**3. Cause of myocarditis and classification**

Myocarditis is classified by cause, clinical type, and pathological picture. In clinical medicine, myocarditis presenting as a sudden development should be attended to because any delay of treatment presents a risk of fatal circulatory failure. It should be recognized that there is different prognosis depending on the clinical type of myocarditis. The classification of myocarditis is shown in Table 1.

#### **3.1 Causes**

Several causes or mechanisms of the development of myocarditis have been detected, among which infection is the most the frequent and important. In earlier years, myocarditis was often caused by rheumatic fever and diphtheria. More recently, in advanced nations it is mostly caused by viral infections. Bowles et al. (1986) reported that Coxsackie B virus was detected in patients with myocarditis using a dot blot hybridization method. Coxsackie virus, an enterovirus belonging to the picornavirus family, was extracted from patients with polio in 1982 and is particularly compatible with myocardium (Clements, 1993). Half of group A types and all of group B types of the Coxsackie virus cause myocarditis accompanied by symptoms of the common cold.

Presently, it is possible to detect many viruses with polymerase chain reaction or in situ hybridization. Therefore, we can detect myocarditis due to viral infection in most cases. In

In this chapter, we explain the causes, mechanisms as presently known, classification, and clinical course of myocarditis. Additionally, we outline the recommended treatment for the

The clinical course of myocarditis varies. The symptoms range widely, from slight to severe, and it is difficult to investigate myocarditis epidemiologically. In 2002 in Japan, a large-scale investigation for cardiomyopathy was performed and reported that cardiomyopathy was found in 21.3 per 100,000 population (Miura et al., 2002). However, the subjects of this investigation were consulted patients with data provided by hospitals. It is thought that actual morbidity is higher, because there are many non-consulted persons with occult cardiomyopathy, such as early stage dilated cardiomyopathy or hypertrophic cardiomyopathy with no symptoms. Therefore, we still cannot grasp the exact morbidity of myocarditis in Japan. Okada et al. (1989) reported that among 10,000 autopsied cases during 1958–1978 there were 115 cases of myocarditis. In another report, occult myocarditis was found in 0.6% of autopsied cases in which cardiac disease had not detected while the patients were alive (Feely et al., 2000). Therefore, it should be recognized that myocarditis is not clinically infrequent and includes a mild type that displays no symptoms. The mortality rate for myocarditis has not been established. An investigative committee of the Ministry of Public Welfare and Labor in Japan reported in 1986 that 13 (4.7%) of 274 patients died within 1 month in a small-scale investigation targeting acute-phase myocarditis (Kawamura et al., 1986). Among those cases, the causes of death were cardiogenic shock in six cases (46%), congestive heart failure in five cases (38%), and complete atrioventricular block in two cases (15%). Intensive treatment for severe cardiac dysfunction and fatal arrhythmias

are important to reduce mortality during the acute phase of severe myocarditis.

Myocarditis is classified by cause, clinical type, and pathological picture. In clinical medicine, myocarditis presenting as a sudden development should be attended to because any delay of treatment presents a risk of fatal circulatory failure. It should be recognized that there is different prognosis depending on the clinical type of myocarditis. The

Several causes or mechanisms of the development of myocarditis have been detected, among which infection is the most the frequent and important. In earlier years, myocarditis was often caused by rheumatic fever and diphtheria. More recently, in advanced nations it is mostly caused by viral infections. Bowles et al. (1986) reported that Coxsackie B virus was detected in patients with myocarditis using a dot blot hybridization method. Coxsackie virus, an enterovirus belonging to the picornavirus family, was extracted from patients with polio in 1982 and is particularly compatible with myocardium (Clements, 1993). Half of group A types and all of group B types of the Coxsackie virus cause myocarditis

Presently, it is possible to detect many viruses with polymerase chain reaction or in situ hybridization. Therefore, we can detect myocarditis due to viral infection in most cases. In

**3. Cause of myocarditis and classification** 

classification of myocarditis is shown in Table 1.

accompanied by symptoms of the common cold.

