**6. Clinical manifestation of complications**

Despite the fact that a substantial number of myocarditis are never coming to medical attention, a less frequent form of myocarditis is fulminant and leads rapidly to cardiovascular collapse and shock that required mechanical ventilation support. In contradiction, if these patients survive the first 3-4 weeks of illness they have almost complete recovery and far fewer long term complications compared with those patients with more indolent courses (Chau et al., 2006; Khabbaz et al., 2007). Generally, there are a number of well recognized complications that may encounter in the variety of clinical scenarios of patients with myocarditis.

#### **6.1 Congestive heart failure**

In many patients who develop heart failure, fatigue and decreased exercise capacity are the initial manifestations. However, diffuse, severe myocarditis, if rapid in evolution, can result in acute myocardial failure and cardiogenic shock. Signs of right ventricular failure include increased jugular venous pressure, hepatomegaly, and peripheral edema may supervene. The decline in right ventricular function "protects" the left side of the circulation so that signs of left ventricular failure may not be seen. If, however, there is predominant left ventricular involvement, the patient may present with the symptoms of pulmonary congestion including dyspnea, orthopnea, pulmonary crackles, and, in severe cases, acute pulmonary edema. Patients with persistent viral genome expression show limited recovery of left ventricular function, decreased stroke volume index and more stiffness of the ventricle with the resultant long-term morbidity of heart failure and a mortality of nearly 25 percent (Fuse et al., 2000).

#### **6.2 Arrhythmias**

A number of arrhythmias may be seen during the clinical course of myocarditis. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias, while palpitations secondary to premature atrial or, more often, ventricular premature complexes are common. Ventricular arrhythmias and variable heart blocks are uncommon, but well recognized clinical presentations (Hosenpud et al., 1986; Marboe & Fenoglio et al., 1988). Persistent complex ventricular arrhythmias after apparent resolution of myocarditis were reported in children and young adults as well (Friedman et al., 1994).

observed during the course of disease. The ECG must be timely repeated, since minor

The ECG findings associated with myocarditis may include first, second or third degree atrioventricular block, intraventricular conduction delay (widened QRS complex), bundle branch or fascicle block, reduced R wave height, abnormal Q waves, ST-T segment changes or low voltage. In one report, either ST-segment elevation or T-wave inversion is present as the most sensitive ECG criterion in <50% of patients, even during the first weeks of the disease (Morgera et al., 1992). A gradual increase in the width of the QRS complex may be a sign of exacerbation of myocarditis. Frequent premature beats, supraventricular tachycardia and atrial fibrillation may arise as well. Arrhythmias such as sinus arrest, ventricular tachycardia, ventricular fibrillation or asystole may occur and threaten the life of patients with myocarditis. Hence, continuous ECG monitoring is crucial to detect potentially fatal

Despite the fact that a substantial number of myocarditis are never coming to medical attention, a less frequent form of myocarditis is fulminant and leads rapidly to cardiovascular collapse and shock that required mechanical ventilation support. In contradiction, if these patients survive the first 3-4 weeks of illness they have almost complete recovery and far fewer long term complications compared with those patients with more indolent courses (Chau et al., 2006; Khabbaz et al., 2007). Generally, there are a number of well recognized complications that may encounter in the variety of clinical

In many patients who develop heart failure, fatigue and decreased exercise capacity are the initial manifestations. However, diffuse, severe myocarditis, if rapid in evolution, can result in acute myocardial failure and cardiogenic shock. Signs of right ventricular failure include increased jugular venous pressure, hepatomegaly, and peripheral edema may supervene. The decline in right ventricular function "protects" the left side of the circulation so that signs of left ventricular failure may not be seen. If, however, there is predominant left ventricular involvement, the patient may present with the symptoms of pulmonary congestion including dyspnea, orthopnea, pulmonary crackles, and, in severe cases, acute pulmonary edema. Patients with persistent viral genome expression show limited recovery of left ventricular function, decreased stroke volume index and more stiffness of the ventricle with the resultant long-term morbidity of heart failure and a mortality of nearly 25

A number of arrhythmias may be seen during the clinical course of myocarditis. Sinus tachycardia is more frequent than serious atrial or ventricular arrhythmias, while palpitations secondary to premature atrial or, more often, ventricular premature complexes are common. Ventricular arrhythmias and variable heart blocks are uncommon, but well recognized clinical presentations (Hosenpud et al., 1986; Marboe & Fenoglio et al., 1988). Persistent complex ventricular arrhythmias after apparent resolution of myocarditis were

reported in children and young adults as well (Friedman et al., 1994).

abnormalities detected initially may become subsequently more apparent.

arrhythmias.

**6. Clinical manifestation of complications** 

scenarios of patients with myocarditis.

