Acute and Fulminant Myocarditis: a Pragmatic Clinical Approach to Diagnosis and Treatment.

PURPOSE OF REVIEW: To review the clinical features of acute myocarditis, including its fulminant presentation, and present a pragmatic approach to the diagnosis and treatment, considering indications of American and European Scientific Statements and recent data derived by large contemporary registries. RECENT FINDINGS: Patients presenting with acute uncomplicated myocarditis (i.e., without left ventricular dysfunction, heart failure, or ventricular arrhythmias) have a favorable short- and long-term prognosis: these findings do not support the indication to endomyocardial biopsy in this clinical scenario. Conversely, patients with complicated presentations, especially those with fulminant myocarditis, require an aggressive and comprehensive management, including endomyocardial biopsy and availability of advanced therapies for circulatory support. Although several immunomodulatory or immunosuppressive therapies have been studied and are actually prescribed in the real-world practice, their effectiveness has not been clearly demonstrated. Patients with specific histological subtypes of acute myocarditis (i.e., giant cell and eosinophilic myocarditis) or those affected by sarcoidosis or systemic autoimmune disorders seem to benefit most from immunosuppression. On the other hand, no clear evidence supports the use of immunosuppressive agents in patients with lymphocytic acute myocarditis, even though small series suggest a potential benefit. Acute myocarditis is a heterogeneous condition with distinct pathophysiological pathways. Further research is mandatory to identify factors and mechanisms that may trigger/maintain or counteract/repair the myocardial damage, in order to provide a rational for future evidence-based treatment of patients affected by this condition.

Atrial giant cell myocarditis: a distinctive clinicopathologic entity.

BACKGROUND: Giant cell myocarditis (GCM) typically causes fulminant heart failure, arrhythmias, or heart block, necessitating aggressive immunosuppression, ventricular assist device insertion, or cardiac transplantation. We describe a novel variant of GCM, primarily involving the atria, that displays distinctive clinical features and follows a more benign course than ventricular GCM. METHODS AND RESULTS: We identified 6 patients (median age 67.5 years, 4 male) with atrial GCM in our pathology consultation practices from 2010 to 2012. Clinical history, imaging, and pathology materials were reviewed. Clinically, 4 patients had atrial fibrillation, 1 had acute heart failure, and 1 had incidental disease at autopsy. Among the 5 living patients, echocardiography revealed severe atrial dilatation (5 cases), mitral/tricuspid regurgitation (5), atrial mural thrombus (3), atrial wall thickening (2), and atrial hypokinesis (2). Ventricular function was preserved in all 5. Histological review of surgically resected atria showed giant cell and lymphocytic infiltrates, lymphocytic myocarditis-like foci, cardiomyocyte necrosis, and cardiomyocyte hypertrophy in all cases. Other features included interstitial fibrosis (5), poorly-formed granulomas (4), eosinophils (4), neutrophils (1), and vasculitis (1). Treatment consisted of steroids and cyclosporine (1), pacemaker placement for sick sinus syndrome (1), and supportive care (3). All 5 living patients returned to baseline exercise tolerance after 6 to 16 weeks of follow-up. CONCLUSIONS: Atrial GCM represents a distinct clinicopathologic entity with a more favorable prognosis than classic ventricular GCM. This disorder should be included in the differential diagnosis of atrial dilatation, particularly when associated with atrial wall thickening. The utility of immunomodulatory therapy for this condition remains unknown.

Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease.

In the WHO 1996 classification of cardiomyopathies, myocarditis is defined as an "inflammatory disease of the myocardium associated with cardiac dysfunction" and is listed among "specific cardiomyopathies". Myocarditis is diagnosed on endomyocardial biopsy (EMB) by established histological, immunological, and immunohistochemical criteria, and molecular techniques are recommended to identify viral etiology. Infectious, autoimmune, and idiopathic forms of inflammatory cardiomyopathy are recognized that may lead to dilated cardiomyopathy. According to Dallas criteria, myocarditis is diagnosed in the setting of an "inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of ischemic damage associated with coronary artery disease". The majority of experts in the field agree that an actual increase in sensitivity of EMB has now been reached by using immunohistochemistry together with histology. A value of >14 leukocytes/mm(2) with the presence of T lymphocytes >7 cells/mm(2) has been considered a realistic cut off to reach a diagnosis of myocarditis. The development of molecular biological techniques, particularly amplification methods like polymerase chain reaction (PCR) or nested-PCR, allows the detection of low copy viral genomes even from an extremely small amount of tissue such as in EMB specimens. Positive PCR results obtained on EMB should always be accompanied by a parallel investigation on blood samples collected at the time of the EMB. According to the recent Association for European Cardiovascular Pathology guidelines, optimal specimen procurement and triage indicates at least three, preferably four, EMB fragments, each 1-2 mm in size, that should immediately be fixed in 10 % buffered formalin at room temperature for light microscopic examination. In expected focal myocardial lesions, additional sampling is recommended. Moreover, one or two specimens should be snap-frozen in liquid nitrogen and stored at -80 °C or alternatively stored in RNA-later for possible molecular tests or specific stains. A sample of peripheral blood (5-10 ml) in EDTA or citrate from patients with suspected myocarditis allows molecular testing for the same viral genomes sought in the myocardial tissue.