**3.1 Causes** 

acute phase of myocarditis.

**2. Epidemiology and prognosis** 


Table 1. classification of myocarditis. modified from the guideline for the diagnosis and treatment of myocarditis (JCS, 2005).

1. Nonsteroidal anti-inflammatory drugs Indomethacin, oxyphenbutazone, phenylbutazone 2. Psychotropic drugs (Tricyclic) antidepressant: imipramine, clomipramine, amitriptyline Antimanic: lithium carbonate, lithium oxalic acid Antiepileptic: phenytoin, carbamazepine 3. Diuretic: acetazolamide, hydrochlorothiazide, spironolactone, chlorthalidone 4. Depressor: methyldopa 5. Anticancer drug: adriamycin, daunorubicin, mitoxantrone 6. Antibiotics Amphotericin B, penicillin, ampicillin, tetracycline Chloramphenicol, streptomycin 7. Sulfaminum: sulfadiazine, sulfisoxazole 8. Antiphthisic: isoniazid (INH), para-aminosalicylic acid (PAS) 9. Biological agents: tetanus toxoid, α-interferon, interleukin 2 (IL-2) 10. Antidiabetic: sulfonylurea 11. Others: catecholamines, cocaine, amphetamine, arsenic

Table 2. Drugs that cause myocarditis.

Acute Myocarditis in Emergency Medicine 73

differential diagnosis between viral myocarditis and eosinophilic myocarditis is often impossible because the eosinophil count is normal during the early phase of eosinophilic myocarditis (Morimoto et al., 2003). White blood cells (WBCs) gradually increase with the development of an inflammatory reaction; and materials toxic to the myocardium released from eosinophilic leukocytes cause severe contraction of the myocardium as the eosinophil

In most cases, the increase in eosinophils is detected in a peripheral blood examination. However, some patients who suffer from circulatory insufficiency exhibit a delayed increase in eosinophils (Gets et al., 1991). Therefore, we should perform more frequent eosinophil counts during the acute phase. Infiltration of eosinophilic leukocytes, degranulation, and

The main causes are an allergic reaction, drugs, and parasitic infection. Most cases, however, are treated as idiopathic myocarditis (Forrester et al., 1976). It has been reported that the mortality rate among patients with acute-phase eosinophilic myocarditis is approximately

Myocarditis is clinically classified as acute or chronic. Since it is possible to detect the exact onset of acute myocarditis, it is easier to estimate the circulatory parameters for diagnosis and establish the strategy for treatment of acute myocarditis than for chronic myocarditis. In some cases of acute myocarditis, we treat it as fulminant myocarditis that has developed suddenly and may progress to severe circulatory failure during the acute phase (Aoyama et al., 2002). The worldwide morbidity and mortality rates associated with fulminant myocarditis are not yet clear. Cupta et al. (2008) reported that the frequency of fulminant

The global concept of chronic myocarditis has not been established, although several studies have suggested that viral infection (Fujioka et al., 2000) or autoimmunity (Lauer et al., 2000) play a role in its development. There are clinically two types of chronic myocarditis, and they have different clinical courses. One type has persistent, continuous symptoms, and the

In an investigation of clinical types of myocarditis in 48 patients reported by Kodama et al. (2001), nine were the acute type, 21 were the fulminant type, three were the chronic persistent symptom type, and 15 were the chronic unremarkable symptom type. The mortality rates during the first admission were 22% for the acute type, 43% for the fulminant type, 33% for the chronic persistent symptom type, and 40% for the chronic unremarkable symptom type. The long-term prognosis for patients who recovered from their cardiac dysfunction during the early phase was good. However, the long-term prognosis for patients who were diagnosed with the chronic, unremarkable symptom type was not good because they developed irreversible circulatory dysfunction, such as dilated

Clinically, symptoms range from slight problemsfever, pharyngeal pain, cough, vomiting, diarrhea, and arthropathies, as observed with the common coldto severe circulatory failure. Therefore, we cannot list any symptoms characteristic of acute-phase myocarditis. In

myocarditis is 10% among all cases of acute myocarditis in the United States.

destruction of myocardium are observed in the biopsy specimen.

