**7.3.5 Legionella myocarditis**

Myocardial involvement is a rare manifestation of Legionella infection, though, the most common extrapulmonary site of Legionnaires' disease is the heart. Numerous reports have described myocarditis, pericarditis, postcardiotomy syndrome, and prosthetic valve endocarditis (Antonarakis et al., 2006; Lowry & Tompkins, 1993; Tompkins et al., 1988). Most cases have been hospital acquired. Legionella carditis in the adult population is invariably seen in association of pneumonia, however, isolated Legionella myocardial involvement without associated pneumonia have been reported (Burke et al., 2009).

## **7.3.6 Mycoplasma myocarditis**

Cardiac abnormalities rarely reported in conjunction with *Mycoplasma pneumoniae* infection including myocarditis and pericarditis (Martin & Bates, 1991; Paz & Potasman, 2002).

Clinical Presentation 21

rheumatic carditis does not show significant evidence of myocyte damage (Narula et al., 1993). In addition, echocardiographic left ventricular ejection fraction and indices of myocardial contractility remain normal in patients with rheumatic carditis even in the presence of CHF (Essop et al., 1993). Further, CHF occurs only in the presence of

The diagnosis of ARF is established largely on clinical grounds. The clinical manifestations initially described by Jones (Jones, 1944). Subsequently revised and lastly the established guidelines for the diagnosis of rheumatic fever reviewed by the American Heart Association Working Group in 2002 (Ferrieri, 2002). The five major manifestations include migratory arthritis, carditis and valvulitis, central nervous system involvement (eg, Sydenham chorea), erythema marginatum and subcutaneous nodules. Whereas, the four minor manifestations include, arthralgia, fever, elevated acute phase reactants (erythrocyte sedimentation rate, Creactive protein) and prolonged PR interval. The probability of ARF is high in the setting of group A streptococcal infection followed by two major manifestations or one major and two minor manifestations. Strict adherence to the Jones criteria in areas of high prevalence may result in under detection of the disease. This was illustrated in a report of 555 cases of confirmed ARF among Australian aboriginals in whom monoarthritis and low-grade fever

Chagas disease is a protozoan infection due to *Trypanosoma cruzi*; transmitted by an insect vector, produces an extensive myocarditis that typically becomes evident years after the initial infection. It is a major public health problem in endemic areas and in immigrants from rural Central or South America. Chagas myocarditis is by far the most common form of cardiomyopathy in Latin American countries (Schofield & Dias, 1991). Chagas disease consists of acute and chronic phases. During the chronic phase, many patients present the indeterminate form. The latter describes patients who have positive serology, but no

The first signs of acute Chagas' disease develop at least 1 week after contact with the infected vector. Local skin indurated erythema and swelling produces the typical portal of entry lesions at the skin known as chagomas accompanied by local lymphadenopathy. The conjunctiva portal of entry may result in a unilateral painless periorbital edema and swelling of the palpebrae (Romana's sign). Infection can also occur through blood transfusion, congenital transmission, and, much less often, organ transplantation, laboratory accident, breast feeding, and oral contamination (Benchimol Barbosa, 2006). Although heart transplantation for Chagas cardiomyopathy has been successfully performed, reactivation of *Trypanosoma cruzi* is common. These initial local signs may be followed by malaise, fever sweating, myalgias anorexia, and a morbilliform rash may also appear. Generalized lymphadenopathy and hepatosplenomegaly may develop. Cardiac failure occur secondary to myocarditis; cardiac involvement is present in over 90 percent of those in whom the diagnosis is made (Pinto et al., 2004). The frequency and severity of myocarditis are inversely proportional to age (Dias & Kloetzel, 1968). The acute symptoms resolve spontaneously in virtually all patients, who then enter the asymptomatic or indeterminate phase of chronic T. cruzi infection. The electrocardiogram normalized in over 90 percent of

symptoms, physical signs, or laboratory evidence of organ involvement (Dias, 1989).

hemodynamically significant valvular lesions.

were important manifestations (Carapetis & Currie, 2001).

