPC3) including one missense (A848V) and two frameshift mutations (c.3713delTG and c.702ins26bp). The c.702ins26bp insertion resulted from the duplication of a 26-bp fragment in a 54-year-old female HCM patient presenting with clinical signs of heart failure due to diastolic dysfunction. Although such large duplications (>10 bp) in the MYBPC3 gene are very rare and have been identified only in 4 families reported so far, the identical duplication mutation was found earlier in a Dutch patient, demonstrating that it may constitute a hitherto unknown founder mutation in central European populations. This observation underscores the significance of insertions into the coding sequence of the MYBPC3 gene for the development and pathogenesis of HCM.

Viral genomes in the pericardial fluid and in peri- and epicardial biopsies from a German cohort of patients with large to moderate pericardial effusions.

The aetiology of pericardial effusion has been generally assessed by clinical work-up only, which leaves a large cohort of patients with "idiopathic" effusions virtually undiagnosed. In accordance with the ESC guidelines, this contribution intends to change this attitude. After therapeutic or diagnostic pericardiocentesis of 259 patients with large to moderate pericardial effusions, pericardial fluid, epicardial and pericardial biopsies, and blood samples were analysed by PCR for cardiotropic microbial agents. Cytology, histology, immunohistology of tissue and fluids and laboratory tests were performed. Of the 259 patients, 35 % suffered from an autoreactive aetiology, 28 % suffered from a malignant and 14 % from an infectious cause. Investigating all samples by PCR, we identified viral genomes in 51 (19.7 %) patients, parvovirus B19 (B19 V) being identified in 25 and Epstein-Barr virus (EBV) in 19 cases. In patients with a sole infectious aetiology (n = 36), B19 V was detected in 21 and EBV in 10 cases. When differentiating with regard to the material investigated for the presence of cardiotropic viruses, parvovirus B19 was most often detected in the epicardium and EBV was most frequently detected in the pericardial fluid independent from the final diagnostic categorisation. Bacterial cultures including tests for tuberculosis were all negative. Molecular techniques improve sensitivity, specificity and diagnostic accuracy for the underlying aetiology in pericarditis patients with effusion. The identification of specific viral signatures will help to understand pathogenetic mechanisms in pericarditis and allow to tailor an adequate therapy beyond antiphlogistic treatment.

Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy.

Recently, missense mutations in titin-associated proteins have been linked to the pathogenesis of dilated cardiomyopathy (DCM). The objective of this study was to search for novel disease-associated mutations in the two human titin-binding proteins myopalladin and its amino-terminal-interacting partner cardiac ankyrin-repeat protein (CARP). In a cohort of 255 cases with familial and sporadic DCM, we analyzed the coding regions and all corresponding intron flanks located in the MYPN and CARP-encoding ANKRD1 gene. Two heterozygous missense mutations were detected in the MYPN gene (p.R955W and p.P961L), but neither of these mutations was found in 300 healthy controls. Both mutations were located in the α-actinin-binding region of myopalladin. Endomyocardial biopsies from the p.R955W carrier showed normal subcellular localization of myopalladin and α-actinin in cardiac myocytes, while their regular sarcomeric staining pattern was significantly disrupted in the p.P961L carrier, indicating that disturbed myofibrillogenesis and altered sarcomere assembly are the cause of the disease. In the ANKRD1 gene, we identified synonymous base exchanges (c.108T>C and c.-79C>T, respectively), but no non-synonymous mutations. In summary, we have identified novel missense mutations in the third immunoglobulin-like domain of myopalladin, which have either no or profound effects on the molecular composition of the sarcomere. According to our epidemiological data, the prevalence of ANKRD1 mutations seems to be lower than that of its binding partner myopalladin, indicating the clinical significance of myopalladin for the functional integrity of the sarcomeric apparatus and the protection against DCM.

Identification of a missense mutation in the melusin-encoding ITGB1BP2 gene in a patient with dilated cardiomyopathy.

In a heterogeneous cohort of patients (n=255) with sporadic and familial dilated cardiomyopathy (DCM), we searched for novel disease-associated mutations in the human melusin-encoding ITGB1BP2 gene and found only one missense mutation, which was a substitution of alanine for glycine at position 313 located in the carboxy-terminal spacer region of the molecule. This point mutation (c.938C>G) was identified in a 45-year-old male with familial DCM and severe impairment of left-ventricular function, but was absent in 300 healthy control subjects. However, its functional significance in the context of heart failure is unclear, as this amino acid substitution was predicted to be without disease-causing effects. In this report, we confirm the low prevalence of mutations and single nucleotide polymorphisms in the coding sequence of the human melusin gene in patients with DCM, ruling out the possibility that genetic variations in this myocardially transcribed gene may have a significant impact on the epidemiology of DCM-induced heart failure.

Cardiomyopathies: classification, diagnosis, and treatment.

