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Molecular Pathobiology of Myocarditis
Introduction
In the 1995 World Health Organization (WHO) Definition of Cardiomyopathies , myocarditis (also called inflammatory cardiomyopathy), is defined as an ‘inflammatory disease of the myocardium associated with cardiac dysfunction’ and is listed among ‘specific cardiomyopathies.’ Myocarditis is diagnosed in vivo on endomyocardial biopsy (EMB) by established histological, immunological, and immunohistochemical criteria, and molecular testing on EMB specimens is recommended to identify viral etiology. Infectious, autoimmune, and idiopathic forms of inflammatory cardiomyopathy are recognized as distinct subtypes of myocarditis that may lead to dilated cardiomyopathy (DCM).
In the 2006 American Heart Association consensus document on cardiomyopathies, myocarditis is listed among primary cardiomyopathies under the acquired subgroup, with infectious, autoimmune, and toxic causes; moreover, it is also identifiable under the mixed subgroup of cardiomyopathies, in the form of inflammatory DCM (i.e. predominantly non-genetic, with infectious, autoimmune, and toxic causes). The actual incidence of myocarditis is difficult to determine since EMB, the diagnostic gold standard, is performed in a minority of cases. Studies of sudden cardiac death in young people report a highly variable autopsy prevalence of myocarditis, ranging from 2 to 42% of cases. Similarly, biopsy-proven myocarditis is reported in 9–16% of adult patients with unexplained non-ischaemic DCM and in 46% of children with a known cause of DCM.
The clinical presentation of myocarditis is highly variable, ranging from subclinical to severe, and includes unexplained congestive heart failure (i.e., exertional dyspnea, fatigue) or cardiogenic shock, chest pain with myocardial enzyme release mimicking myocardial infarction, arrhythmias, syncope, or even sudden death. A viral prodrome including fever, rash, myalgias, arthralgias, fatigue, and respiratory or gastrointestinal symptoms often precedes the onset of myocarditis by several days to a few weeks. The disease may affect individuals of all ages, although it is most frequent in the young. The wide spectrum of clinical scenarios implies that the diagnosis of myocarditis requires a high level of suspicion and the use of appropriate investigations. In all cases of suspected myocarditis, it is mandatory to exclude coronary artery disease and other cardiovascular or extracardiac diseases that could explain the clinical presentation. Rarely patients with other cardiovascular disorders (such as coronary artery disease, cardiomyopathy, and hypertensive heart disease) present with a clinical deterioration caused by myocarditis that is wrongly ascribed to the pre-existing disease. If this is strongly suspected by the clinician, further investigation including EMB may be appropriate.
Heterogeneity of clinical presentation, including subclinical or asymptomatic forms, explains why the incidence and prevalence of myocarditis is still unknown and probably underestimated. The clinical outcome is highly variable and may be related to the different causes and/or genetic susceptibility, thus clarifying why there are patients who resolve completely, those who have deterioration, and those who progress to DCM.
Most affected patients who present with acute onset of left ventricular dysfunction have a relatively mild myocarditis that resolves with few short-term sequelae. Children often have a more fulminant presentation. Certain clinical ‘red flags’ often identify those at higher risk. For instance, rash, fever, blood eosinophilia, or history of recent medications could suggest a hypersensitivity myocarditis. Giant-cell myocarditis (GCM) should be considered in patients with acute left ventricular dysfunction associated with thymoma, autoimmune disorder, or ventricular tachycardia. An unusual cause of myocarditis, such as cardiac sarcoidosis, should be suspected in patients who present with chronic heart failure, DCM, and new ventricular arrhythmias, second-degree or third-degree heart block, or those who do not respond to standard care.
Diagnosis of myocarditis requires a multiparametric approach including laboratory tests, non-invasive and invasive tools. Biomarkers of cardiac injury are elevated in a minority of patients with acute myocarditis but are useful to confirm the diagnosis. The electrocardiogram may show sinus tachycardia with non-specific ST segment and T-wave abnormalities and, occasionally, the changes mimic an acute myocardial infarction.