**7.5 Chagas myocarditis** 

**7.5.1 Acute phase** 

patients after one year.

Myocarditis has been described in rare autopsy reports as well. Cardiac manifestations include rhythm disturbances, congestive heart failure, chest pain, and conduction abnormalities on the electrocardiogram.

#### **7.3.7 Q fever myocarditis**

Myocarditis, though uncommon, may be a particularly severe manifestation of Q fever. A study of 1070 patients with acute Q fever from southern France, 1 percent had pericarditis, and 1 percent had myocarditis. In other series of 1276 patients with Q fever over a 15-year period, only eight developed myocarditis but two were among only 12 total patients with Q fever who died (Fournier et al., 2001). Q fever may also cause endocarditis which usually occurs in patients with previous valvular damage or immunocompromise particularly a bicuspid aortic valve or a prosthetic valve.

#### **7.3.8 Chlamydial myocarditis**

Chlamydial infection also has been reported in association with clinical manifestations of myocarditis (Mavrogeni et al., 2008).

#### **7.3.9 Relapsing fever myocarditis**

Relapsing fever is an arthropod-borne infection characterized by recurrent episodes of fever, caused by spirochetes of the genus Borrelia. The first episode of illness tends to be the most severe. Myocarditis appears to be common in both louse-borne and tick-borne relapsing fever. Clinical and electrocardiographic evidence of myocarditis and myocardial dysfunction includes a prolonged QTc interval, commonly a galloping third heart sound, elevated central venous pressure, arterial hypotension, and rare pulmonary congestion. Heart involvement has been prominent in fatal cases (Wengrower et al., 1984).

#### **7.4 Acute rheumatic fever**

Acute rheumatic fever (ARF) is a nonsuppurative complication of group A streptococcus pharyngitis that occurs two to four weeks following infection and arises as an autoimmune response to extracellular or somatic bacterial antigens that share similar epitopes in human tissue. Rheumatic fever remains one of the most important cardiovascular diseases that cause significant cardiac morbidity and mortality in developing countries (Hutchison, 1998). In developed countries, ARF is generally preceded by pharyngitis but not skin infection (Guidelines for the diagnosis of rheumatic fever, JAMA 1992). However, data from endemic regions with ARF and rheumatic heart disease suggest a less clear association (McDonald et al., 2004, 2006; Noel et al., 2005).

Acute rheumatic fever occurs most frequently in children from 5 to 15 years of age. The incidence of rheumatic heart disease in patients with a history of ARF is variable; in general, valvular damage manifesting as a murmur later in life is likely to occur in about 50 percent of patients with evidence of carditis at initial presentation (Albert et al., 1995; Meira et al., 2005). The myocardial lesions consist of nonspecific lymphocytic myocarditis and Aschoff nodules. The latter are pathognomonic of ARF. Myocarditis is often indicated by cardiomegaly and/or congestive heart failure (CHF) particularly in the absence of a significant pericardial effusion. The presence of valvulitis is established clinically by auscultatory findings. Although CHF in rheumatic fever patients traditionally has been ascribed to severe myocardial inflammation, endomycardial biopsy in patients with

Myocarditis has been described in rare autopsy reports as well. Cardiac manifestations include rhythm disturbances, congestive heart failure, chest pain, and conduction

Myocarditis, though uncommon, may be a particularly severe manifestation of Q fever. A study of 1070 patients with acute Q fever from southern France, 1 percent had pericarditis, and 1 percent had myocarditis. In other series of 1276 patients with Q fever over a 15-year period, only eight developed myocarditis but two were among only 12 total patients with Q fever who died (Fournier et al., 2001). Q fever may also cause endocarditis which usually occurs in patients with previous valvular damage or immunocompromise particularly a

Chlamydial infection also has been reported in association with clinical manifestations of

Relapsing fever is an arthropod-borne infection characterized by recurrent episodes of fever, caused by spirochetes of the genus Borrelia. The first episode of illness tends to be the most severe. Myocarditis appears to be common in both louse-borne and tick-borne relapsing fever. Clinical and electrocardiographic evidence of myocarditis and myocardial dysfunction includes a prolonged QTc interval, commonly a galloping third heart sound, elevated central venous pressure, arterial hypotension, and rare pulmonary congestion.