**6.1 Congestive heart failure** 

percent (Fuse et al., 2000).

**6.2 Arrhythmias** 

Several series have examined the frequency of myocarditis among patients evaluated for life threatening ventricular arrhythmias that occurred in the absence of structural heart disease (Strain et al., 1983; Sugrue et al., 1984; Vignola et al., 1984). These patients tended to be young (younger than 50 years) and to have normal or near-normal left ventricular systolic function. The frequency of syncope or cardiac arrest as reported has ranged from 8 percent to 61 percent (Strain et al., 1983; Sugrue et al., 1984). Biopsy evidence of myocarditis among patients without structural heart disease has ranged from 8 percent to 50 percent. On the other hand, patients with ventricular arrhythmias due to lymphocytic or granulomatous myocarditis stay at higher risk. Sustained ventricular tachycardia or new heart block in the setting of rapidly progressive congestive heart failure suggests giant cell myocarditis. Granulomatous myocarditis has been associated more frequently with life threatening ventricular arrhythmias, syncope, and high-grade atrioventricular block requiring temporary or permanent ventricular pacing than has lymphocytic myocarditis (Davidoff et al., 1991; Fleming & Bailey, 1981; Sekiguchi et al., 1996). Furthermore, granulomatous myocarditis might be suspected in patients who present with apparently chronic dilated cardiomyopathy yet with new ventricular arrhythmias or heart block or who do not have a response to optimal care (Yazaki et al., 1998).

#### **6.3 Sudden cardiac death**

The risk of sudden dysrhythmic death in patients with myocarditis is increasingly appreciated in the current morbidity and mortality data. The discovery of myocarditis in 1 to 9 percent of routine postmortem examinations suggests that myocarditis is a major cause of sudden, unexpected death (Feldman & McNamara, 2000).

Although heart failure and cardiomyopathy are more common clinical presentations, patients with myocarditis may present with syncope or unexpected sudden cardiac death, presumably due to ventricular tachycardia or fibrillation (Drory et al., 1991; Eckart et al., 2004; Maron et al., 2003; Theleman et al., 2001). Myocarditis is a significant cause of sudden, unexpected death in adults younger than age 40 years and elite young athletes. In these presumably healthy individuals, autopsy findings have revealed myocarditis in up to 20 percent of cases (Wesslen et al., 1996). In an autopsy series of patients under age 40 who presented with sudden death in the absence of known heart disease, myocarditis was responsible for 22 percent of cases under age 30 and 11 percent in older subjects (Drory et al., 1991). In another autopsy study of sudden death occurring in 1866competitive athletes, myocarditis was present in 6 percent of the cardiovascular deaths (Maron et al., 2009). In one more series of autopsies in military recruits, myocarditis accounted for 20 percent of deaths due to identifiable structural cardiac abnormalities (Eckart et al., 2004).

#### **6.4 Dilated cardiomyopathy**

A substantial subset of symptomatic cases of postviral or lymphocytic myocarditis present with a syndrome of heart failure and dilated cardiomyopathy. A clinical and pathologic syndrome that is similar to dilated cardiomyopathy (DCM) may develop after resolution of viral myocarditis in animal models and biopsy proven myocarditis in human subjects (Gilbert & Mason, 1987). This has led to speculation that DCM may develop in some individuals as a result of subclinical viral myocarditis. Theoretically, an episode of myocarditis could initiate a variety of autoimmune reactions that injure the myocardium and ultimately result in the development of DCM. These abnormalities in immune

Clinical Presentation 13

is well recognized in patients with acute rheumatic fever. It is also demonstrated in subsequent pregnancies after peripartum cardiomyopathy and recurrence should be suspected if ventricular function subsequently deteriorates (Dec et al., 1985). Women should be counseled to avoid pregnancy after a diagnosis of peripartum cardiomyopathy. Recurrence was also described in giant cell myocarditis in transplanted heart which responded to intensive immunosuppression. History of third time recurrences of active myocarditis proven by endomyocardial biopsy associated with complete atrioventricular block was described as well and viral studies showed no evidence of recent infection (Kanazawa et al., 2004). Another report present recurrent viral myocarditis and vaccineassociated myocarditis in a single patient with complete reversal of the cardiomyopathy and return to normal cardiac function (Makaryus et al., 2006). Moreover, some cases were observed to have recurrent myocarditis after tapering of immunosuppressive therapy and

One report indicated that pericarditis on initial presentation may be associated with a higher rate of recurrence of myocarditis (Fowler et al., 1973). However, in reality, there are no

Specific clinical forms of myocarditis of variable etiologies will be described below. Table 2 summarized some key clinical hints among specific forms of myocarditis that help with the

