Inflammatory Dilated Cardiomyopathy (DCMI)

Cardiomyopathies are heart muscle diseases, which have been defined by their central hemodynamics and macropathology and divided in five major forms: dilated (DCM), hypertrophic (HCM), restrictive (RCM), right ventricular (RVCM), and nonclassifiable cardiomyopathies (NCCM). Furthermore, the most recent WHO/WHF definition also comprises, among the specific cardiomyopathies, inflammatory cardiomyopathy as a distinct entity, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy has been defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm(2)), the term viral cardiomyopathy or viral persistence in DCM should be applied according to the WHF Task Force recommendations.Within the German heart failure net it is the authors' working hypothesis, that DCM shares genetic risk factors with other diseases of presumed autoimmune etiology and, therefore, the same multiple genes in combination with environmental factors lead to numerous different autoimmune diseases including DCM. Therefore, the authors' primary goal is to acquire epidemiologic data of patients with DCM regarding an infectious and inflammatory etiology of the disease. Circumstantial evidence points to a major role of viral myocarditis in the etiology of DCM. The common presence of viral genetic material in the myocardium of patients with DCM provides the most compelling evidence, but proof of causality is still lacking. In addition, autoimmune reactions have been described in many studies, indicating them as an important etiologic factor. Nevertheless, data on the proportion of patients, in whom both mechanisms play a role are still missing.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 has been described in about 20-30% of cases, with the presence of autoantibodies and abnormal cytokine profiles in first-degree relatives with asymptomatic left ventricular enlargement. This suggests the involvement of a disrupted humoral and cellular immunity early in the development of the disease. A similar pattern of humoral and cellular immune dysregulation has been described in other autoimmune diseases. There is considerable evidence that genetic factors play an important role in the pathogenesis of DCM, either as contributors to the susceptibility to environmental factors or as determinants of functional and structural changes that characterize the phenotypic expression of the disease.Yet, it is not known whether the susceptibility to immunologically mediated myocardial damage reflects the presence of genetic risk factors shared by other autoimmune diseases. Preliminary investigations suggest, that this is the case, because the frequency of autoimmune disorders other than DCM was higher in first-degree relatives of the subjects with DCM including juvenile diabetes, rheumatoid arthritis, thyroiditis, psoriasis, and asthma.The nature of the genetic risk is undetermined and probably involves genes in the major histocompatibility (MHC) locus as well as other susceptibility loci. Therefore, the authors started their investigation with the search for MHC class 2 DQ polymorphisms in the peripheral blood of patients with DCM in parallel to the search for new interesting susceptibility loci by the use of the microarray analysis regarding genes responsible for inflammatory and autoimmune diseases. By this approach a new insight in the familial clustering of other autoimmune diseases in patients with DCM and in genetic predisposition can be expected.     

Inflammation in Dilated Cardiomyopathy

Inflammation is an important component in the pathogenesis of many common cardiovascular diseases. In most cases, the role of inflammation is a natural response to injury, and an important mechanism for healing and tissue repair. However, the inflammatory response can be either inadequate or overwhelming, leading to direct injury or severe host disease. Accumulating data has revealed an important inflammatory component in the pathogenesis of dilated cardiomyopathy (DCM), and there is growing evidence, that myocarditis and DCM are closely related. Many faces of DCM coexist, while 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 without an infectious agent and cardiac inflammation. Separation between the phases is not always distinct, they may overlap one another and phase 1 and 2 may recur after progression of DCM. Appropriate treatment during phase 1 includes eradication of virus and amelioration of injury caused by the virus. During phase 2, which is characterized by autoimmune processes, immunosuppression is the most appropriate therapy and warrants sophisticated diagnostic strategies including molecular biological and immunohistochemical techniques. Phase 3, DCM, although a result of viral and autoimmune injury, may then progress independently. The more attention given to serologic, molecular and immunologic factors to characterize and diagnose DCM lead to several changes in the terminology. The term cardiomyopathy is no longer reserved for the idiopathic forms but can be used interchangeably with the term heart muscle diseases including specific, secondary forms. Right ventricular cardiomyopathy (RVCM), valvular, hypertensive, ischemic, and inflammatory cardiomyopathy have been introduced. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and is then termed inflammatory viral cardiomyopathy. Because of the overlap of pathophysiological stages in DCM, design of the appropriate therapy is important. It requires the immunohistochemical and molecular biological investigation of endomyocardial biopsies in parallel. In the modern molecular era the infective agent-immune system-host interaction has to be clarified leading to a better knowledge of the etiology of DCM. This may change the management of the disease in the future. One of the hopes is to discern the underlying dominant mechanism in a given patient to make a decision for the most promising therapy.     