Acute rheumatic fever (ARF) is a nonsuppurative complication of group A streptococcus pharyngitis that occurs two to four weeks following infection and arises as an autoimmune response to extracellular or somatic bacterial antigens that share similar epitopes in human tissue. Rheumatic fever remains one of the most important cardiovascular diseases that cause significant cardiac morbidity and mortality in developing countries (Hutchison, 1998). In developed countries, ARF is generally preceded by pharyngitis but not skin infection (Guidelines for the diagnosis of rheumatic fever, JAMA 1992). However, data from endemic regions with ARF and rheumatic heart disease suggest a less clear association (McDonald et

Acute rheumatic fever occurs most frequently in children from 5 to 15 years of age. The incidence of rheumatic heart disease in patients with a history of ARF is variable; in general, valvular damage manifesting as a murmur later in life is likely to occur in about 50 percent of patients with evidence of carditis at initial presentation (Albert et al., 1995; Meira et al., 2005). The myocardial lesions consist of nonspecific lymphocytic myocarditis and Aschoff nodules. The latter are pathognomonic of ARF. Myocarditis is often indicated by cardiomegaly and/or congestive heart failure (CHF) particularly in the absence of a significant pericardial effusion. The presence of valvulitis is established clinically by auscultatory findings. Although CHF in rheumatic fever patients traditionally has been ascribed to severe myocardial inflammation, endomycardial biopsy in patients with

Heart involvement has been prominent in fatal cases (Wengrower et al., 1984).

abnormalities on the electrocardiogram.

bicuspid aortic valve or a prosthetic valve.

**7.3.8 Chlamydial myocarditis** 

myocarditis (Mavrogeni et al., 2008).

**7.3.9 Relapsing fever myocarditis** 

**7.4 Acute rheumatic fever** 

al., 2004, 2006; Noel et al., 2005).

**7.3.7 Q fever myocarditis** 

rheumatic carditis does not show significant evidence of myocyte damage (Narula et al., 1993). In addition, echocardiographic left ventricular ejection fraction and indices of myocardial contractility remain normal in patients with rheumatic carditis even in the presence of CHF (Essop et al., 1993). Further, CHF occurs only in the presence of hemodynamically significant valvular lesions.

The diagnosis of ARF is established largely on clinical grounds. The clinical manifestations initially described by Jones (Jones, 1944). Subsequently revised and lastly the established guidelines for the diagnosis of rheumatic fever reviewed by the American Heart Association Working Group in 2002 (Ferrieri, 2002). The five major manifestations include migratory arthritis, carditis and valvulitis, central nervous system involvement (eg, Sydenham chorea), erythema marginatum and subcutaneous nodules. Whereas, the four minor manifestations include, arthralgia, fever, elevated acute phase reactants (erythrocyte sedimentation rate, Creactive protein) and prolonged PR interval. The probability of ARF is high in the setting of group A streptococcal infection followed by two major manifestations or one major and two minor manifestations. Strict adherence to the Jones criteria in areas of high prevalence may result in under detection of the disease. This was illustrated in a report of 555 cases of confirmed ARF among Australian aboriginals in whom monoarthritis and low-grade fever were important manifestations (Carapetis & Currie, 2001).

### **7.5 Chagas myocarditis**

Chagas disease is a protozoan infection due to *Trypanosoma cruzi*; transmitted by an insect vector, produces an extensive myocarditis that typically becomes evident years after the initial infection. It is a major public health problem in endemic areas and in immigrants from rural Central or South America. Chagas myocarditis is by far the most common form of cardiomyopathy in Latin American countries (Schofield & Dias, 1991). Chagas disease consists of acute and chronic phases. During the chronic phase, many patients present the indeterminate form. The latter describes patients who have positive serology, but no symptoms, physical signs, or laboratory evidence of organ involvement (Dias, 1989).