[Non-rheumatic myocarditis in practice of outpatient therapist and cardiologist].

Non-rheumatic myocarditis occurs in therapeutic and cardiological practice both at prehospital and hospital stages. Diagnosis of this myocarditis at early stages is difficult. The course and outcome of this disease and its present-day treatment are outlined to help clinical and cardiological practitioners.

[Inflammatory cardiomyopathy: state-of-the-art].

Cardiomyopathy (CMP) is a major cause of early disability and death in young cardiac patients, remaining at the same time a little studied problem. The generally accepted term "dilated cardiomyopathy" is only a portrayal of morphological signs. As of now, the foreign literature most commonly uses the term "inflammatory cardiomyopathy" to denote CMP caused by viral and/or bacterial agents. Owing to the wide use of novel laboratory and instrumental diagnostic techniques, namely: molecular genetic and immunohistochemical studies and endomyocardial biopsy, there has been a possibility to conduct a more accurate and fuller study of inflammatory CMP. Despite the fact that the problems in nosology, classification, choice of the optimal diagnostic methods and management tactics for these patients.

Myocardial dysfunction in rheumatic carditis--does it really exist?

OBJECTIVES: Acute rheumatic fever (ARF) continues to affect millions of children in developing countries. Aim of the present study was to evaluate the role of myocardial dysfunction in the genesis of heart failure in patients with rheumatic carditis. There are limited studies on this subject. METHODS AND RESULTS: In this prospective study, 108 consecutive patients of ARF were evaluated by echocardiography and assay of cardiac troponin I blood levels. The patients were divided into three groups. Group A (n = 30): patients with no evidence of carditis; Group B (n = 45): patients with first attack of carditis; and group C (n = 33): patients with recurrent attacks of carditis. Left ventricular dimensions tended to be larger in Group B and C patients. Left ventricular ejection fraction did not differ between the groups (Group A: 63 +/- 8.1%, Group B: 58 +/- 7.9%, Group C: 61.2 +/- 9%, p = ns). Heart failure was present in 37.7% patients of Group B, and in 60.6% patients of Group C (p = < 0.05). Ejection fraction was normal in majority of heart failure patients (75.7%). It was reduced in 29.4% of patients in Group B and in 20% of Group C patients with heart failure (p = ns). All patients with low ejection fraction had hemodynamically significant regurgitant valvular lesions. Mean cardiac troponin I values, an index of myocardial damage, did not differ between the three groups (Group A: 0.062 +/- 0.027 ng/ml, Group B: 0.068 +/- 0.019 ng/ml, Group C: 0.071 +/- 0.031 ng/ml, p = ns). CONCLUSION: The present study did not demonstrate any echocardiographic abnormalities or cardiac troponin I elevation suggesting significant myocardial involvement during acute rheumatic fever. This lends credence to the view that myocardial involvement does not play any significant role in the genesis of heart failure in patients with rheumatic carditis.

Clinical implications of anti-cardiac immunity in dilated cardiomyopathy.

Criteria of organ-specific autoimmunity are fulfilled in a subset of patients with myocarditis/dilated cardiomyopathy (DCM). In particular, circulating heart-reactive autoantibodies are found in such patients and symptom-free relatives. These autoantibodies are directed against multiple antigens, some of which are expressed in the heart (organ-specific), others in heart and some skeletal muscle fibres (partially heart-specific) or in heart and skeletal muscle (muscle-specific). Distinct autoantibodies have different frequency in disease and normal controls. Different techniques detect one or more antibodies, thus they cannot be used interchangeably for screening. It is unknown whether the same patients produce more antibodies or different patient groups develop autoimmunity to distinct antigens. IgG antibodies, shown to be cardiac- and disease-specific for myocarditis/DCM, can be used as autoimmune markers for relatives at risk as well as for identifying patients in whom immunosuppression may be beneficial. Some autoantibodies may also have a functional role, but further work is needed.