Dilated Cardiomyopathies as a Cause of Congestive Heart Failure

Definition and Classification: Cardiomyopathies are disorders affecting the heart muscle that frequently result in congestive heart failure. Five major forms are recognized: dilated, hypertrophic, restrictive, right ventricular, and nonclassifiable cardiomyopathies with distinct hemodynamic properties. Furthermore, the new WHO/WHF definition also comprises inflammatory cardiomyopathy, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm²), the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied. Diagnosis and Treatment: In recent years, there have been breakthroughs in understanding the molecular and genetic mechanisms involved in this group of conditions, enabling improvement of diagnostic strategies and introduction of new therapies. Ongoing evaluation of antiviral, immunoglobulin, and immunosuppressive therapies including the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID), removal of antibodies by immunoadsorption, anticytokine and gene therapy, as well as the mechanical support devices may provide new treatment options. Definition und Klassifikation: Die gegenwärtig akzeptierte klinisch-pathophysiologische Einteilung der Kardiomyopathien als Herzmuskelerkrankungen (WHO/ISFC Task Force), die mit einer kardialen Funktionsstörung einhergehen unterscheidet Kardiomyopathien nach ihrem klinischem Phänotyp, d. h. nach ihrer Hämodynamik und ihrer makroskopischen Anatomie in folgende Formen: dilatative, hypertrophische, restriktive, arrhythmogene rechtsventrikuläre und nicht klassifizierbare Kardiomyopathien. Diese Übersicht befasst sich mit der häufigsten Form der Kardiomyopathien, der dilatativen (früher kongestiven) Form (DCM). Hierunter fallen u. a. familiäre, genetisch determinierte und sporadische Kardiomyopathien unterschiedlicher Ätiologie. Bemerkenswert ist, dass selbst bei familiären Formen der klinische Phänotyp außerordentlich variabel sein kann (Heterogenitätsprinzip). Diagnostik: Ein besonderer Schwerpunkt der Übersicht liegt in der ätiopathogenetisch häufigen und deshalb klinisch und differentialdiagnostisch bedeutenden Ursache: der Entzündung bei Myokarditis bzw. bei der inflammatorischen Kardiomyopathie. Hier gehören die Quantifizierung des Infiltrats und der Nachweis des Erregers in der Endomyokardbiopsie mittels Polymerasekettenreaktion oder In-situ-Hybridisierung zum erforderlichen Standard. Nur so lässt sich die hämodynamische Klassifikation der DCM durch eine ätiopathogenetische Einteilung ergänzen bzw. ersetzen, damit die idiopathischen Kardiomyopathien von den ätiopathogenetischen bekannten "sekundären Formen" differenziert werden können. Hämodynamisch handelt es sich bei der DCM um einen überwiegend systolischen Pumpfehler. Die DCM ist charakterisiert durch eine Vergrößerung des linken und/oder rechten Ventrikels und eine Reduktion der Ejektionsfraktion. Eine begleitende Störung der Relaxation (Lusitropie) kann hinzutreten. Therapie: Die Therapieprinzipien der Herzinsuffizienz gelten auch für die DCM. Sie stellen auch die Basistherapie der spezifischen, ätiologisch bekannten Kardiomyopathien dar. Da bei der idiopathischen DCM die auslösenden Faktoren nicht bekannt sind, stehen nur symptomatische Maßnahmen (4 Ds) zur Verfügung. Das Prinzip der körperlichen Schonung gilt unverändert für entzündliche Kardiomyopathien. Bei den nicht entzündlichen Formen erscheint eine dosierte Bewegungstherapie die Lebensqualität zu verbessern, ohne die Prognose zu belasten. Die klassischen 4 Ds der Therapie umfassen :diätetische Maßnahmen mit Kochsalz- und Flüssigkeitsrestriktion, Alkoholkarenz, Nikotinverzicht; Gabe von Diuretika, Vasodilatatoren (z.B. ACE-Hemmer und/oder AT1-Rezeptor-Antagonisten) und Digitalistherapie, insbesondere bei tachykardem Vorhofflimmern, sowie die Betablockertherapie (langsam und mit niedrigen Dosen einschleichen und vorsichtig steigern). Kleinere Studien belegen positive Effekte durch eine chirurgische Verkleinerung des linken Ventrikels (umstritten: Batista-Operation, Ventrikelreduktionsplastiken). In Erprobung sind die biventrikuläre Stimulation (Ventrikelresynchronisation) bei Linksschenkelblock zur Optimierung des Kontraktionsablaufs oder die allgemeine oder spezifische Immunadsorption zur Elimination möglicherweise kardiodepressiver Antikörper u.a. gegen den #-Rezeptor. Als Ultima Ratio bei konservativ nicht mehr behandelbarer Kardiomyopathie ist an eine Herztransplantation zu denken.     