#### **7.5.1 Acute phase**

The first signs of acute Chagas' disease develop at least 1 week after contact with the infected vector. Local skin indurated erythema and swelling produces the typical portal of entry lesions at the skin known as chagomas accompanied by local lymphadenopathy. The conjunctiva portal of entry may result in a unilateral painless periorbital edema and swelling of the palpebrae (Romana's sign). Infection can also occur through blood transfusion, congenital transmission, and, much less often, organ transplantation, laboratory accident, breast feeding, and oral contamination (Benchimol Barbosa, 2006). Although heart transplantation for Chagas cardiomyopathy has been successfully performed, reactivation of *Trypanosoma cruzi* is common. These initial local signs may be followed by malaise, fever sweating, myalgias anorexia, and a morbilliform rash may also appear. Generalized lymphadenopathy and hepatosplenomegaly may develop. Cardiac failure occur secondary to myocarditis; cardiac involvement is present in over 90 percent of those in whom the diagnosis is made (Pinto et al., 2004). The frequency and severity of myocarditis are inversely proportional to age (Dias & Kloetzel, 1968). The acute symptoms resolve spontaneously in virtually all patients, who then enter the asymptomatic or indeterminate phase of chronic T. cruzi infection. The electrocardiogram normalized in over 90 percent of patients after one year.

Clinical Presentation 23

and variation in the QT interval (QT dispersion) are frequent findings (Salles et al., 2003).Virtually all types of atrial and ventricular arrhythmias occur frequently, atrial

A potentially serious complication of chronic Chagas heart disease is thromboembolism. In a review of 1345 autopsies, cardiac thrombus or thromboemboli reported in 44 percent; both right and left cardiac chambers equally affected (Samuel et al., 1983). Although thromboembolic phenomena were more common in the systemic circulation, pulmonary embolism accounted for 14 percent of deaths. Cardioembolism appears to be an important cause of acute ischemic stroke. One series of 94 patients with Chagas disease in Brazil reported higher rate of cardioembolism (56 versus 9 percent) as compared to control group (Carod-Artal et al., 2005). Stroke was also reported significantly more frequent in patients who had Chagas disease related cardiomyopathy compared with patients who had other cardiomyopathies (15.0 versus 6.3 percent), (Oliveira-Filho et al., 2005). Echocardiography or contrast ventriculography may reveal a left ventricular apical aneurysm, regional wall motion abnormalities,or diffuse cardiomyopathy. The cause of death is either intractable

CHF or an arrhythmia, with a minority of patients dying from embolic phenomena.

involve the heart. Rarely Cryptococcus identified as a cause of myocarditis as well.

The association between eosinophilia (eosinophil count >500/mm3) and heart disease was first identified by Loeffler (Loeffler, 1936). A specific eosinophilic form of myocarditis identified following drug-induced hypersensitivity reactions and systemic

Eosinophilic myocarditis is characterized by a predominantly mature eosinophils infiltration of the myocardium and other organ systems. It occurs in association with systemic diseases such as hypereosinophilic syndrome, Churg-Strauss syndrome and Löffler's endomyocardial fibrosis. Also it may occur in association with cancer, parasitic, helminthic or protozoal infections such as Chagas disease, toxoplasmosis, schistosomiasis, trichinosis, hyatid cysts and visceral larval migrans (Corradi et al., 2004; Corssmit et al., 1999; Spodick, 1997). Eosinophilic myocarditis has been reported after vaccination for several diseases, including smallpox (Arness et al., 2004; Barton et al., 2008). Acute eosinophilic necrotizing myocarditis is a rare aggressive form of eosinophilic myocarditis and may represent an extreme form of hypersensitivity myocarditis which characterized by acute onset and rapidly results in cardiovascular deterioration and circulatory collapse carried high mortality rates (Cooper & Zehr, 2005). The clinical manifestations of eosinophilic myocarditis may include right and left congestive heart failure, endocardial and valvular

**7.7 Eosinophilic and hypersensitivity myocarditis** 

hypereosinophilic syndromes (Taliercio et al., 1985).