This article comments on the recent classifications of cardiomyopathies by the American Heart Association and the European Society of Cardiology with respect to their clinical applicability. Taking them and the statement on the role of endomyocardial biopsies in different clinical scenarios together, the clinician is now able to identify genetic, autoimmune, and viral causative factors by using a thorough and logical approach to reach a diagnosis in patients with familial and nonfamilial forms of the underlying structural heart muscle diseases. In this overview, a special emphasis is also placed on the management of inflammatory and viral cardiomyopathies.

Genotype-specific effects on left ventricular function in parvovirus B19-positive patients with dilated cardiomyopathy.

Genotype-specific effects of parvovirus B19 (B19V) infections on left ventricular function in patients with dilated cardiomyopathy (DCM) have not been investigated so far. In this prospective clinical study, the prevalences of B19V genotypes in endomyocardial biopsies from patients presenting with inflammatory heart disease and DCM were determined. A total of 139 consecutive patients were included in the study; among them 53 patients were diagnosed as DCM. Among the total study cohort, B19V DNA was detected in 65 study participants (46.8%). Genotyping of the B19V genomes in the total cohort identified genotype 1 in 38 samples (27.3%), genotype 2 in 25 samples (18.0%), and genotype 3 in only two patients (1.4%). During an average follow-up period of 8 months left ventricular ejection fraction (LVEF) improved significantly both in B19V-positive (7.1 ± 13.8%, n = 17, P = 0.038) as well as B19V-negative patients with DCM (9.5 ± 13.9%, n = 20, P = 0.017). However, mean LVEF improved only in patients with genotype 1 (11.0 ± 14.4%, n = 7), whereas it even decreased in patients with genotype 2 (-6.2 ± 6.3%, n = 5, P = 0.033). These data from a small sample of patients diagnosed as DCM suggested that myocardial function during short-time follow-up differed between genetic variants of B19V. Patients with genotype 1 were on average younger than genotype 2 and appeared to be more prone to a beneficial course of left ventricular function than patients with genotype 2. Future studies with larger sample sizes and longer follow-up periods will be required to confirm this observation.

Genetic association study identifies HSPB7 as a risk gene for idiopathic dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is a structural heart disease with strong genetic background. Monogenic forms of DCM are observed in families with mutations located mostly in genes encoding structural and sarcomeric proteins. However, strong evidence suggests that genetic factors also affect the susceptibility to idiopathic DCM. To identify risk alleles for non-familial forms of DCM, we carried out a case-control association study, genotyping 664 DCM cases and 1,874 population-based healthy controls from Germany using a 50K human cardiovascular disease bead chip covering more than 2,000 genes pre-selected for cardiovascular relevance. After quality control, 30,920 single nucleotide polymorphisms (SNP) were tested for association with the disease by logistic regression adjusted for gender, and results were genomic-control corrected. The analysis revealed a significant association between a SNP in HSPB7 gene (rs1739843, minor allele frequency 39%) and idiopathic DCM (p = 1.06 × 10⁻6, OR  = 0.67 [95% CI 0.57-0.79] for the minor allele T). Three more SNPs showed p < 2.21 × 10⁻5. De novo genotyping of these four SNPs was done in three independent case-control studies of idiopathic DCM. Association between SNP rs1739843 and DCM was significant in all replication samples: Germany (n =564, n = 981 controls, p = 2.07 × 10⁻³, OR = 0.79 [95% CI 0.67-0.92]), France 1 (n = 433 cases, n = 395 controls, p =3.73 × 10⁻³, OR  = 0.74 [95% CI 0.60-0.91]), and France 2 (n = 249 cases, n = 380 controls, p = 2.26 × 10⁻4, OR  = 0.63 [95% CI 0.50-0.81]). The combined analysis of all four studies including a total of n = 1,910 cases and n = 3,630 controls showed highly significant evidence for association between rs1739843 and idiopathic DCM (p = 5.28 × 10⁻¹³, OR= 0.72 [95% CI 0.65-0.78]). None of the other three SNPs showed significant results in the replication stage.This finding of the HSPB7 gene from a genetic search for idiopathic DCM using a large SNP panel underscores the influence of common polymorphisms on DCM susceptibility.

Evidence for CTLA4 as a susceptibility gene for dilated cardiomyopathy.