Myocardial Remodeling in Viral Heart Disease: Possible Interactions Between Inflammatory Mediators and MMP-TIMP System

Matrix metalloproteinases (MMP), a family of proteases, are involved in the degradation of extracellular matrix proteins and hence in the determination of interstitial architecture. In the heart, MMPs have been found to play a significant role in the development of myocardial remodeling and congestive heart failure. Tissue inhibitors of matrix metalloproteinases (TIMPs) represent a family of proteins which are known to regulate the expression and activity of MMPs. TIMPs are endogenous physiological inhibitors of MMPs and their concomitant downregulation in heart failure suggests the existence of a critical balance between MMPs and TIMPs in the normal maintenance of myocardial interstitial homeostasis. In addition, cytokines regulate expression of both MMPs and TIMPs besides eliciting a direct effect on myocardial cell function. Therefore, myocardial inflammation may also contribute to the development of cardiac remodeling along with other stimuli like mechanical stress and humoral factors. Viral myocarditis, a predisposing factor for dilated cardiomyopathy, is a condition in which extent of intramyocardial inflammation is thought to determine the progression of disease. Inflammatory events in the heart following viral infection are speculated to be responsible for the transition of myocarditis to dilated cardiomyopathy. In viral myocarditis and other inflammatory heart diseases, the inflammatory cells and their battery of cytokines may also alter the myocardial MMP-TIMP system and eventually lead to dilation of the heart and ventricular dysfunction. The objective of this review is to present an overall picture of the inflammatory phase in viral myocarditis and discuss the possible interactions between inflammation and myocardial MMP profiles which may lead to the evolution of dilated cardiomyopathy.     

Targeting Matrix Metalloproteinase Activity and Expression for the Treatment of Viral Myocarditis

Infectious agents including viruses can infect the heart muscle, resulting in the development of heart inflammation called myocarditis. Chronic myocarditis can lead to dilated cardiomyopathy (DCM). DCM develops from the extensive extracellular matrix (ECM) remodeling caused by myocarditis and may result in heart failure. Epidemiological data for viral myocarditis has long suggested a worse pathology in males, with more recent data demonstrating sex-dependent pathogenesis in DCM as well. Matrix metalloproteinases (MMPs), long known modulators of the extracellular matrix, have important roles in mediating heart inflammation and remodeling during disease and in convalescence. This ability of MMPs to control both the inflammatory response and ECM remodeling during myocarditis makes them potential drug targets. In this review, we analyze the role of MMPs in mediating myocarditis/DCM disease progression, their sex-dependent expression, and their potential as drug targets during viral myocarditis and DCM.     