The incidence of invasive fungal disease has dramatically increased over the past few decades corresponding to the rising number of immunocompromised patients. Cardiac fungal infection, especially myocarditis, may be difficult to recognize clinically and may in itself produce a fatal outcome. Myocardial involvement frequently occurs in disseminated fungal infection in which multiple organs often affected. Conditions that appear predisposing to fungal infection are human immunodeficiency virus infection, medication like, corticosteroids, antineoplastic agents or broad-spectrum antibiotics, alone or in combination with invasive medical procedures (Nosanchuk, 2002). Candida was the most frequently observed organism, while Aspergillus was the second most frequent fungus to

**7.6 Fungal myocarditis** 

fibrillation and low QRS voltage may be observed in advanced disease.

The indeterminate form usually lasts 10 to 30 years and only approximately 30 percent of the patients develop overt cardiac disease. Most patients remain asymptomatic throughout life. The natural history of this phase of disease is characterized by subtle degree of cardiac involvement and gradual appearance of clinical or electrocardiographic markers of cardiac involvement, which signals the onset of the chronic phase. In one review, progression from indeterminate to the full-blown clinical form in the chronic phase occurred at approximately 2 percent per year (Dias, 1989). In another report, 38.3 percent of patients with positive serology but without symptoms developed chagasic cardiomyopathy over a 10-year period (Coura et al., 1985). About 50 percent of patients remain with the indeterminate form indefinitely (Marin-Neto et al., 2003).

#### **7.5.2 Chronic phase**

The chronic form is characterized by dilatation of several cardiac chambers, fibrosis and thinning of the ventricular wall, aneurysm formation (especially at the left ventricular apex), and mural thrombi.

Chronic progressive heart failure is the rule and is associated with poor survival. Mortality associated with the chronic phase almost exclusively due to cardiovascular involvement. The cause of death is sudden cardiac death in 55 to 65 percent, progressive heart failure in 25 to 30 percent, and stroke in 10 to 15 percent (Rassi et al., 2001). Symptoms and physical signs at this stage of the disease arise from three basic syndromes that often coexist in the same patient, heart failure, cardiac dysrhythmia, and thromboembolism (systemic and pulmonary). Heart failure in Chagas heart disease is usually biventricular and commonly presented with fatigue. However, right-sided failure manifested with increased jugular venous pressure, peripheral edema, ascites, and hepatomegaly is characteristically more pronounced than those of left-sided failure manifested with dyspnea and pulmonary rales. Both systolic and diastolic dysfunction can occur (Sousa et al., 1988). Cardiac examination typically reveals the findings of murmurs of mitral and tricuspid regurgitation, wide splitting of the second heart sound due to right bundle branch block and prominent diffuse apical thrust.

Cardiac arrhythmias may cause palpitation, lightheadedness, dizziness, or syncope. Autonomic dysfunction results in marked abnormalities in the heart rate changes. Chest pain is common symptom and usually atypical in Chagas heart disease. It may mimic angina due to abnormal coronary vasomotion postulated as underlying mechanism (Marin-Neto et al., 1992). Sudden cardiac death accounts for 55 to 65 percent of deaths in CD; the real frequency of this complication is probably underestimated, particularly in rural areas (Rassi et al., 2001). Sudden cardiac arrest can occur even in previously asymptomatic patients (Rassi Júnior et al., 1995). However, most patients have severe underlying heart disease, including ventricular aneurysms at multiple sites (posterior-lateral, inferior basal, or apical), which is a characteristic finding in Chagas heart disease (Rassi Júnior et al., 1995). Sudden death is usually precipitated by exercise, and can be caused by VT or fibrillation, asystole, or complete AV block (Mendoza et al., 1986). The electrocardiogram is abnormal in most patients with cardiac involvement and typically shows right bundle branch block, left anterior hemiblock and diffuse ST-T changes, which may progress to complete atrioventricular block.Ventricular arrhythmia may also be seen in form of premature beats that may be multiform and runs of nonsustained ventricular tachycardia. The severity of ventricular arrhythmias tends to correlate with the degree of LV dysfunction. Other changes like, abnormal Q waves, various degrees of atrioventricular block, QT interval prolongation

