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.

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.

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.

[Myocarditis]. / Myocardites.

Myocarditis is an inflammatory disease of the myocardium associated with cardiac dysfunction. Etiologies of myocarditis are numerous - viral causes being the most frequent - as well as their clinical presentations which varies from isolated increase in cardiac enzymes during a viral pericarditis, fulminant myocarditis associated with cardiogenic shock to endomyocardial biopsy proven inflammation discovered during the etiologic diagnosis of a dilated cardiomyopathy. This article will discuss the importance of recognition of specific clinical scenarios of myocarditis and their echocardiographic presentations that are very useful for the etiologic diagnosis and to decide the medical strategy. Recent advances in the field of myocarditis concern improvement in understanding the pathophysiology, in the diagnostic approach with the use of noninvasive imaging (MRI) and molecular biology. However, specific treatment is still limited. Clinical trials with antiviral medications are not conclusive, and the medical strategies remain mainly based on the symptomatic treatment of heart failure.

[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.

Relationship between cardioscopic images and histological changes in the left ventricle of patients with idiopathic myocarditis.

AIMS: Endomyocardial biopsy is essential for definite diagnosis of idiopathic myocarditis. However, since endomyocardial biopsy is guided by fluoroscopy, whether or not the diseased myocardium is biopsied depends on chance, and this may lead to misdiagnosis. If the endocardial surface represents changes indicative of stages of myocarditis, staging of myocarditis and targeted cardioscope-guided biopsy could be used for accurate histological diagnosis. METHODS AND RESULTS: The relationship between left ventricular endocardial surface colour observed by cardioscopy and biopsy findings were examined in 78 patients with suspected idiopathic myocarditis. Of these, 59 patients were diagnosed histologically as idiopathic myocarditis. Endocardial colour was classified into red, milky white, purple, yellowish brown, or white. Biopsied specimens with red and milky white wall segments exhibited histological changes compatible with acute myocarditis; purple segments, active chronic myocarditis; and yellowish brown and white segments, inactive chronic myocarditis. The sensitivity, specificity, and predictive value of red and milky white colours for detecting acute myocarditis were 100, 100, and 100%, respectively; of purple for detecting active chronic myocarditis were 83, 92, and 78%, respectively; and yellowish brown and white for detecting inactive chronic myocarditis were 82, 74, and 53, respectively. CONCLUSION: Red and milky white endocardial surface colours predicted histological acute myocarditis, and purple predicted active chronic myocarditis. However, yellowish brown and white colours did not predict inactive chronic myocarditis.

[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.

Low troponin-I levels on admission are associated with worse prognosis in patients with fulminant myocarditis.

BACKGROUND: The clinical outcomes of patients with fulminant acute myocarditis (FAM) range from death to complete recovery. We sought to identify clinical, biological, and echocardiographic characteristics of prognostic value for this population. METHODS AND RESULTS: We prospectively included 185 patients with the diagnosis of acute myocarditis who were admitted to our institution between 2000 and 2007, selecting 15 who displayed FAM, namely, severe congestive heart failure or cardiogenic shock, requiring inotropic and/or mechanical circulatory support. Their mean age was 27.9 +/- 12.4 years (range, 12-52) and mean left ventricular ejection fraction (LVEF) was 22 +/- 8.4% (range, 10-35). Seven subjects had poor outcomes, defined as death (n = 4), urgent transplantation (x = 2), or persistent left ventricular dysfunction (n = 3). The other 6 individuals experienced complete recovery of ventricular function. Troponin-I values below 1 ng/mL on admission were significantly associated with greater in-hospital (P = .05) and mid-term poor outcomes (P = .001). Additionally, patients with poor outcomes showed significantly lower LVEF (17.6 +/- 6.2% vs 28.8 +/- 6.9%; P = .006). CONCLUSION: Among patients with FAM, normal or minimal elevation of troponin-I and low LVEF on admission were associated with worse in-hospital and mid-term prognosis.

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.

Echocardiography findings in 16 cases of cardiac echinococcosis: proposal for a new classification system.

BACKGROUND: Echocardiography is a reliable method for diagnosing cardiac echinococcosis (CE). Currently, there is no echocardiographic classification system for CE, but such a scheme would facilitate diagnosis. This article presents echocardiographic data for 16 cases with CE and outlines a method for echocardiographic classification of CE based on the World Health Organization's ultrasonographic classification of cystic echinococcosis. METHODS: We assessed the echocardiographic features of hydatid cysts in 16 patients with CE (9 women and 7 men; mean age, 41 +/- 18.3 years), all of whom underwent cardiac surgery. The proposed classification system identifies 3 types of CE lesions: active (unilocular or multilocular and echolucent, showing double-layered cyst wall and hydatid sand); transitional (shrunken as a result of reduced intracystic pressure, and showing water lily sign); and inactive (completely degenerated contents creating the ball-of-wool sign). Preoperative echocardiographic findings (lesion location, imaging appearance [unilocular/multilocular, solid/semisolid], echocardiographic classification/type, number of lesions) were compared with computed tomographic, intraoperative echocardiographic, surgical, and parasitological findings. RESULTS: Preoperative echocardiography revealed 18 hydatid cysts (10 myocardial, 7 pericardial, 1 on the ascending aorta). In all, 10 lesions appeared multilocular, 6 unilocular, and 2 solid. A total of 11 were active, 5 transitional, and 2 inactive. Computed tomography identified 20 lesions total, therefore, two were missed on echocardiography. The preoperative echocardiographic findings correlated well with intraoperative echocardiographic, surgical, and parasitological findings. CONCLUSION: The 3 types of CE lesions defined in this proposed classification system feature distinct echocardiographic characteristics. This new system is reliable and practical, and could assist with diagnosis and rapid treatment of CE.

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.

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.