Echocardiography is needed to exclude other causes of heart failure, but there are no specific features of acute myocarditis. Segmental or global wall-motion abnormalities in myocarditis can simulate myocardial infarction. A small left ventricular cavity size with increased wall thickness and diastolic disfunction is often observed in fulminant myocarditis.
Cardiac magnetic resonance (CMR) is being used with increasing frequency as a diagnostic test in suspected acute myocarditis and may serve to localize sites for EMB. Based on pre-clinical and clinical studies, an ‘International Consensus Group on CMR Diagnosis of Myocarditis’ published detailed recommendations for appropriate CMR techniques in the non-invasive diagnosis of myocarditis (Lake Louise criteria). CMR findings are consistent with myocardial inflammation, if at least two of the following criteria are present: (a) regional or global myocardial signal intensity increase in T2-weighted edema images; (b) increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images; and (c) there is at least one focal lesion with non-ischemic regional distribution in inversion recovery-prepared gadolinium-enhanced T1-weighted images (late gadolinium enhancement).
Etiology
Myocarditis has multiple causes, both infectious and non-infectious ( Table 8.1 ).
TABLE 8.1
Myocarditis: Causes
| Infective | Viruses | DNA: Adenovirus, Chikungunya virus, Flavivirus, Hepatitis B virus, Herpes viruses (Human Herpes virus type 1, Cytomegalovirus, Varicella virus, Epstein-Barr virus, Human herpesvirus-6), Parvovirus B-19, Poliovirus, Rabies virus, Rubella virus, Variola virus RNA: Arborvirus, Hepatitis C virus, Orthomyxovirus (Influenza A and B viruses), Paramyxovirus (rubeola virus, mumps virus, respiratory syncytial virus), Picornavirus (entero, echo, rhino), retrovirus (HIV) |
| Bacteria | Burkholderia pseudomallei, Brucella, Chlamydia, Clostridium, Corynebacterium diphtheriae, Francisella tularensis, Haemophilus influenzae, Gonococcus, Legionella pneumophila, Mycobacterium (avium intracellulare, leprae, tuberculosis), Mycoplasma, Neisseria meningitidis, Salmonella, Staphylococcus, Streptococcus A, Streptococcus pneumoniae, Vibrio cholera | |
| Spirochaete | Borrelia burgdorferi, Borrelia recurrentis, Leptospira, Treponema pallidum | |
| Rickettsiae | Coxiella burnetii, Rickettsia prowazekii, Rickettsia rickettsii | |
| Fungi | Actinomyces, Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus Histoplasma, Mucor species, Nocardia, Sporothrix schenckii, Strongyloides stercoralis | |
| Protozoa | Balantidium, Entamoeba histolytica, Leishmania, Plasmodium falciparum, Sarcocystis, Trypanosoma cruzi, Trypanosoma brucei, Toxoplasma gondii | |
| Helminths | Ascaris, Echinococcus granulosus, Heterophyes, Paragonimus westermani, Schistosoma, Strongyloides stercoralis, Taenia solium, Toxocara canis, Trichinella spiralis, Wuchereria bancrofti | |
| Immune mediated | Allergens | Serum sickness, Tetanus toxoid, Vaccines Drugs: amitriptyline, cefaclor, colchicine, furosemide, isoniazid, lidocaine, methyldopa, penicillin, phenylbutazone, phenytoin, sulfonamides, tetracycline, thiazide diuretics |
| Alloantigens | Heart transplant rejection | |
| Autoantigens | Infection-negative lymphocytic, infection-negative giant cell Associated with autoimmune or immune-oriented disorders: Churg-Strauss syndrome, inflammatory bowel disease, insulin-dependent diabetes mellitus, Kawasaki’s disease, myasthenia gravis, polymyositis, rheumatoid arthritis, thyrotoxicosis, rheumatic heart disease (rheumatic fever), sarcoidosis, scleroderma, systemic lupus erythematosus, Wegener’s granulomatosis |