The indeterminate form usually lasts 10 to 30 years and only approximately 30 percent of the patients develop overt cardiac disease. Most patients remain asymptomatic throughout life. The natural history of this phase of disease is characterized by subtle degree of cardiac involvement and gradual appearance of clinical or electrocardiographic markers of cardiac involvement, which signals the onset of the chronic phase. In one review, progression from indeterminate to the full-blown clinical form in the chronic phase occurred at approximately 2 percent per year (Dias, 1989). In another report, 38.3 percent of patients with positive serology but without symptoms developed chagasic cardiomyopathy over a 10-year period (Coura et al., 1985). About 50 percent of patients remain with the indeterminate form

The chronic form is characterized by dilatation of several cardiac chambers, fibrosis and thinning of the ventricular wall, aneurysm formation (especially at the left ventricular apex),

Chronic progressive heart failure is the rule and is associated with poor survival. Mortality associated with the chronic phase almost exclusively due to cardiovascular involvement. The cause of death is sudden cardiac death in 55 to 65 percent, progressive heart failure in 25 to 30 percent, and stroke in 10 to 15 percent (Rassi et al., 2001). Symptoms and physical signs at this stage of the disease arise from three basic syndromes that often coexist in the same patient, heart failure, cardiac dysrhythmia, and thromboembolism (systemic and pulmonary). Heart failure in Chagas heart disease is usually biventricular and commonly presented with fatigue. However, right-sided failure manifested with increased jugular venous pressure, peripheral edema, ascites, and hepatomegaly is characteristically more pronounced than those of left-sided failure manifested with dyspnea and pulmonary rales. Both systolic and diastolic dysfunction can occur (Sousa et al., 1988). Cardiac examination typically reveals the findings of murmurs of mitral and tricuspid regurgitation, wide splitting of the second heart sound due to right bundle branch block and prominent diffuse

Cardiac arrhythmias may cause palpitation, lightheadedness, dizziness, or syncope. Autonomic dysfunction results in marked abnormalities in the heart rate changes. Chest pain is common symptom and usually atypical in Chagas heart disease. It may mimic angina due to abnormal coronary vasomotion postulated as underlying mechanism (Marin-Neto et al., 1992). Sudden cardiac death accounts for 55 to 65 percent of deaths in CD; the real frequency of this complication is probably underestimated, particularly in rural areas (Rassi et al., 2001). Sudden cardiac arrest can occur even in previously asymptomatic patients (Rassi Júnior et al., 1995). However, most patients have severe underlying heart disease, including ventricular aneurysms at multiple sites (posterior-lateral, inferior basal, or apical), which is a characteristic finding in Chagas heart disease (Rassi Júnior et al., 1995). Sudden death is usually precipitated by exercise, and can be caused by VT or fibrillation, asystole, or complete AV block (Mendoza et al., 1986). The electrocardiogram is abnormal in most patients with cardiac involvement and typically shows right bundle branch block, left anterior hemiblock and diffuse ST-T changes, which may progress to complete atrioventricular block.Ventricular arrhythmia may also be seen in form of premature beats that may be multiform and runs of nonsustained ventricular tachycardia. The severity of ventricular arrhythmias tends to correlate with the degree of LV dysfunction. Other changes like, abnormal Q waves, various degrees of atrioventricular block, QT interval prolongation

indefinitely (Marin-Neto et al., 2003).

**7.5.2 Chronic phase** 

and mural thrombi.

apical thrust.

and variation in the QT interval (QT dispersion) are frequent findings (Salles et al., 2003).Virtually all types of atrial and ventricular arrhythmias occur frequently, atrial fibrillation and low QRS voltage may be observed in advanced disease.

