**3. Clinical manifestation**

Myocarditis is synonymous with inflammatory cardiomyopathy which has a wide range of clinical presentation, from subtle to devastating clinical scenario that contributes to the difficulties in diagnosis and classification of this disorder. There are few population-based, epidemiologic studies which have defined the presenting symptoms of acute myocarditis; this is due to the absence of a safe and sensitive noninvasive test that can confirm the diagnosis. Worldwide, the true frequency of disease in its less severe forms, whether clinical or subclinical, across various age segments of the population are more difficult to appreciate. Table 1 summarized the most significant clinical manifestations and physical findings in patients presented with myocarditis. Typically myocarditis has a bimodal age distribution in the general population, with the acute presentation more commonly seen in young children and teenagers. In contrast, the presenting symptoms are more subtle and insidious, often with dilated cardiomyopathy and heart failure in the older adult population. Most studies of acute myocarditis reported a slight preponderance in male patients (Caforio et al., 2007). The male-to-female ratio is 1.5 to 1, which may be related to a protective effect of natural hormone variations on immune responses in women (Schwartz et al., 2004). The variable clinical manifestation of myocarditis in part reflects the variability in histological disease severity. Myocardial inflammation may be focal or diffuse, involving any or all cardiac chambers. Severe, diffuse myocarditis can result in a clinical manifestation of acute dilated cardiomyopathy.

Many patients with myocarditis present with a nonspecific illness characterized by fatigue, mild dyspnea, and myalgias. Most cases of viral myocarditis are subclinical; therefore, the patient infrequently seeks medical attention during acute illness. These subclinical cases may have transient electrocardiographic abnormalities. The reported antecedent infectious viral syndrome is highly variable, ranging from 10 percent to 80 percent of patients with viral myocarditis (Baboonian & Treasure, 1997; Feldman & McNamara, 2000; Imazio et al., 2008; Mason et al., 1995). The appearance of cardiac specific symptoms occurs primarily in the subacute virus clearing phase; therefore, patients commonly present two weeks after the acute viremia.

A few patients present acutely with fulminant congestive heart failure secondary to widespread myocardial involvement. Animal models have lead to a much greater understanding of the fulminant clinical course of myocarditis in which a rapid progression, severe ventricular dysfunction and cardiovascular collapse occurs (Ellis & Di Salvo, 2007). Fulminant myocarditis, manifested by severe hemodynamic compromise requiring high dose vasopressor support or mechanical circulatory support, was identified in 15 of 147 patients (10.2 percent) in a large prospective study (McCarthy et al., 2000). Fulminant cases were additionally characterized by a distinct viral prodrome, fever, and abrupt onset (generally <3 days) of advanced heart failure symptoms. These patients typically have severe global left ventricular dysfunction and minimally increased left ventricular enddiastolic dimensions. Of note, either borderline or active lymphocytic myocarditis can produce this dramatic clinical presentation. The histological features of chronic myocarditis are usually produced a more subtle clinical course. Adults may present with heart failure years after initial index event of myocarditis.

recommendations proposed by these criteria are based on limited data and that not all

Myocarditis is synonymous with inflammatory cardiomyopathy which has a wide range of clinical presentation, from subtle to devastating clinical scenario that contributes to the difficulties in diagnosis and classification of this disorder. There are few population-based, epidemiologic studies which have defined the presenting symptoms of acute myocarditis; this is due to the absence of a safe and sensitive noninvasive test that can confirm the diagnosis. Worldwide, the true frequency of disease in its less severe forms, whether clinical or subclinical, across various age segments of the population are more difficult to appreciate. Table 1 summarized the most significant clinical manifestations and physical findings in patients presented with myocarditis. Typically myocarditis has a bimodal age distribution in the general population, with the acute presentation more commonly seen in young children and teenagers. In contrast, the presenting symptoms are more subtle and insidious, often with dilated cardiomyopathy and heart failure in the older adult population. Most studies of acute myocarditis reported a slight preponderance in male patients (Caforio et al., 2007). The male-to-female ratio is 1.5 to 1, which may be related to a protective effect of natural hormone variations on immune responses in women (Schwartz et al., 2004). The variable clinical manifestation of myocarditis in part reflects the variability in histological disease severity. Myocardial inflammation may be focal or diffuse, involving any or all cardiac chambers. Severe, diffuse myocarditis can result in a clinical manifestation