7% (Morimot et al., 2003), (Mori et al., 2004).

other has unremarkable symptoms (JCS, 1996).

**4. Clinical symptoms and diagnosis** 

**4.1 Clinical symptoms and physical symptoms** 

count exceeds 500/nm3.

**3.3 Clinical classification** 

cardiomyopathy.

recent reports, adenovirus, sharing the same receptors as the Coxsackie virus, parvovirus B19, human herpes virus 6, and hepatitis C virus, are known to cause myocarditis (Okabe et al., 1997).

Myocarditis does not always develop in patients infected by a virus compatible with the myocardium (e.g., the Coxsackie virus). In such cases, symptoms of myocarditis are unremarkable or slight, and the mechanism of development of myocarditis remains unknown. Based on the results in experimental animal models, Cupta et al. (2008) suggested a developmental pattern of myocardial damage by an infective virus and the host's reactions as follows: (1) initial infection of virus in myocardial cells; (2) innate immune reaction; (3) defense by adaptive immunity; and (4) recovery of inflammatory reaction.

Several kinds of drugs, external physical stimulations such as exposure to irradiation or excessive heat, metabolic disorders, pregnancy, collagen diseases, sarcoidosis, and Kawasaki disease are important causes of myocarditis. It should be well noted that drug-induced myocarditis, particular in Japan, Europe, and the United States, is caused by many of the drugs that are administered or prescribed to patients in advanced countries. Drugs that cause myocarditis are shown in Table 2.

#### **3.2 Histological classification**

Histologically, myocarditis is classified as lymphocytic myocarditis, giant cell myocarditis, eosinophilic leukocyte myocarditis, and granuloma myocarditis. Most cases of lymphocytic myocarditis are caused by infection. Other types are due to materials toxic to the myocardium, a drug allergy, or an autoimmune reaction.

#### **3.2.1 Lymphocytic myocarditis**

Lymphocytic myocarditis is the most frequent histological type, and most cases are caused by a viral infection. Kodama et al. found that 85% of patients with myocarditis were diagnosed with the lymphocytic variety (Kodama et al., 2001). The primary symptomsfever and pharyngeal painare not specific for myocarditis during the early phase, but symptoms of circulatory failure, such as edema, are specific and are observed during the developed phase. The severity of circulatory failure ranges widely from slight to fulminant.

#### **3.2.2 Giant cell myocarditis**

Giant cell myocarditis is encountered infrequently. Clinically, it has a poor prognosis because it can easily progress to fulminant myocarditis. After the onset, circulatory failure develops suddenly and in many cases rapidly progresses to a fatal state. It is suggested that an allergic reaction or an autoimmune reaction participates in this development. Infiltration by inflammatory cells and multinucleated cells are observed in the myocardium (Davidoff et al., 1991). Cardiac function markedly deteriorates with massive necrosis of the myocardium. Identification of multinucleated cells is necessary for a definitive diagnosis. It is difficult to decide on the timing of a biopsy because multinucleated cells are seen only during the acute phase. In patients presenting with a chronic course, cardiac sarcoidosis must be excluded (Shield et al., 2002).