|
| Toxic | Drugs | Aminophylline, amphetamines, anthracyclines, catecholamines, chloramphenicol, cocaine, cyclophosphamide, doxorubicin, ethanol, 5-flurouracil, imatimib mesylate, interleukin-2, methysergide, phenytoin, trastuzumab, zidovudin |
| Heavy Metals | Copper, iron, lead (rare, more commonly cause intramyocyte accumulation) | |
| Miscellaneous | Arsenic, bee and wasp stings, carbon monoxide, inhalants, phosphorus, scorpion sting, snake and spider bites, sodium azide | |
| Hormones | Phaeochromocytoma | |
| Vitamins | Beri-beri | |
| Physical agents | Electric shock, radiation |
Infectious – Virus
Viral infection is the most common cause of myocarditis in Western Europe and North America. Using molecular techniques, viral genomic material can be identified in a varying subset of patients with acute and chronic myocarditis ( Table 8.2 ). The prevalence of enteroviral RNA in EMB specimens from patients with myocarditis, assessed by reverse transcription polymerase chain reaction (RT-PCR) or nested RT-PCR, ranged from 1% to 50%. In another study, enteroviral RNA was detected in 14% of EMB specimens from patients with myocarditis. Kühl et al. showed that in 56/172 patients (32.6%) with histology-proven myocarditis, enteroviral RNA was detectable; in 28/56 (50%) of those patients, viral RNA was eliminated spontaneously with a significant improvement in ejection fraction, whereas in the remaining 28 patients, persistence of viral genomes on subsequent biopsies was correlated with a significant decrease in ejection fraction.
TABLE 8.2
Cardiotropic Viruses, Target Myocardial Cells Receptors and Co-receptors, and Prevalence of Viral Infections Detected by Molecular Biology-Based Techniques in Active Myocarditis
(Modified from Reference ).
| Virus (Viral Genome) | Cell Target in the Heart | Receptors - Co-receptors | Prevalence (%) |
|---|---|---|---|
| Coxsackievirus (RNA) | Cardiomyocytes, B-cells, CD4+ T-cells, macrophages, fibroblasts | CAR - DAF | 3–50 |
| Adenovirus (DNA) | Cardiomyocytes, B-cells, CD4+ T-cells, macrophages, fibroblasts | CAR - α V β3 and α V β5 integrins | 1–23 |
| Parvovirus B19 (DNA) | Endothelial cells, cardiomyocytes (?) | Erythrocyte P antigen - α5β1 integrin | 1–56 |
| Human herpesvirus-6 (DNA) | T-cells, endothelial cells | CD46 | <18 |
| Epstein-Barr virus (DNA) | B cells, T-cells, macrophages | MHCII- CD21 | <1 |
| Cytomegalovirus (DNA) | Cardiomyocytes, macrophages, fibroblasts, endothelial cells | HSPG, EGFR - α V β3 integrin | 6–15 |
| Influenza virus (RNA) | Cardiomyocytes, macrophages, lymphocytes | Sialic acid | <1 |
| Hepatitis C virus (RNA) | Cardiomyocytes | CD81 - SR-B1 | <1 |
| HIV (RNA) | CD4+ T-cells, macrophages | CD4 - CCR5, CXCR4 | <1 |
CAR, Coxsackievirus and adenovirus receptor; CCR, β-chemokine receptor; CXCR, α-chemokine receptor; DAF, decay-accelerating factor; EGFR, epidermal growth factor receptor; HSPG, Heparin sulfate proteoglycan; MHC II, major histocompatibility complex; SR-B1, Scavenger receptor class B member 1.
Several respiratory tract viruses may cause myocarditis at variable frequencies. In particular, adenoviruses (type 2 and 5) have been shown to be an important cause of myocarditis and DCM both in childhood and adulthood. Rhinovirus-associated myocarditis has also been reported rarely. Many cases of acute myocarditis have been described in association with pandemic H1N1 influenza virus infections, especially in young patients. Genomes of influenza A/H1N1 virus have been detected by RT-PCR analysis in blood as well as in myocardial tissue in patients with lethal influenza virus infection.