Many patients with myocarditis present with a nonspecific illness characterized by fatigue, mild dyspnea, and myalgias. Most cases of viral myocarditis are subclinical; therefore, the patient infrequently seeks medical attention during acute illness. These subclinical cases may have transient electrocardiographic abnormalities. The reported antecedent infectious viral syndrome is highly variable, ranging from 10 percent to 80 percent of patients with viral myocarditis (Baboonian & Treasure, 1997; Feldman & McNamara, 2000; Imazio et al., 2008; Mason et al., 1995). The appearance of cardiac specific symptoms occurs primarily in the subacute virus clearing phase; therefore, patients commonly present two weeks after the

A few patients present acutely with fulminant congestive heart failure secondary to widespread myocardial involvement. Animal models have lead to a much greater understanding of the fulminant clinical course of myocarditis in which a rapid progression, severe ventricular dysfunction and cardiovascular collapse occurs (Ellis & Di Salvo, 2007). Fulminant myocarditis, manifested by severe hemodynamic compromise requiring high dose vasopressor support or mechanical circulatory support, was identified in 15 of 147 patients (10.2 percent) in a large prospective study (McCarthy et al., 2000). Fulminant cases were additionally characterized by a distinct viral prodrome, fever, and abrupt onset (generally <3 days) of advanced heart failure symptoms. These patients typically have severe global left ventricular dysfunction and minimally increased left ventricular enddiastolic dimensions. Of note, either borderline or active lymphocytic myocarditis can produce this dramatic clinical presentation. The histological features of chronic myocarditis are usually produced a more subtle clinical course. Adults may present with heart failure

centers will be able to apply all components of the suggested protocol.

**3. Clinical manifestation** 

of acute dilated cardiomyopathy.

years after initial index event of myocarditis.

acute viremia.


Table 1. The most significant clinical manifestations and physical findings in patient with myocarditis

The medical history may embrace a number of hints that merits an emphasis. Previous history of rheumatic heart disease or symptoms defined by Jones criteria e.g. fever or arthralgia can be a clue for the clinical diagnosis acute rheumatic fever. History of tick bite may correlate with suspected Lyme disease. Patients treated for neoplastic disorders with chemotherapeutic agents like doxorubicin may draw attention to anthracyclines-induced myocarditis. History of travel to Central or South America can be a clue for the diagnosis of Chagas disease. Additionally, giant-cell myocarditis should be considered in patients with acute dilated cardiomyopathy associated with thymoma, autoimmune disorders, ventricular tachycardia, or high-grade heart block. Furthermore, an unusual cause of myocarditis, such as cardiac sarcoidosis, should be suspected in patients who present with chronic heart

al., 2008).

**3.5 Other symptoms** 

the clinical course.

myocarditis.

**5. Electrocardiogram findings** 

**4. Physical examination** 

suggest a possibility of hypersensitivity myocarditis.

Clinical Presentation 9

upper respiratory tract infection before admission occurs in 50 percent of patients (Imazio et

Apart from the nonspecific symptoms recognized like malaise, myalgias and arthralgias, other extracardiac symptoms may identify infectious, toxic agents or autoimmune diseases affecting the heart and resulting in a myocarditis. A viral prodrome of fever, myalgias, and muscle tenderness may precede viral myocarditis, while a delayed hypersensitivity reaction may be first apparent from a cutaneous rash. Rash, fever, peripheral eosinophilia, or a temporal relation with recently initiated medications or the use of multiple medications

The clinical diagnosis of myocarditis is challenging due to its varying presentation, nonspecific symptoms and physical findings. Accordingly, a high level of clinical suspicion is warranted and a presumptive diagnosis usually made based on patient demographics and