Myocarditis: the immunologist's view on pathogenesis and treatment

Viral myocarditis is a frequent and often unrecognised cause of post-inflammatory cardiomyopathy. The role of viral persistence and heart-specific autoimmunity in the development of myocarditis and heart failure is still controversial. This review updates the current view on the immunological mechanisms of disease development and addresses the current and future role of immunomodulation and immunosuppression as treatment options for defined subgroups of patients with myocarditis or dilated cardiomyopathy.     

The European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID) First Epidemiological Results

By including immunohistochemical parameters the WHF Task Force for the Definition of Acute and Chronic Myocarditis expanded the light microscopical Dallas criteria of myocarditis. The rapid development of new molecular biological techniques such as polymerase chain reaction (PCR) and in-situ hybridization has improved our understanding of the underlying etiological and pathophysiological mechanisms in inflammatory heart disease. Treatment of dilated cardiomyopathy with inflammation is still controversial, however. The American Myocarditis Treatment Trial could not demonstrate a significant difference in the improvement of ejection fraction between patients with active myocarditis in the cyclosporine/prednisolone treated group when compared to placebo. In the European Study of Epidemiology and Treatment of Inflammatory Heart Disease (ESETCID) patients with acute or chronic myocarditis are treated specifically according to the etiology of the disease. Patients are screened not only for infiltrating cells, but also for the presence of persisting viral genome (enterovirus, cytomegalovirus and adenovirus). By investigating endomyocardial biopsies of 3,055 patients ongoing inflammatory processes in the heart could be found in 17.2%. Only 182 showed a reduced ejection fraction below 45% fulfilling the entrance criteria for the ESETCID trial. These data imply that in symptomatic patients inflammatory heart muscle disease has to be considered regardless of left ventricular function and that endomyocardial biopsy can be an important tool for diagnosis. Virus could be detected in 11.8% (enterovirus 2.2%, cytomegalovirus 5.4%, adenovirus 4.2%). These first epidemiological results of this prospective randomized study demonstrate that viral persistence may contribute to the pathogenesis of inflammatory heart muscle disease, and that in chronic myocarditis viral persistence occurs in a smaller percentage of patients compared to previously published studies which were performed on highly selected patients.     

From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future

A progression from viral myocarditis to dilated cardiomyopathy has long been hypothesized, but the actual extent of this progression has been uncertain. However, a causal link between viral myocarditis and dilated cardiomyopathy has become more evident than before with the tremendous developments in the molecular analyses of autopsy and endomyocardial biopsy specimens, new techniques of viral gene amplification, and modern immunology. The persistence of viral RNA in the myocardium beyond 90 days after inoculation, confirmed by the method of polymerase chain reaction, has given us new insights into the pathogenesis of dilated cardiomyopathy. Moreover, new knowledge of T-cell-mediated immune responses in murine viral myocarditis has contributed a great deal to the understanding of the mechanisms of ongoing disease processes. Apoptotic cell death may provide the third concept to explain the pathogenesis of dilated cardiomyopathy, in addition to persistent viral RNA in the heart tissue and an immune system-mediated mechanism. Beneficial effects of alpha1-adrenergic blocking agents, carteolol, verapamil, and ACE inhibitors have been shown clinically and experimentally in the treatment of viral myocarditis and dilated cardiomyopathy. Antiviral agents should be more extensively investigated for clinical use. The rather discouraging results obtained to date with immunosuppressive agents in the treatment of viral myocarditis indicated the importance of sparing neutralizing antibody production, which may be controlled by B cells, and raised the possibility of promising developments in immunomodulating therapy.     

Persistence of viral genome into late stages of murine myocarditis detected by polymerase chain reaction.