Cytomegalovirus (CMV) is a recognized cause of acute infectious myocarditis. CMV-specific genome has been detected in the myocytes of EMBs from 3% to 38% of patients with myocarditis. Human herpes virus (HHV) 6-induced myocarditis has been reported in a small number of patients, occasionally with a fatal outcome. In large studies of patients with inflammatory heart diseases, analyses for HHV6 and Epstein-Barr virus (EBV) have been included. Prevalence for HHV6 genomes detected in patients with myocarditis are up to 20% and for EBV genomes are up to 5%.
Parvovirus B19 (PV B19), the causative agent of erythema infectiosum, also called fifth disease, has been reported to be a rare but severe cause of myocarditis in infants and children. PV B19 genomes have been detected in up to 56% of patients with myocarditis. As indicated above for enterovirus, the persistence of PV B19 in patients with left ventricle dysfunction was also found to be associated with progressive impairment of left ventricle ejection fraction, whereas spontaneous viral elimination was associated with a significant improvement in left ventricle function. However, in contrast to enterovirus, spontaneous virus elimination of PV B19 was observed in only 22% of patients. In situ hybridization revealed that endothelial cells are the principal cell target for PV B19, even though myocyte tropism has also been demonstrated. Human immunodeficiency virus and hepatitis C virus have also been seldom associated with myocarditis.
While adenovirus and enterovirus have long been considered the most important viruses leading to myocarditis, recent multicenter analyses showed a wide discrepancy in results. In a US multicenter analysis of histologically identified myocarditis, adenovirus, enterovirus and CMV were the most commonly identified viruses by PCR from EMB samples. In studies performed in Germany, a high prevalence of PV B19 has been found in patients with a history of clinically suspected myocarditis or idiopathic DCM. In Italy, in a series of 120 adult EMBs with a diagnosis of myocarditis collected from 1992 to 2005, enterovirus was the most frequent virus followed by adenovirus and EBV. This wide discrepancy in viral prevalences could have several explanations, such as differences in detection procedures, changing prevalence of viruses in local populations, or the differences in the stage of the disease. This emphasizes the need for standardization of protocols to achieve comparable results among molecular laboratories.
Infectious – Non-Virus
Although numerous bacterial infections can cause myocarditis, in industrialized countries bacterial-induced myocarditis is far less common than viral-induced myocarditis. Toxin-producing bacteria, including Clostridium and diphtheria, can cause severe myocardial damage. Bacteremia from any source may result in myocarditis, with the most common pathogens being Meningococcus, Streptococcus, Mycobacterium, and Listeria. The spirochete Borrelia burgdorferi causes Lyme disease, which can result in both acute and chronic myocarditis. Infection with the protozoa Trypanosoma cruzi (Chagas disease), common in Central and South America, can present as acute myocarditis or chronic DCM.
Toxoplasma gondii poses significant problems among recipients of cardiac transplants. A study reported that 57% of transplanted patients lacking antibodies to that agent developed Toxoplasma myocarditis. However, toxoplasmosis may become reactivated in antibody-positive transplant recipients, and myocarditis has been reported in 4–53% of transplant cases. This large variation in rate is probably due to differences in antibody testing methods. After the introduction of pyrimethamine prophylaxis, this complication has decreased substantially.
Fungal myocarditis frequently occurs in the setting of disseminated disease. The major fungal pathogen responsible for myocardial infection is Aspergillus fumigatus. The incidence of invasive fungal disease has dramatically increased over the past few decades corresponding to the increasing number of immunocompromised patients.
Immune-Mediated
Allergens
Drug-induced hypersensitivity reactions can cause an eosinophilic myocarditis that often responds to withdrawal of the offending medication, though adjuvant corticosteroid therapy is often necessary. Drugs associated with hypersensitivity myocarditis include clozapine, sulfonamide antibiotics, methyldopa, and some anti-seizure drugs. The US civilian vaccination program reported myocarditis after smallpox vaccination. Fortunately, myocarditis after other vaccines is rare. Eosinophilic myocarditis has been diagnosed in explanted hearts from patients treated with dobutamine or other inotrope drugs. Whether it is caused by dobutamine itself or the preservative sodium bisulfate is still unclear. De novo development of eosinophilic myocarditis with left ventricular assist device support as a bridge to transplantation was described by Pereira et al., although the patient was also receiving a leukotriene-receptor antagonist for asthma. In parasitic infections, eosinophilic myocarditis is not infrequent. It is often associated with protozoal infections such as Trypanosoma cruzi, Toxoplasma gondii, Trichinella spiralis, Entamoeba fragilis, Echinococcus. It is thought that the heart is infiltrated with eosinophils because of the significant and persistent blood eosinophilia caused by the parasites.
