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The aetiology of dilated cardiomyopathy is unknown by definition. Viral myocarditis is often viewed as an early stage in the progression of the disease leading to cardiomyopathy and heart failure in humans. The chronic inflammatory process is manifested histologically as a sparse, diffuse lymphocytic infiltration of the myocardium, classified as borderline or ongoing myocarditis according to the Dallas classification. Because of limitations of light microscopy, chronic myocarditis remains an enigmatic condition to diagnose and to treat. In contrast to routine histological staining procedures, immunohistochemical methods enable better identification and quantification of infiltrating cells and also provide further evidence that the activated immunological process within the myocardium is ongoing. In 176 patients with clinically suspected dilated cardiomyopathy, borderline myocarditis was diagnosed in only 14 cases (8%) histologically. However, using immunohistological analysis of endomyocardial biopsies, pathologically increased Ivmphocytic infiltration was revealed in 67 biopsy specimens (38%), and activated lymphocytes or activated macrophages in all analysed inflamed cardiac tissues. All positive biopsies showed an activated vascular endothelium, demonstrated by the enhanced expression of different adhesion molecules. Various cytokines were locally released from activated inflammatory cells. This may cause a cytokine-rich micro-environment which could be responsible for the enhanced expression of adhesion molecules and thereby contribute to the inflammatory traffic of immune cells into inflamed myocardial areas. These observations underline the hypothesis that the immune process is still active in a group of patients with clinically suspected dilated cardiomyopathy, causing progression of the disease [ABSTRACT FROM PUBLISHER]

Dilated cardiomyopathy (DCM) continues to be an aetiologically unknown heart muscle disease. Recent clinical and experimental data have suggested a temporal relationship with viral myocarditis. The clinical diagnosis of a chronic myocarditis is unspecific. The evaluation of endomyocardial biopsies by light microscopy and their histological classification according to the Dallas criteria is limited by the difficulty in differentiating and quantifying infiltrating lymphocytes from non-inflammatory interstitial cells. Using immunohistological methods that allow better identification and quantification of infiltrating lymphocytes and which provide further evidence for an activated immunological process within the myocardium, myocarditis was diagnosed on endomyocardial biopsy in 48 of 130 patients (37%). According to both haemodynamic and immunohistological findings, 31 of these patients were allocated for immunosuppressive treatment. After a 6 month treatment period with 6-methylprednisolone, 23 patients reported an improvement according to the NY HA classification. Lymphocytic infiltrations were abolished by corticoid treatment in 24 patients. Left ventricular systolic function was improved in 20 patients (64%) as indicated by an increased ejection fraction and stroke volume with a concomitant decrease of left ventricular end diastolic pressure. Our study suggests that immunosuppressive treatment in a subgroup of patients with dilated cardiomyopathy who have a continuing active immunohistologically proven inflammatory process results in a clinical, haemodynamic and immunohistological improvement in 60-70% of patients. [ABSTRACT FROM PUBLISHER]

We recently described autoantibodies to the ADP/ATP carrier of the inner mitochondrial membrane as an organ specific autoantigen found in high frequencies in sera of patients with myocarditis and dilated cardiomyopathy. These antibodies not only showed an intracellular binding at the mitochondrial membrane, but also crossreact with antigenic determinants at the cardiac myocyte plasma membrane. They therefore may account, at least in part, for the so-called sarcolemmal-bound IgG of heart-reactive autoantibodies found to be associated with these diseases. Heart muscle diseases are associated with electrocardiographic abnormalities such as complex ventricular arrhythmias and disturbed ventricular function. Our data indicate that abnormalities in current spread and impaired heart contractility might also be caused by an antibody mediated disturbance of calcium channel gating leading to prolongation of the action potential and potentiation of tension. The enhanced calcium permeability of the cell may moreover cause calcium overload and cell death. The calcium channel complex plays a central role in cardiac contractility. Disturbing calcium channel gating by antibodies might therefore contribute to the pathogenesis of these diseases. [ABSTRACT FROM PUBLISHER]

Antibodies against the ADP/ATP translocator located in the inner mitochondrial membrane cross-react with two proteins of the plasma membrane of cardiac myocytes. Antibody binding to the cell surface can be demonstrated by immunofluorescence methods and by radio binding tests. The specificity of the antigen-antibody reaction with the cell surface protein is shown by inhibition assays using the purified ADP/ATP translocator for neutralization of the antibodies. The antibodies bind to two proteins on the cell surface of cardiac myocytes, having molecular weights of 47000 and 29000 Daltons, respectively. These binding sites might serve as receptors for ‘receptor-mediated endocytosis’ by which antibodies might penetrate the cardiac myocyte cell membrane. [ABSTRACT FROM PUBLISHER]

Antibodies to the ADP/ATP carrier, a protein of the inner mitochondrial membrane, cross-react with the cell surface of cardiac myocytes. The binding of these antibodies is time and concentration dependent and causes a time and concentration dependent decrease in cell viability. The specificity of this immunoreaction of IgGs is shown by neutralization of the antibodies with isolated ADP/ATP carrier. [ABSTRACT FROM PUBLISHER]