The physical examination of patient presented with myocarditis is frequently normal. Mild cases of patients with myocarditis may appear to have a simple viral syndrome. More acutely ill patients with acute myocarditis have the classic signs of circulatory impairment due to congestive heart failure. Patients may shows signs of fluid overload including elevated jugular venous pressure, bibasilar crackles, hepatomegaly, ascites and peripheral edema. More severe cases may show cardiovascular collapse and signs of shock. In addition to the signs of fluid overload, the physical examination may reveal direct evidence of cardiovascular signs in symptomatic patients. Tachypnea and tachycardia are common. Tachycardia is often out of proportion to fever. Cyanosis may occur as well. The apex beat may be diffuse and laterally displaced suggesting cardiomegaly. Heart auscultation may reveal diminished intensity of first heart sound. The third and occasionally fourth heart sound summation gallops may be noted with impaired ventricular function, particularly when biventricular acute myocardial involvement results in systemic and pulmonary congestion. If the right or left ventricular dilatation is severe, auscultation may reveal murmurs of mitral or tricuspid valves regurgitation. Table 1 summarized the most significant clinical manifestations and physical findings in patients presented with

A pericardial friction rub and effusion may become evident in some patients with diffuse inflammation as a result of myopericarditis. Pericardial tamponade was reported in very rare occasions. Pleural friction rub may develop as the inflammatory process involves surrounding structures. In cases where a dilated cardiomyopathy has developed, signs of peripheral or pulmonary thromboembolism may be encountered. Certain physical findings may imply a specific cause of myocarditis. Enlarged lymph nodes might suggest systemic sarcoidosis. A pruritic, maculopapular rash may suggest a hypersensitivity reaction, often to

Generally, the Electrocardiogram (ECG) is a sensitive means in myocarditis. However, its diagnostic value is limited by the low specificity and a wide diversity of changes which

a drug or toxin. Acute rheumatic fever can present with the modified Jones criteria.

failure, dilated cardiomyopathy and new ventricular arrhythmias, or second-degree or third degree heart block or who do not have a response to standard care (Yazaki et al., 1998). In the European Study of the Epidemiology and Treatment of Inflammatory Heart Disease, a 3055 patients with suspected acute or chronic myocarditis were screened, of them 72 percent had dyspnea, 32 percent had chest pain, and 18 percent had arrhythmias (Hufnagel et al., 2000). The most important clinical manifestations in patients with myocarditis are as followed:

#### **3.1 Shortness of breath**

Dyspnea on exertion and fatigue are common. A history of shortness of breath at rest, orthopnea, pedal edema or paroxysmal nocturnal dyspnea is suggestive of congestive heart failure. Dyspnea is due to left ventricular dysfunction causes elevated left ventricular diastolic pressure and low cardiac output.

#### **3.2 Chest pain**

Chest pain is usually associated with concomitant pericarditis. Chest discomfort is reported in one third of patients. The pain is most commonly described as a pleuritic, sharp, stabbing precordial pain. It may be substernal and squeezing and, therefore, difficult to distinguish from that typical of ischemic pain. However, myocarditis can be masquerading as an acute coronary syndrome both clinically and on the electrocardiogram, particularly in younger patients (Angelini et al., 2000). In one series of 34 patients with known normal coronary anatomy presenting with symptoms and electrocardiographic changes consistent with an acute coronary syndrome, 11 (32 percent) of the patients were found to have myocarditis on biopsy (Dec et al., 1992). Sarda et al., using myocardial indium111-labeled antimyosin antibody and rest thallium imaging, identified 35 of 45 patients (78 percent) who presented with acute chest pain, ischemic electrocardiographic abnormalities, and elevated cardiac biomarkers as having diffuse or focal myocarditis. However biopsy verification of actual myocarditis was not undertaken in this series. Complete recovery of left ventricular function occurred at six months in 81 percent of these patients (Sarda et al., 2001). Some presentations of myocarditis, especially those related to parvovirus B19, present like an acute lateral wall myocardial infarction. The ischemia associated with myocarditis may be due to localized inflammation or occasionally, due to coronary artery spasm (McCully et al,. 2005). It is essential for clinicians to consider acute myocarditis in younger patients who present with acute coronary syndromes when coronary risk factors are absent, electrocardiographic abnormalities extend beyond a single coronary artery territory or global rather than segmental left ventricular dysfunction is evident on echocardiography.