Alloantigens
Acute rejection is caused by antigen-specific Th1 and cytotoxic T-lymphocytes. They recognize transplanted tissue because of expression of alloantigens.
Autoantigens
Idiopathic GCM is a rare, autoimmune form of myocarditis histologically defined by the presence of multinucleated giant cells, lymphocytic inflammatory infiltrate, and myocyte necrosis. This disease usually occurs in young adults and typically causes fulminant heart failure, arrhythmias, or rarely heart block, necessitating aggressive immunosuppression, ventricular assist device insertion, or cardiac transplantation. Fatal outcome occurs frequently unless cardiac transplantation is performed. In some patients, GCM is associated with other autoimmune disorders, and drug hypersensitivity reactions. GCM is rarer in children and, in this setting, is often associated with immune-mediated disease in other organs. A variant of GCM has been reported that primarily involves the atria, displays distinctive clinical features, and follows a more benign course than typical ventricular GCM.
Cardiac sarcoidosis is another unusual form of idiopathic myocarditis that is distinct from GCM in that it is characterized histologically by granulomas with epithelioid macrophages and giant cells but without caseous necrosis. It has a lower fatality rate than GCM. Clinical manifestations of cardiac sarcoidosis are dependent on the location, extent, and activity of disease, and range from clinically silent disease to sudden cardiac death. Conduction abnormalities, ventricular arrhythmias, and heart failure may occur. Ventricular tachycardia is the second most common manifestation of cardiac sarcoidosis and has been reported in nearly one-fourth of patients even mimicking arrhythmogenic cardiomyopathy.
Eosinophilic myocarditis has been reported as a consequence of systemic diseases, such as Churg-Strauss syndrome, celiac disease, cancer, and hypereosinophilic syndrome. Churg-Strauss syndrome is a multisystem disease characterized by rhinitis, asthma, peripheral blood eosinophilia, and necrotizing vasculitis (notably glomerulonephritis). Cardiac involvement has been found in 64% of autopsy cases. Cardiac pathologic findings include myocardial inflammatory infiltration with eosinophils and myocytolysis, intracavitary endocardial thrombi, coronary vasculitis, acute fibrinous pericarditis, and pericardial fibrosis. Eosinophilic myocarditis can be seen in patients with eosinophilic neoplastic disorders as well as T-cell lymphoma and carcinomas (notably lung and biliary tract cancers). In hypereosinophilic syndrome there is marked unexplained blood and tissue eosinophilia in combination with a variety of clinical manifestations. Tissue infiltration with eosinophils is found in many organs, i.e. skin, brain, liver, spleen, heart, lungs, etc. In the heart, a spectrum of disease is observed, from an acute inflammatory to a fibrotic stage.
Toxic
Drugs can cause myocardial inflammation by either a direct toxic effect on the heart or by inducing hypersensitivity reactions. Among the various drugs, anthracyclines and cocaine in particular have often been implicated in acute myocarditis due to myocardial toxicity ( Table 8.1 ).