Aims: An anti-angiogenic cleaved prolactin fragment is considered causal for peripartum cardiomyopathy (PPCM). Experimental and first clinical observations suggested beneficial effects of the prolactin release inhibitor bromocriptine in PPCM., Methods and Results: In this multicentre trial, 63 PPCM patients with left ventricular ejection fraction (LVEF) ≤35% were randomly assigned to short-term (1W: bromocriptine, 2.5 mg, 7 days) or long-term bromocriptine treatment (8W: 5 mg for 2 weeks followed by 2.5 mg for 6 weeks) in addition to standard heart failure therapy. Primary end point was LVEF change (delta) from baseline to 6 months assessed by magnetic resonance imaging. Bromocriptine was well tolerated. Left ventricular ejection fraction increased from 28 ± 10% to 49 ± 12% with a delta-LVEF of + 21 ± 11% in the 1W-group, and from 27 ± 10% to 51 ± 10% with a delta-LVEF of + 24 ± 11% in the 8W-group (delta-LVEF: P = 0.381). Full-recovery (LVEF ≥ 50%) was present in 52% of the 1W- and in 68% of the 8W-group with no differences in secondary end points between both groups (hospitalizations for heart failure: 1W: 9.7% vs. 8W: 6.5%, P = 0.651). The risk within the 8W-group to fail full-recovery after 6 months tended to be lower. No patient in the study needed heart transplantation, LV assist device or died., Conclusion: Bromocriptine treatment was associated with high rate of full LV-recovery and low morbidity and mortality in PPCM patients compared with other PPCM cohorts not treated with bromocriptine. No significant differences were observed between 1W and 8W treatment suggesting that 1-week addition of bromocriptine to standard heart failure treatment is already beneficial with a trend for better full-recovery in the 8W group., Clinical Trial Registration: ClinicalTrials.gov, study number: NCT00998556., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

Aims: Dilated cardiomyopathy (DCM) is one of the leading causes for cardiac transplantations and accounts for up to one-third of all heart failure cases. Since extrinsic and monogenic causes explain only a fraction of all cases, common genetic variants are suspected to contribute to the pathogenesis of DCM, its age of onset, and clinical progression. By a large-scale case-control genome-wide association study we aimed here to identify novel genetic risk loci for DCM., Methods and Results: Applying a three-staged study design, we analysed more than 4100 DCM cases and 7600 controls. We identified and successfully replicated multiple single nucleotide polymorphism on chromosome 6p21. In the combined analysis, the most significant association signal was obtained for rs9262636 (P = 4.90 × 10(-9)) located in HCG22, which could again be replicated in an independent cohort. Taking advantage of expression quantitative trait loci (eQTL) as molecular phenotypes, we identified rs9262636 as an eQTL for several closely located genes encoding class I and class II major histocompatibility complex heavy chain receptors., Conclusion: The present study reveals a novel genetic susceptibility locus that clearly underlines the role of genetically driven, inflammatory processes in the pathogenesis of idiopathic DCM.

Despite considerable advances in our understanding of myocarditis pathogenesis, the clinical management of myocarditis has changed relatively little in the last few years. This review aims to help bridge the widening gap between recent mechanistic insights, which are largely derived from animal models, and their potential impact on disease burden. We illustrate the pathogenetic mechanisms that are prime targets for novel therapeutic interventions. Pathway and pathogen-specific molecular diagnostic tests have expanded the role for endomyocardial biopsy. State of the art cardiac magnetic resonance imaging can now provide non-invasive tissue characterization and localize inflammatory infiltrates but imaging techniques are misleading if infectious agents are involved. We emphasize the gaps in our current clinical knowledge, particularly with respect to aetiology-based therapy, and suggest opportunities for high impact, translational investigations.

In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies. In clinical medicine, similar principles are used to standardise the nomenclature of disease. For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases). In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme. The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.

Experimental and clinical data suggest a relationship between myocarditis and dilated cardiomyopathy. One postulated mechanism is a viral infection triggering a host response with autoimmune features directed against the heart, resulting in an initial myocarditis which is followed by dilated cardiomyopathy. Until now, the importance of myocarditis as an aetiological factor in the pathogenesis of isiopathic cardiomyopathy has been unknown. This investigation was undertaken to determine immunohistologically the frequency of lymphocytic infiltrations in endomyocardial biopsies of patients with clinically suspected dilated cardiomyopathy. T-lymphocytic subsets and other immunological features were also analysed to explore possible relationships between immunohistologically documented myocarditis and dilated cardiomyopathy.

To elucidate the incidence and clinical significance of ventricular late potentials (LP) and reduced heart rate variability (HRV) in primary and secondary heart muscle disease, 157 patients with dilated cardiomyopathy (DCM, n = 19), chronic myocarditis (MC, n = 50), hypertrophic cardiomyopathy (HCM, n = 27) and systemic hypertension (HT, n = 61) were studied. LP measured by the signal averaging technique were found in 24% of the total study group--47% of the patients with DCM, 28% with MC, 29% with HCM and 10% with HT. Complex ventricular arrhythmias were detected during Holter monitoring in 56% of patients with DCM, in 41% with MC, in 21% with HT and in 16% with HCM. An electrophysiological study was performed in a total of 75 patients. Non-sustained or sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) were inducible during programmed ventricular stimulation in 32% of patients with MC, in 30% with HT, in 20% with DCM and in 17% with HCM. The total duration of the signal-averaged, filtered QRS complex was the only independent predictive factor for severe arrhythmic events and sudden cardiac death. HRV measured in 39 patients were most reduced in patients with DCM (RR interval standard deviation (HRV-SD) 39 +/- 23 ms), followed by 44 +/- 16 ms in patients with HCM, 45 +/- 28 ms in patients with HCM and 67 +/- 51 ms in patients with HT. A significant reduction in the HRV-SD below 30 ms was recorded in 24% of patients measured.(ABSTRACT TRUNCATED AT 250 WORDS)