Myocarditis and inflammatory cardiomyopathy: histomorphological diagnosis.

Myocarditis is a non-ischemic inflammatory disease of the myocardium associated with cardiac dysfunction. It most often results from infectious agents, hypersensitivity responses, or immune-related injury. In spite of the development of various diagnostic modalities, early and definite diagnosis of myocarditis still depends on the detection of inflammatory infiltrates in endomyocardial biopsy specimens according to Dallas criteria. Routine application of immunohistochemistry (for characterization of inflammatory cell infiltration) and Polymerase Chain Reaction PCR analysis (for identification of infective agents) has become an essential part of the diagnostic armamentarium for a more precise biopsy report. A new morphological classification is advanced to overcome the limits of Dallas criteria. A semiquantitative assessment of myocyte damage/inflammation (grading) as well as of fibrosis (staging) is indicated, thus providing histopathological diagnosis useful to the clinician for more appropriate patient risk stratification and for the application of new therapies. Consequently, the final diagnosis of myocarditis should be mainly based on three features: etiology, grade, and stage of the disease.

Clinicopathologic description of myocarditis.

Histologic evidence of myocarditis was demonstrated in 35 of 348 patients submitted to endomyocardial biopsy over 5 years. Analysis of the histologic findings and clinical course of these patients resulted in a new clinicopathologic classification of myocarditis in which four distinct subgroups are identified. Patients with fulminant myocarditis become acutely ill after a distinct viral prodrome, have severe cardiovascular compromise, multiple foci of active myocarditis by histologic study and ventricular dysfunction that either resolves spontaneously or results in death. Patients with acute, chronic active and chronic persistent myocarditis have a less distinct onset of illness. Patients with acute myocarditis present with established ventricular dysfunction and may respond to immunosuppressive therapy or their condition may progress to dilated cardiomyopathy. Those with chronic active myocarditis initially respond to immunosuppressive therapy, but they have clinical and histologic relapses and develop ventricular dysfunction associated with chronic inflammatory changes including giant cells on histologic study. Chronic persistent myocarditis is characterized by a persistent histologic infiltrate, often with foci of myocyte necrosis but without ventricular dysfunction despite other cardiovascular symptoms such as chest pain or palpitation.

Twenty years of progress and beckoning frontiers in cardiovascular pathology: cardiomyopathies.

In the last 20 years, with the advent of cardiac transplantation and the availability of molecular biology techniques, major advancements were achieved in the understanding of cardiomyopathies. Novel cardiomyopathies have been discovered (arrhythmogenic right ventricular, primary restrictive, and noncompacted myocardium) and added in the update of WHO classification. Myocarditis was also included with the name "inflammatory cardiomyopathy." Adenoviruses and parvoviruses were found to be frequent cardiotropic viruses in addition to enteroviruses. The extraordinary progress accomplished in molecular genetics of inherited cardiomyopathies allowed to establish hypertrophic and restrictive cardiomyopathies as sarcomeric ("force generation") diseases, dilated cardiomyopathies as cytoskeleton ("force transmission") disease, and arrhythmogenic right ventricular cardiomyopathy (ARVC) as cell junction disease. If we consider also cardiomyopathy as ion channel disease (long and short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), because they are diseases of the myocardium associated with electrical dysfunction, then a genomic/postgenomic classification of inherited cardiomyopathies may be put forward: cytoskeletal cardiomyopathy, sarcomeric cardiomyopathy, cell junction cardiomyopathy and ion channel cardiomyopathy.

[Acute myocarditis: from chest pain to cardiogenic shock]. / Les myocardites aiguës: de la douleur thoracique au choc cardiogénique--a propos de trois cas.

We report the observations of three patients with myocarditis. The first one with chest pain, the second one with a pseudo-infarct presentation and the third one with a cardiogenic shock. We discuss the different anatomo-clinical presentations of myocarditis, the diagnosis, the indications of endomyocardial biopsies and the prognosis of this pathology.

Diagnosis of myocarditis by endomyocardial biopsy.

Endomyocardial biopsy is most frequently used to establish a definitive diagnosis of myocarditis, especially since this disorder has been treated with immunosuppressive therapy. Recent diagnostic criteria (the "Dallas Classification") are reviewed, and pitfalls and limitations are discussed.

Prolonged QT interval and sudden infant death--report of two cases.