#### **3.2.3 Eosinophilic myocarditis**

The clinical symptoms of eosinophilic myocarditisfever, pharyngeal pain, coughduring the early phase are similar to those seen with myocarditis due to a viral infection. The

recent reports, adenovirus, sharing the same receptors as the Coxsackie virus, parvovirus B19, human herpes virus 6, and hepatitis C virus, are known to cause myocarditis (Okabe et

Myocarditis does not always develop in patients infected by a virus compatible with the myocardium (e.g., the Coxsackie virus). In such cases, symptoms of myocarditis are unremarkable or slight, and the mechanism of development of myocarditis remains unknown. Based on the results in experimental animal models, Cupta et al. (2008) suggested a developmental pattern of myocardial damage by an infective virus and the host's reactions as follows: (1) initial infection of virus in myocardial cells; (2) innate immune reaction; (3)

Several kinds of drugs, external physical stimulations such as exposure to irradiation or excessive heat, metabolic disorders, pregnancy, collagen diseases, sarcoidosis, and Kawasaki disease are important causes of myocarditis. It should be well noted that drug-induced myocarditis, particular in Japan, Europe, and the United States, is caused by many of the drugs that are administered or prescribed to patients in advanced countries. Drugs that

Histologically, myocarditis is classified as lymphocytic myocarditis, giant cell myocarditis, eosinophilic leukocyte myocarditis, and granuloma myocarditis. Most cases of lymphocytic myocarditis are caused by infection. Other types are due to materials toxic to the

Lymphocytic myocarditis is the most frequent histological type, and most cases are caused by a viral infection. Kodama et al. found that 85% of patients with myocarditis were diagnosed with the lymphocytic variety (Kodama et al., 2001). The primary symptomsfever and pharyngeal painare not specific for myocarditis during the early phase, but symptoms of circulatory failure, such as edema, are specific and are observed during the developed phase. The severity of circulatory failure ranges widely from slight to

Giant cell myocarditis is encountered infrequently. Clinically, it has a poor prognosis because it can easily progress to fulminant myocarditis. After the onset, circulatory failure develops suddenly and in many cases rapidly progresses to a fatal state. It is suggested that an allergic reaction or an autoimmune reaction participates in this development. Infiltration by inflammatory cells and multinucleated cells are observed in the myocardium (Davidoff et al., 1991). Cardiac function markedly deteriorates with massive necrosis of the myocardium. Identification of multinucleated cells is necessary for a definitive diagnosis. It is difficult to decide on the timing of a biopsy because multinucleated cells are seen only during the acute phase. In patients presenting with a chronic course, cardiac sarcoidosis must be excluded

The clinical symptoms of eosinophilic myocarditisfever, pharyngeal pain, coughduring the early phase are similar to those seen with myocarditis due to a viral infection. The

defense by adaptive immunity; and (4) recovery of inflammatory reaction.

cause myocarditis are shown in Table 2.

myocardium, a drug allergy, or an autoimmune reaction.

**3.2 Histological classification** 

**3.2.1 Lymphocytic myocarditis** 

**3.2.2 Giant cell myocarditis** 

(Shield et al., 2002).

**3.2.3 Eosinophilic myocarditis** 

fulminant.

al., 1997).

differential diagnosis between viral myocarditis and eosinophilic myocarditis is often impossible because the eosinophil count is normal during the early phase of eosinophilic myocarditis (Morimoto et al., 2003). White blood cells (WBCs) gradually increase with the development of an inflammatory reaction; and materials toxic to the myocardium released from eosinophilic leukocytes cause severe contraction of the myocardium as the eosinophil count exceeds 500/nm3.

In most cases, the increase in eosinophils is detected in a peripheral blood examination. However, some patients who suffer from circulatory insufficiency exhibit a delayed increase in eosinophils (Gets et al., 1991). Therefore, we should perform more frequent eosinophil counts during the acute phase. Infiltration of eosinophilic leukocytes, degranulation, and destruction of myocardium are observed in the biopsy specimen.

The main causes are an allergic reaction, drugs, and parasitic infection. Most cases, however, are treated as idiopathic myocarditis (Forrester et al., 1976). It has been reported that the mortality rate among patients with acute-phase eosinophilic myocarditis is approximately 7% (Morimot et al., 2003), (Mori et al., 2004).