BACKGROUND. Enteroviruses have been considered as the most common etiologic agents in clinical myocarditis and dilated cardiomyopathy; however, their pathogenetic role remains unknown. Hence, the relation of viral replication and development of cardiomyopathy has been determined in a murine model of myocarditis by evaluating the persistence of viral genome during acute and chronic stages of myocarditis by means of Northern blot hybridization and polymerase chain reaction (PCR). METHODS AND RESULTS. DBA/2 mice (n = 146) were injected peritoneally with 10 plaque-forming units of encephalomyocarditis (EMC) virus, and the control mice (n = 33) were injected with normal saline. Animals were randomly killed at 4, 7, 10, 14, 21, 28, 35, and 42 days after infection. Histology revealed acute myocardial necrosis with massive inflammatory cell infiltrate peaking on day 14 followed by increasing fibrosis and declining chronic inflammation features compatible with dilated cardiomyopathy between days 21 and 42. Northern blot analysis of control and infected hearts showed detectable viral RNA in the infected hearts initially at day 4, peaking by day 7, diminishing between day 7 and day 14, and absent at day 21 and day 28. However, potential viral remnants present in low quantities and undetectable by Northern blot were further detected by PCR followed by confirmation with an internal oligonucleotide probe after day 14 up to day 42. CONCLUSIONS. Viral RNA signals on Northern blot showed a strong correlation with massive myocyte necrosis on day 14, but the viral RNA fragment was consistently detectable into late stages of cardiomyopathy on days 21, 28, 35, and 42 by PCR. This indicated that the mature virions are fully developed early in infection and are capable of persisting in the myocardium after virus-mediated myocytolysis stage. Therefore, PCR is an extremely sensitive method for detecting residual viral genome and viral persistence in the myocardium and may offer insights into the pathogenesis of chronic myocarditis leading to dilated cardiomyopathy.     

Current treatment options in (peri)myocarditis and inflammatory cardiomyopathy

In inflammatory dilated cardiomyopathy and myocarditis there is—apart from heart failure and antiarrhythmic therapies—no alternative to an aetiologically driven specific treatment. Prerequisite are noninvasive and invasive biomarkers including endomyocardial biopsy and PCR on cardiotropic agents. This review deals with the different etiologies of myocarditis and inflammatory cardiomyopathy including the genetic background, the predisposition for heart failure and inflammation. It analyses the epidemiologic shift in pathogenetic agents in the last 20?years, the role of innate and aquired immunity including the T- and B-cell driven immune responses. The phases and clinical faces of myocarditis are summarized. Up-to-date information on current treatment options starting with heart failure and antiarrhythmic therapy are provided. Although inflammation can resolve spontaneously, specific treatment directed to the causative aetiology is often required. For fulminant, acute and chronic autoreactive myocarditis immunosuppressive treatment is beneficial, while for viral cardiomyopathy and myocarditis ivIg can resolve inflammation and is as successful as interferon therapy in enteroviral and adenoviral myocarditis. For Parvo B19 and HHV6 myocarditis eradication of the virus is still a problem by any of these treatment options. Finally, the potential of stem cell therapy has to be tested in future trials. In virus-negative, autoreactive perimyocardial disease a locoregional approach with intrapericardial instillation of high local doses of triamcinolone acetate has been shown to be highly efficient and with few systemic side-effects.     

Standard and etiology-directed evidence-based therapies in myocarditis: state of the art and future perspectives