A potentially serious complication of chronic Chagas heart disease is thromboembolism. In a review of 1345 autopsies, cardiac thrombus or thromboemboli reported in 44 percent; both right and left cardiac chambers equally affected (Samuel et al., 1983). Although thromboembolic phenomena were more common in the systemic circulation, pulmonary embolism accounted for 14 percent of deaths. Cardioembolism appears to be an important cause of acute ischemic stroke. One series of 94 patients with Chagas disease in Brazil reported higher rate of cardioembolism (56 versus 9 percent) as compared to control group (Carod-Artal et al., 2005). Stroke was also reported significantly more frequent in patients who had Chagas disease related cardiomyopathy compared with patients who had other cardiomyopathies (15.0 versus 6.3 percent), (Oliveira-Filho et al., 2005). Echocardiography or contrast ventriculography may reveal a left ventricular apical aneurysm, regional wall motion abnormalities,or diffuse cardiomyopathy. The cause of death is either intractable CHF or an arrhythmia, with a minority of patients dying from embolic phenomena.

### **7.6 Fungal myocarditis**

The incidence of invasive fungal disease has dramatically increased over the past few decades corresponding to the rising number of immunocompromised patients. Cardiac fungal infection, especially myocarditis, may be difficult to recognize clinically and may in itself produce a fatal outcome. Myocardial involvement frequently occurs in disseminated fungal infection in which multiple organs often affected. Conditions that appear predisposing to fungal infection are human immunodeficiency virus infection, medication like, corticosteroids, antineoplastic agents or broad-spectrum antibiotics, alone or in combination with invasive medical procedures (Nosanchuk, 2002). Candida was the most frequently observed organism, while Aspergillus was the second most frequent fungus to involve the heart. Rarely Cryptococcus identified as a cause of myocarditis as well.

#### **7.7 Eosinophilic and hypersensitivity myocarditis**

The association between eosinophilia (eosinophil count >500/mm3) and heart disease was first identified by Loeffler (Loeffler, 1936). A specific eosinophilic form of myocarditis identified following drug-induced hypersensitivity reactions and systemic hypereosinophilic syndromes (Taliercio et al., 1985).

Eosinophilic myocarditis is characterized by a predominantly mature eosinophils infiltration of the myocardium and other organ systems. It occurs in association with systemic diseases such as hypereosinophilic syndrome, Churg-Strauss syndrome and Löffler's endomyocardial fibrosis. Also it may occur in association with cancer, parasitic, helminthic or protozoal infections such as Chagas disease, toxoplasmosis, schistosomiasis, trichinosis, hyatid cysts and visceral larval migrans (Corradi et al., 2004; Corssmit et al., 1999; Spodick, 1997). Eosinophilic myocarditis has been reported after vaccination for several diseases, including smallpox (Arness et al., 2004; Barton et al., 2008). Acute eosinophilic necrotizing myocarditis is a rare aggressive form of eosinophilic myocarditis and may represent an extreme form of hypersensitivity myocarditis which characterized by acute onset and rapidly results in cardiovascular deterioration and circulatory collapse carried high mortality rates (Cooper & Zehr, 2005). The clinical manifestations of eosinophilic myocarditis may include right and left congestive heart failure, endocardial and valvular

Clinical Presentation 25

ventricular tachycardia, heart block, and a downhill clinical course, despite optimal clinical care. In the series of 63 patients with giant cell myocarditis enrolled in the multicenter Giant Cell Myocarditis Treatment Trial, 75 percent identified with heart failure symptoms as the primary presentation, 14 percent with ventricular arrhythmia and heart block in 5 percent (Cooper et al., 1997). Most patients will require cardiac transplantation, the median survival from the onset of symptoms of less than 6 months and has an 89 percent rate of death or transplantation. This represents a significantly worse outcome compared to lymphocytic or viral myocarditis. Despite a 25 percent incidence of post-transplantation recurrence of giant cell myocarditis detected by biopsy, the 5-year survival after transplantation is about 71

percent which is comparable to survival after transplantation for cardiomyopathy.