Amongst the multiple infectious etiologies which have been implicated as the cause of clinically significant acute myocarditis, viral myocarditis being the most common and the enterovirus coxsackie B being the most significant. Numerous seroepidemiologic and molecular studies were linked coxsackievirus B to outbreaks of myocarditis occurred before the 1990s. The spectrum of viruses that were detected in endomyocardial biopsy samples shifted from coxsackievirus B to adenovirus in the late 1990s. In the last decade a number of reports implicate new viruses in the etiology of myocarditis and dilated cardiomyopathy. The parvovirus B19 was identified in patients with myocarditis in Germany (Kühl et al., 2005; Mahrholdt et al., 2006) and hepatitis C virus was reported in Japan (Matsumori 2005,

Early studies suggested that cardiac involvement occurred in 3.5 to 5 percent of patients during outbreaks of coxsackievirus infection (Gerzen et al., 1972; Grist & Bell, 1969). Most cases of enteroviral myocarditis or pericarditis occur in children and young adults in whom more than two-thirds are male. In the majority of patients, active myocarditis remains unsuspected because the subclinical and self-limited pattern of presentation or the presence of myocarditis may infer only by the finding of transient electrocardiographic ST-T-wave abnormalities. In addition, subtle cardiac symptoms and signs may be overshadowed by the systemic manifestations of the underlying infection or disease process. Clinically, the patients give a history of a preceding upper respiratory febrile illness or a flu-like syndrome, and viral nasopharyngitis or tonsillitis may be evident. In the United States Myocarditis Treatment Trial, 89 percent of subjects reported a syndrome consistent with a viral prodrome (Mason et al., 1995). The patient may also have fever, myalgias, and muscle tenderness that is followed by chest pain, dyspnea or arrhythmias, and occasionally heart

previous biopsy specimens showing healed myocarditis.

**7. Manifestations of specific forms of myocarditis** 

clinical diagnosis

2006) as well.

**7.1 Viral myocarditis** 

reliable predictors that identify patients likely to have recurrence.

regulation and the variety of antimyocardial antibodies present in DCM are consistent with this hypothesis. Enteroviral RNA sequences may be found in heart biopsy samples in DCM but with a very variable frequency (0–30 percent), (Bowles et al., 1986; Giacca et al., 1994). Furthermore, analysis of human viruses other than enteroviruses suggests that adenoviruses, herpes, and cytomegalovirus can also cause myocarditis and potentially DCM, particularly in children and young subjects (Martin et al., 1994; Pauschinger et al., 1999).

In most acute cases of lymphocytic myocarditis, left ventricular function improves over one to six months with standard heart failure care. However a substantial minority will develop a persistent inflammation that leads to chronic cardiomyopathy. In the patients who develop chronic cardiomyopathy, the risk of heart transplantation and death is high. In a large review of 1230 cases of initially unexplained cardiomyopathy, 9 percent were thought to be due to myocarditis (Felker et al., 2000). A similar prevalence of 10 percent was noted in the Myocarditis Treatment Trial in which endomyocardial biopsy was performed in over 2200 patients with unexplained heart failure of less than two years duration (Mason et al., 1995).

#### **6.5 Thromboembolism**

Thromboembolism, arterial and venous, is more evident in patients with left ventricular dysfunction, and appears to be quite frequent complication in certain forms of myocarditis and cardiomyopathies. Additionally, the risk of thromboembolism from either tissue or thrombus from the biopsy site is higher in left ventricular biopsy. Right-sided thromboembolism can be due to thrombus from the venous access sheath especially with the internal jugular approach. The possibility of some small added diagnostic yield by taking biopsy samples of the left ventricle in addition to the right is outweighed by the small attendant risk of systemic embolism.

Thromboembolism is frequent in advanced Chagas disease, and its occurrence is probably underestimated (Bestetti, 2000; Samuel et al., 1983). At autopsy, 73 percent of patients have left or right ventricular mural thrombi, with evidence of pulmonary or systemic embolization in 60 percent (Arteaga-Fernandez et al., 1989). The apical aneurysm typical of Chagas disease is particularly prone to the formation of thrombi and is associated with a high incidence of thromboembolic events (Fernandes et al., 1987). Furthermore, there is a high incidence of thromboembolism in population with peripartum cardiomyopathy. Thrombi are the result of the hypercoagulable state of pregnancy and of stasis and turbulent flow in the dilated heart. Thrombi often form in patients with lower left ventricular ejection fraction (<35 percent), (Amos et al., 2006; Sliwa et al., 2006). Higher mortality rates have been reported to be due to thromboembolism as well (Ford et al., 2000).