#### **3.3 Palpitation, presyncope or syncope**

Palpitation is a common presentation in patient with myocarditis. Presyncope or syncope in a patient with a presentation consistent with myocarditis may be a signal for high-grade atrioventricular block and risk for sudden death. Small focal inflammation in electrically sensitive areas may be the etiology of patients whose initial presentation is sudden death.

#### **3.4 Fever**

Fever with or without sweats and chills occur in 20 percent of patients presenting with myocarditis. A history of fever or flu-like syndrome in form of pharyngitis, tonsillitis, or

failure, dilated cardiomyopathy and new ventricular arrhythmias, or second-degree or third degree heart block or who do not have a response to standard care (Yazaki et al., 1998). In the European Study of the Epidemiology and Treatment of Inflammatory Heart Disease, a 3055 patients with suspected acute or chronic myocarditis were screened, of them 72 percent had dyspnea, 32 percent had chest pain, and 18 percent had arrhythmias (Hufnagel et al., 2000). The most important clinical manifestations in patients with myocarditis are as

Dyspnea on exertion and fatigue are common. A history of shortness of breath at rest, orthopnea, pedal edema or paroxysmal nocturnal dyspnea is suggestive of congestive heart failure. Dyspnea is due to left ventricular dysfunction causes elevated left ventricular

Chest pain is usually associated with concomitant pericarditis. Chest discomfort is reported in one third of patients. The pain is most commonly described as a pleuritic, sharp, stabbing precordial pain. It may be substernal and squeezing and, therefore, difficult to distinguish from that typical of ischemic pain. However, myocarditis can be masquerading as an acute coronary syndrome both clinically and on the electrocardiogram, particularly in younger patients (Angelini et al., 2000). In one series of 34 patients with known normal coronary anatomy presenting with symptoms and electrocardiographic changes consistent with an acute coronary syndrome, 11 (32 percent) of the patients were found to have myocarditis on biopsy (Dec et al., 1992). Sarda et al., using myocardial indium111-labeled antimyosin antibody and rest thallium imaging, identified 35 of 45 patients (78 percent) who presented with acute chest pain, ischemic electrocardiographic abnormalities, and elevated cardiac biomarkers as having diffuse or focal myocarditis. However biopsy verification of actual myocarditis was not undertaken in this series. Complete recovery of left ventricular function occurred at six months in 81 percent of these patients (Sarda et al., 2001). Some presentations of myocarditis, especially those related to parvovirus B19, present like an acute lateral wall myocardial infarction. The ischemia associated with myocarditis may be due to localized inflammation or occasionally, due to coronary artery spasm (McCully et al,. 2005). It is essential for clinicians to consider acute myocarditis in younger patients who present with acute coronary syndromes when coronary risk factors are absent, electrocardiographic abnormalities extend beyond a single coronary artery territory or global rather than

segmental left ventricular dysfunction is evident on echocardiography.

Palpitation is a common presentation in patient with myocarditis. Presyncope or syncope in a patient with a presentation consistent with myocarditis may be a signal for high-grade atrioventricular block and risk for sudden death. Small focal inflammation in electrically sensitive areas may be the etiology of patients whose initial presentation is sudden death.

Fever with or without sweats and chills occur in 20 percent of patients presenting with myocarditis. A history of fever or flu-like syndrome in form of pharyngitis, tonsillitis, or

followed:

**3.2 Chest pain** 

**3.1 Shortness of breath** 

diastolic pressure and low cardiac output.

**3.3 Palpitation, presyncope or syncope** 

**3.4 Fever** 

upper respiratory tract infection before admission occurs in 50 percent of patients (Imazio et al., 2008).