Diagnosis
Histopathology
In order to develop uniform and reproducible criteria for the pathologic diagnosis of myocarditis, the so-called Dallas criteria were put forward in 1987, based upon histological features on EMB. Accordingly, myocarditis is defined as an ‘inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of ischemic damage associated with coronary artery disease.’ Two distinct diagnoses are then used for the first and subsequent biopsies ( Table 8.3 ). Several limitations of the Dallas criteria have been raised: (a) inflammatory cell characterization by immunohistochemistry and the degree of fibrosis are not part of the criteria; (b) the type and extent of myocyte damage is not taken into account; (c) the phenotypic characteristics of the inflammatory cell infiltrate (i.e., lymphocytic, eosinophilic, polymorphous, giant cell, and granulomatous myocarditis) are only listed secondarily as a descriptive modifier; (d) a diagnosis of healing or healed myocarditis was not recommended for the first EMB, but only when unequivocal myocarditis has been previously diagnosed; (e) the recommended term ‘borderline myocarditis.’ for cases with limited amounts of inflammation including chronic forms of myocarditis, is not useful for treating and managing patients; (f) finally, any reference to etiological agents, such as viruses, was lacking because molecular techniques were not available at that time.
TABLE 8.3
Dallas Criteria: Morphological Diagnosis of Myocarditis
| First biopsy | Myocarditis with/without fibrosis |
| Borderline myocarditis (repeat biopsy may be indicated) | |
| No myocarditis | |
| Subsequent biopsy | Ongoing (persistent) myocarditis with/without fibrosis |
| Resolving (healing) myocarditis with/without fibrosis | |
| Resolved (healed) myocarditis with/without fibrosis |
EMB represents a fundamental step in the diagnosis of myocarditis. Although the disease is a diffuse process, the intensity and distribution of the inflammatory infiltrate are highly variable, including solitary small foci and multifocal aggregates, causing a low diagnostic yield on EMB due to sampling error. The number, size, and processing of EMB samples have been demonstrated to influence the diagnostic sensitivity of EMB in the setting of myocarditis. The Stanford-Caves and Cordis bioptomes have been shown to yield greater sensitivity compared with other smaller bioptomes. It has also been shown that serial sectioning of the specimens and examination of multiple histologic levels increases the sensitivity of EMB in the evaluation of myocarditis. Although biventricular EMB, rather than simply right ventricular EMB, has been demonstrated to improve the sensitivity in the detection of myocarditis ; this approach is more aggressive and may entail greater risk of complications.
Histopathological assessment not only remains the gold standard for the diagnosis of myocarditis but it is essential to reach a classification of myocarditis based upon histological criteria, i.e. lymphocytic, eosinophilic, polymorphous, granulomatous, and giant cell, where the histology often reflects a different etiopathogenesis of the myocardial inflammatory process ( Figure 8.1 ). To overcome the limits of the Dallas criteria, a classification of myocarditis based upon semi-quantitative histological criteria has been proposed ( Table 8.4 ), which includes assessment of the inflammatory cell type, grading the extent of myocyte damage and inflammation, and staging of the disease by semi-quantitative assessment of fibrosis ( Table 8.4 ). Grading and staging have been traditionally applied to tumor pathology for many years, as well as to non-neoplastic conditions such as chronic hepatitis. Grading can be used in inflammatory cardiomyopathy to describe the intensity of necro-inflammatory activity; staging, on the other hand, reflects the degree of fibrosis and architectural changes, which are the consequence of tissue injury and repair ( Figure 8.2 ).
TABLE 8.4
Inflammatory Cardiomyopathy Classification: Grading and Staging
| Grading (Burden of Myocyte Damage and Inflammation) | ||
|---|---|---|
| (A) Myocyte damage | Absent | 0 |
| Focal | 1 | |
| Plurifocal | 2 | |
| (B) Interstitial inflammation | ≤7 T-cells/mm 2 | 0 |
| >7 to ≤14 T-cells/mm 2 | 1 | |
| >14 T-cells/mm 2 | 2 | |
| (C) Endocardial involvement (inflammation, thrombosis) | Absent | 0 |
| Present | 1 | |
| Maximum score | 5 | |
| Staging (fibrosis) | ||
|---|---|---|
| (A) Interstitial/replacement fibrosis | Absent | 0 |
| >10 to ≤20 % | 1 | |
| >20 to ≤40 % | 2 | |
| >40 % | 3 | |
| (B) Subendocardial fibrosis | Absent | 0 |
| Present | 1 | |
| (C) Endocardial fibroelastosis | Absent | 0 |
| Present | 1 | |
| Maximum score | 5 | |
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