In the two cases where infants died suddenly and unexpectedly the electrocardiogram (ECG) of a younger sibling (case 1) and of a living twin (case 2) led to the suspicion that the two infants could have died from long QT syndrome (LQTS). In case 1, a His bundle (HB) dispersion and a pronounced hypoplasia of the right external nucleus arcuatus were detected. In case 2, a severe interstitial pneumonia and an accompanying mild myocarditis were found by histology. Molecular genetic investigations of the coding regions of the genes, HERG, KVLQT1 and SCN5A gave no indication for the mutations, thus, affecting related myocardial ion channels as possible sources of inhomogeneity of repolarisation. Since a molecular genetic deviation could not yet be elaborated the possible role of related disturbance remains unknown.

Myocarditis: emergency department recognition and management.

Myocarditis is an acute inflammatory syndrome involving the heart and related structures. In many instances, the presentation is obvious, and appropriate treatment and disposition follow accordingly. In other situations, patients present with viral illness of the respiratory or gastrointestinal tracts (or both) or nonspecific symptoms such as fatigue and weakness,leading the clinician astray. Management is largely supportive, including aggressive cardiorespiratory support.

[Distomatosis and cardiac disease. Apropos of 2 new cases. Trials of classification and pathogenetic hypotheses]. / Distomatose et cardiopathie. A propos de deux nouvelles observations. Essais de classification et hypothèses pathogéniques.

The authors report two new cases of cardiac disease associated with distomatosis: one case of biventricular fibroblastic parietal endocarditis affecting mainly the left side in a young female of 26 years, and one case of cardiomyopathy with atrial endocardial fibrosis, affecting especially the left ventricle in a man of 47. Bearing in mind the five cases reported in the literature, the authors propose a classification of cardiac disorders supposed to be due to distomatosis using three groups (endocardial fibrosis, cardiomyopathy, myocarditis) and relate them to a common pathogenesis based on immuno-allergic theory.

[Myocardial diseases: their etiology, nomenclature and classification (apropos of the classification of noncoronarogenic myocardial lesions published in Kardiologiia No. 5, 1978)]. / Bolezni serdechnoi myshtsy: ikh étiologiia, nomenklatura, klassifikatsiia (po povodu klassifikatsii nekoronarogennykh povrezhdenii miokarda, opublikovannoi v No. 5 zhurnala "Kardiologiia" za 1978 g.).

The main forms of "noncoronarogenous" diseases of the heart muscle and the problems of their nomenclature are discussed, an attempt is made in particular to determine the borderline between the concepts of "myocardial dystrophy" and "cardiomyopathy". The article also deals with the role of infections in the origin of inflammatory processes in the heart muscle (myocarditis) and its dystrophy. A conclusion is drawn on the expediency, from the standpoint of nomenclature, to designate the pathological condition of the myocardium in the course of an infectious disease only by the term "myocarditis". The relation between "primary cardiomyopathies" and Fiedler's idiopathic myocarditis is discussed. The possible role of virus infection in the origin of the indicated forms of myocardial diseases is considered. The classification of noncoronarogenous myocardial lesions published in Kardiologia (1978, No. 5) is discussed. The author of the present article thinks that it may be appraised quite favourably on the whole, and also makes some remarks.

[Diagnosis of nonrheumatic myocarditis]. / O diagnostike nerevmaticheskikh miokarditov.

Titres of antibodies neutralizing Coxsackie B1-6 virus were examined in 272 patients with nonrheumatic myocarditis and myocarditic cardiosclerosis, and also in two groups of controls (150 normal subjects and 70 patients with other cardiac diseases). A group of 123 patients were screened simultaneously for antibodies to Coxsackie B virus, influenza, parainfluenza, adenoviruses and beta-hemolytic Group A streptococcus. The diagnosis of myocarditis was based on clinical, electrocardiographic, enzymologic and functional electrocardiographic findings. Serologic data demonstrated that most cases of nonrheumatic myocarditis were associated with Coxsackie and influenza viruses. An etiologic classification, diagnostic criteria and problems of differential diagnosis of nonrheumatic myocarditis are discussed.

[The hemodynamic status of patients with infectious myocarditis]. / Stan hemodynamiku u khvorykh na infektsiinyi miokardyt.

Acute infectious myocarditis is accompanied by disturbances in the contractile function of the left ventricle, its degree being related to the gravity of the disease course. Improvement in the condition of the left ventricular contractile function correlates both with degree of severity of the illness and methodological approaches to the conducted therapy.