In inflammatory dilated cardiomyopathy and myocarditis, there is apart from heart failure and antiarrhythmic therapies no alternative to an etiologically driven specific treatment. Their prerequisites are noninvasive and invasive biomarkers including endomyocardial biopsy and PCR on cardiotropic agents. This review deals with the different etiologies of myocarditis and inflammatory cardiomyopathy including the genetic background, the predisposition for heart failure and inflammation. It analyses the epidemiologic shift in pathogenetic agents in the last 20 years, the role of innate and acquired immunity including the T cell and B cell driven immune responses. On this basis, it summarizes phases and clinical faces of myocarditis. It gives an up-to-date information on current treatment options starting with heart failure and antiarrhythmic therapy. Although inflammation can resolve spontaneously, often specific treatment directed to the causative etiology is required. For fulminant, acute and chronic autoreactive myocarditis immunosuppressive treatment is beneficial; for viral cardiomyopathy and myocarditis, IVIG can resolve inflammation and is as successful as interferon therapy in enteroviral and adenoviral myocarditis. Eradication of parvovirus B19 and HHV6 myocarditis is still a problem by anyone of these treatment options. The potential of stem cell therapy has to be tested in future trials. In perimyocardial disease, a locoregional approach with high local doses and low systemic side effects have been shown highly efficient by intrapericardial treatment of triamcinolonacetate facilitated by pericardioscopy for adequate etiopathogenetic diagnosis.     

Viral myocarditis--new advances

The role of viruses in cardiovascular disease has been increasingly recognized in recent years. They are now thought to be the main agent in acute myocarditis and inflammatory cardiomyopathy in the western world. We describe new perspectives on the part viral agents play in heart disease, from molecular mechanisms to recently available diagnostic and therapeutic options. We present a case of post-viral dilated cardiomyopathy in a 29-year-old woman in order to illustrate the severe damage that a viral infection can cause and the different therapeutic options that may be available in the near future.     

Myocarditis

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.     

Viral myocarditis: from experimental models to molecular diagnosis in patients

Cardiotropic viruses have been implicated as major pathogenetic agents in acute and chronic forms of myocarditis. By the introduction of molecular tools, such as (RT-) polymerase chain reaction ((RT-) PCR) and in situ hybridization in the diagnosis of inflammatory heart disease, genomes of various RNA and DNA viruses comprising enteroviruses, adenoviruses, parvovirus B19 (B19V) and herpesviruses (EBV, HHV6, HCMV) were detected in endomyocardial biopsies of patients with myocarditis and dilated cardiomyopathy. Meanwhile, it is known that the outcome of a virus infection in the heart resulting in myocarditis is determined by genetic host factors as well as by the viral pathogenicity which considerably varies in the different virus infections. A considerable portion of our knowledge about the etiopathogenetic mechanisms in viral heart disease is derived from animal studies. Whereas the evolvement of cardiac inflammation in enterovirus infections is guided by viral cytotoxicity and virus persistence, in herpesvirus infections, the pathophysiology is rather determined by primary immune-mediated pathogenicity. By investigation of immunocompetent and gene-targeted mice, valuable new insights into host and virus factors relevant for the control of cardiac viral infection and inflammation were gained which are reviewed in this paper.     

Recurrent reversible dilated cardiomyopathy secondary to viral and streptococcal pneumonia vaccine-associated myocarditis

Myocarditis is inflammation of cardiac muscle, which may be acute, subacute, or chronic with either focal or diffuse involvement of the myocardium. This leads to a cardiomyopathy with clinical features of heart failure as well as echocardiographic evidence of global dilation of the cardiac chambers. There are numerous reports in the literature of viral myocarditis causing dilated cardiomyopathy; however, there are no reports of recurrent viral myocarditis and vaccine-associated myocarditis in a single patient with complete reversal of the cardiomyopathy and return to normal cardiac function. We present a case of recurrent myocarditis in a female patient caused by a viral upper respiratory infection and streptococcal pneumonia vaccination who presented with recurrent episodes of reversible cardiomyopathy.     

Physical Exercise in Patients with Heart Failure Due to Myocarditis and Dilated Cardiomyopathy