#### **6.6 Recurrent myocarditis**

The clinical course of myocarditis in the majority of patients is self-limited and there is complete resolution of myocardial inflammation without further relapse or sequelae. However, the disease has been observed to recur in a similar scenario to initial presentation, which then may resolve spontaneously or be associated with heart failure, arrhythmias, or death. Chronic myocarditis may be considered to be one of the mechanisms of the process of recurrence. Recurrence was reported to in 10 to 25 percent of patients after apparent resolution of the initial illness (Daly et al., 1984; Dec et al., 1985). Recurrence of myocarditis

regulation and the variety of antimyocardial antibodies present in DCM are consistent with this hypothesis. Enteroviral RNA sequences may be found in heart biopsy samples in DCM but with a very variable frequency (0–30 percent), (Bowles et al., 1986; Giacca et al., 1994). Furthermore, analysis of human viruses other than enteroviruses suggests that adenoviruses, herpes, and cytomegalovirus can also cause myocarditis and potentially DCM, particularly in children and young subjects (Martin et al., 1994; Pauschinger et al.,

In most acute cases of lymphocytic myocarditis, left ventricular function improves over one to six months with standard heart failure care. However a substantial minority will develop a persistent inflammation that leads to chronic cardiomyopathy. In the patients who develop chronic cardiomyopathy, the risk of heart transplantation and death is high. In a large review of 1230 cases of initially unexplained cardiomyopathy, 9 percent were thought to be due to myocarditis (Felker et al., 2000). A similar prevalence of 10 percent was noted in the Myocarditis Treatment Trial in which endomyocardial biopsy was performed in over 2200 patients with unexplained heart failure of less than two years duration (Mason et al.,

Thromboembolism, arterial and venous, is more evident in patients with left ventricular dysfunction, and appears to be quite frequent complication in certain forms of myocarditis and cardiomyopathies. Additionally, the risk of thromboembolism from either tissue or thrombus from the biopsy site is higher in left ventricular biopsy. Right-sided thromboembolism can be due to thrombus from the venous access sheath especially with the internal jugular approach. The possibility of some small added diagnostic yield by taking biopsy samples of the left ventricle in addition to the right is outweighed by the small

Thromboembolism is frequent in advanced Chagas disease, and its occurrence is probably underestimated (Bestetti, 2000; Samuel et al., 1983). At autopsy, 73 percent of patients have left or right ventricular mural thrombi, with evidence of pulmonary or systemic embolization in 60 percent (Arteaga-Fernandez et al., 1989). The apical aneurysm typical of Chagas disease is particularly prone to the formation of thrombi and is associated with a high incidence of thromboembolic events (Fernandes et al., 1987). Furthermore, there is a high incidence of thromboembolism in population with peripartum cardiomyopathy. Thrombi are the result of the hypercoagulable state of pregnancy and of stasis and turbulent flow in the dilated heart. Thrombi often form in patients with lower left ventricular ejection fraction (<35 percent), (Amos et al., 2006; Sliwa et al., 2006). Higher mortality rates have

The clinical course of myocarditis in the majority of patients is self-limited and there is complete resolution of myocardial inflammation without further relapse or sequelae. However, the disease has been observed to recur in a similar scenario to initial presentation, which then may resolve spontaneously or be associated with heart failure, arrhythmias, or death. Chronic myocarditis may be considered to be one of the mechanisms of the process of recurrence. Recurrence was reported to in 10 to 25 percent of patients after apparent resolution of the initial illness (Daly et al., 1984; Dec et al., 1985). Recurrence of myocarditis

been reported to be due to thromboembolism as well (Ford et al., 2000).

1999).

1995).

**6.5 Thromboembolism** 

attendant risk of systemic embolism.

**6.6 Recurrent myocarditis** 

is well recognized in patients with acute rheumatic fever. It is also demonstrated in subsequent pregnancies after peripartum cardiomyopathy and recurrence should be suspected if ventricular function subsequently deteriorates (Dec et al., 1985). Women should be counseled to avoid pregnancy after a diagnosis of peripartum cardiomyopathy. Recurrence was also described in giant cell myocarditis in transplanted heart which responded to intensive immunosuppression. History of third time recurrences of active myocarditis proven by endomyocardial biopsy associated with complete atrioventricular block was described as well and viral studies showed no evidence of recent infection (Kanazawa et al., 2004). Another report present recurrent viral myocarditis and vaccineassociated myocarditis in a single patient with complete reversal of the cardiomyopathy and return to normal cardiac function (Makaryus et al., 2006). Moreover, some cases were observed to have recurrent myocarditis after tapering of immunosuppressive therapy and previous biopsy specimens showing healed myocarditis.

One report indicated that pericarditis on initial presentation may be associated with a higher rate of recurrence of myocarditis (Fowler et al., 1973). However, in reality, there are no reliable predictors that identify patients likely to have recurrence.