The cytotoxic T-lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed on activated T cells with downregulatory properties. The aim of this study was to analyse whether single-nucleotide polymorphisms (SNPs) within the CTLA4 gene are associated with the diagnosis and disease course of dilated cardiomyopathy (DCM). In two independent cohorts of DCM patients (n=251 and 223) and healthy controls (n=591), the promoter and all four exons of the CTLA4 gene, including their flanking regions, were genotyped, and the resulting allele and genotype distributions of the identified SNPs were compared between the groups. We confirmed two known SNPs in the promoter region (-318C>T) and in exon 1 (+49A>G;Thr17Ala). The allelic frequencies and genotypic distribution of the promoter SNP were similar for DCM patients compared with controls. However, the G/G genotype of the Thr17Ala variant was significantly more frequent in DCM patients compared with controls (37 out of 251 patients (14.7%) versus 44 out of 591 controls (7.4%), P=0.005). The higher frequency of the G/G genotype was confirmed in an additional DCM cohort (29 out of 223 patients (13.0%), P=0.039), indicating that this SNP functions as a risk factor for DCM. At follow-up after 1 year, the ejection fraction and the end-diastolic diameter of the left ventricle did not differ significantly between DCM patients carrying the G/G genotype versus other genotypes (n=199). Our data indicate that the common CTLA4 variant, Thr17Ala, confers susceptibility for DCM, but does not seem to influence the course of the disease 1 year after diagnosis.

Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is familial in approximately 30% of cases, and mutations have been identified in several genes. However, in a majority of familial cases, the responsible genes are still to be discovered. The ANKRD1 gene is over-expressed in heart failure in human and animal models. The encoded protein CARP interacts with partners such as myopalladin or titin, previously shown to be involved in DCM. We hypothesized that mutations in ANKRD1 could be responsible for DCM. METHODS AND RESULTS: We sequenced the coding region of ANKRD1 from 231 independent DCM cases. We identified five missense mutations (three sporadic and two familial) absent from 400 controls and affecting highly conserved residues. Expression of the mutant CARP proteins after transfection in rat neonate cardiomyocytes indicated that most of them led to both significantly less repressor activity measured in a reporter gene assay and greater phenylephrin-induced hypertrophy, suggesting altered function of CARP mutant proteins. CONCLUSION: On the basis of genetic and functional analysis of CARP mutations, we have identified ANKRD1 as a new gene associated with DCM, accounting for approximately 2% of cases.

[Familial predisposition and microbial etiology in dilated cardiomyopathy]. / Familiäre Prädisposition und mikrobielle Atiologie bei dilatativer Kardiomyopathie.

Cardiomyopathies are an important and diverse group of heart muscle diseases in which the heart muscle itself is structurally or functionally abnormal and in which coronary artery disease, hypertension, valvular and congenital heart disease are absent or do not sufficiently explain the observed myocardial abnormality. This often results in severe heart failure accompanied by arrhythmias and/or sudden death. Clinical and morphological diversity of cardiomyopathies can reflect the broad spectrum of distinct underlying molecular causes or genetic heterogeneity. In many cases the disease is inherited and is termed familial dilated cardiomyopathy (FDC), which may account for up to 30% of dilated cardiomyopathies (DCM). FDC is principally caused by genetic mutations in FDC genes that encode for cytoskeletal, nuclear and sarcomeric proteins in the cardiac myocyte. In addition, modifying genes, lifestyle and additional factors were reported to influence onset of disease, disease progression, and prognosis. The individual patient's phenotype may reflect a summation and/or interaction of the underlying mutation(s) with other genetic or environmental factors. During the last years major advances have been made in the understanding of the molecular and genetic basis of this type of disease. Nevertheless, much more progress in the identification of underlying mutations, susceptibility genes and modifier genes is important and indispensable for the development of new etiology-orientated forms of therapy. A pivotal role for autoimmunity in a substantial proportion of patients with DCM is supported by the presence of organ-specific autoantibodies, inflammatory infiltrates and pro-inflammatory cytotoxic cytokines. Furthermore, familial occurrence of DCM goes ahead with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. These relatives suffer from a higher risk for the development of DCM after years. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. There is reasonable clinical and experimental evidence, that DCM in addition may occur as late stage of cardiac infection and inflammation. The large spectrum of clinical forms depends on several factors such as genetic determinants of the infective agent, the genetics, age and gender of the host, and the host immunocompetence. In general, infectious agents, including viruses such as entero-, cytomegalo-, and adenoviruses, bacteria such as Borrelia burgdorferi or Chlamydia pneumoniae, protozoa and even fungi can cause inflammatory heart disease leading to DCM. The infectious agents most often identified in DCM nowadays are parvovirus B19, human herpesvirus 3, and Epstein-Barr virus. Persistence of these viruses within the myocardium is associated with reduction of ejection fraction after 6 months. For patients with suspected inflammatory heart disease the immunohistochemical detection of inflammatory infiltrates is related to poor outcome. Many faces of inflammatory heart disease coexist where different phases of the disease progress simultaneously: phase 1 is dominated by viral infection itself, phase 2 by the onset of (probably) multiple autoimmune reactions, and phase 3 by the progression to cardiac dilatation. Further investigations with regard to the etiology of structural heart diseases should include an intensive clinical investigation of the given patient. A possible family history including a pedigree should be ascertained and with regard to a possible inflammatory or viral heart disease, endomyocardial biopsies should be investigated by polymerase chain reaction and immunohistochemistry.