BACKGROUND: Sudden cardiac death of suspected healthy young athletes is a rare, but deeply moving event. Usually, the affected person has been completely free of symptoms. Commonly, unrecognized inflammatory, hypertrophic or dilated cardiomyopathies are the most frequent causes. All therapeutic principles of angiotensin-converting-enzyme (ACE) inhibition, beta-blockade, and diuretics in heart failure aim to unload the heart. During physical activity increased sympathetic tonus and loading conditions for the heart point into the opposite direction. This raises the question to what extent physical activity in patients with myocarditis, dilated cardiomyopathy or heart failure in general is tolerable. SYNOPSIS: Several experimental studies revealed disadvantages of physical exercise during acute myocarditis leading to an increase in mortality. On the other hand, several small trials in men demonstrate an improvement of physical fitness and quality of life attributed to controlled supervised exercise training in patients with heart failure without assessment of mortality. Dilated cardiomyopathy was diagnosed in one third of these patients. There was no biopsy confirmation of these conditions. The other two thirds of patients suffered from ischemic heart diseases. CONCLUSION: Since the borderline between inflammatory heart disease and noninflammatory or postinflammatory dilated cardiomyopathy is difficult to determine, abstention from physical training during and shortly after inflammatory heart disease is recommended, because it is known that viral persistence or autoimmune processes could last for several months.     

Definition of Inflammatory Cardiomyopathy (Myocarditis): On the Way to Consensus A Status Report

This article reviews the current state of consensus reached for the diagnosis of myocarditis and dilated cardiomyopathy on the basis of conventional histopathological and immunohistochemical methods for inflammatory infiltrates in addition to molecular biological methods for persistence of viral genome in endomyocardial biopsies. Additionally, a brief overview is presented stating the current knowledge on effector mechanisms of the immune system in myocarditis and dilated cardiomyopathy.     

Dilated cardiomyopathy update: infectious-immune theory revisited

Dilated cardiomyopathy is characterized by dilatation of the left or right ventricle, or both ventricles. The degree of myocardial dysfunction is not attributable to abnormal loading conditions. The infectious-immune theory has long been hypothesized to explain the pathogenesis of many etiologically unrecognized dilated cardiomyopathies. Inflammations followed by immune reactions, which may be excessive, in the myocardium, evoked by external triggers such as viral infections and/or autoimmune antibodies, continue insidiously, and lead to the process of cardiac remodeling with ventricular dilatation and systolic dysfunction. This ultimately results in dilated cardiomyopathy. Hepatitis C virus-associated heart diseases are good examples of cardiac lesions definitely induced by viral infections in humans that progress to a chronic stage through complicated immune mechanisms. Therapeutic strategies for myocarditis and dilated cardiomyopathy have been obtained through analyses of the acute, subacute, and chronic phases of experimental viral myocarditis in mice. The appropriate modulation of excessive immune reactions during myocarditis, rather than their complete elimination, appears to be a key option in the prevention and treatment of dilated cardiomyopathy. The clinical application of an NF-κB decoy and immune adsorption of IgG3 cardiac autoantibodies have been used as immunomodulating therapies and may provide novel approaches for the treatment of refractory patients with dilated cardiomyopathy. Conventional therapeutic agents for chronic heart failure such as β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in particular should be re-evaluated on the basis of their anti-inflammatory properties in the treatment of dilated cardiomyopathy.     

Das Herz bei viralen Infektionen

Between 10 and 20% of patients with histologically proven inflammatory disease of the heart muscle develop a chronic disorder after acute myocarditis which results in dilated cardiomyopathy with increasing cardiac insufficiency. Viral infections are a frequent cause of inflammatory heart muscle diseases and thus also responsible for myocardial damage in the initial phase. In the past, evidence for enterovirus, adenovirus, and cytomegalovirus was in the focus of attention. In the meantime, “new” cardiotropic pathogens such as parvovirus B19, Epstein-Barr virus, and human herpesvirus 6 have been detected in patients with dilated cardiomyopathy with and without inflammation. Their persistence in the myocardium correlates with a decline in pumping capability within 6 months. While the virus is still being eliminated, the second phase of the disease begins, which is characterized by autoimmune phenomena and often a cardiac inflammatory response which likewise correlates with a worsening prognosis. The transition to the third and final phase with development of dilated cardiomyopathy occurs gradually and can take years. The goal of every diagnostic and therapeutic intervention must be to eradicate the virus and eliminate the inflammatory response to prevent the disease from progressing to terminal cardiac insufficiency.