Acute myocarditis is an uncommon manifestation of systemic lupus erythematosus (SLE), with a prevalence of 8 to 25 percent in different studies (Apte et al., 2008; Mandell, 1987). Myocarditis frequently asymptomatic but less often may accompany other manifestations of acute SLE. In particular pericarditis, commonly occur in about two-thirds of patients, and generally follows a benign course, however tamponade or constriction may occur

Myocarditis generally parallels the activity of the disease and, although common histologically, rarely results in clinical heart failure unless associated with hypertension. African American ethnicity is associated with a higher risk of myocarditis compared with Hispanic and Caucasian ethnicity (Apte et al., 2008). Myocarditis should be suspected if there is resting tachycardia disproportionate to body temperature, ST and T wave electrocardiographic abnormalities and unexplained cardiomegaly. The cardiomegaly may be associated with symptoms and signs of heart failure, conduction abnormalities or arrhythmias (Moder et al., 1999). Patients with SLE are at increased risk for myocardial ischemia due to accelerated atherosclerosis or coronary arteritis. Endocardial involvement with fibrinous endocarditis (Libman & Sachs, 1924) is another serious manifestation can lead to valvular insufficiencies or embolic events. Likewise patients with the antiphospholipid syndrome have a higher incidence of valvular disease, a variety of thrombotic disorders, myocardial infarction, pulmonary hypertension, and cardiomyopathy. Myocardial biopsy reveal mononuclear cells infiltration distinguish active myocarditis from fibrosis and other causes of cardiomyopathy (Schattner & Liang, 2003) or rarely cardiotoxicity induced by hydroxychloroquine (Keating et al., 2005). Inflammation may lead to fibrosis that may be

It is a granulomatous form of myocarditis. The clinical evidence of myocardial involvement is present in approximately 5 percent of patients with sarcoidosis. However, an autopsy series have reported higher rates of about 25 percent of subclinical cardiac involvement (Chapelon-Abric et al., 2004; Kim et al., 2009; Thomsen & Eriksson et al., 1999). The clinical manifestations of cardiac sarcoidosis are largely nonspecific and may precede, follow, or occur concurrently with involvement of other organs. Sarcoid heart disease should be considered in the evaluation of an otherwise healthy young or middle aged person with cardiac symptoms or in a patient with known sarcoidosis who develops arrhythmias, conduction disease, or heart failure. Patients who present with apparently chronic dilated

**7.9 Systemic lupus erythematosus myocarditis** 

manifested clinically as dilated cardiomyopathy.

**7.10 Sarcoid myocarditis** 

infrequently.

fibrosis leading to regurgitation, and formation of endocardial thrombi. Clinical awareness warranted when presentation may mimics acute myocardial infarction, with ischemic chest pain and ST-segment elevation on electrocardiography (Galiuto et al., 1997).

Hypersensitivity myocarditis is a form of eosinophilic myocarditis due to autoimmune reaction affecting the heart muscle, often induced by drug. It is often first discovered at postmortem examination. In one series, the prevalence of clinically undetected hypersensitivity myocarditis in explanted hearts ranged from 2.4 to 7 percent (Wu et al., 2002).

Numerous drugs have been implicated in hypersensitivity myocarditis including, antibiotics (Burke et al., 1991) like penicillins, cephalosporins and sulfonamides; antipsychotics (Killian et al., 1999) like clozapine and tricyclic antidepressants (Ansari et al., 2003; Burke et al., 1991; Kounis et al., 1989); others like methyldopa, hydrochlorothiazide, furosemide, tetracycline, azithromycin, aminophylline, phenytoin and benzodiazepines (Ben m'rad et al., 2009; Pursnani et al., 2009; Taliercio et al., 1985). Hypersensitivity myocarditis not constantly develop early in the course of medication. Patients taking the antipsychotic agent clozapine have been reported to develop myocarditis more than two years after the drug was started (Haas et al., 2007). Prolonged continuous infusion of dobutamine has also been associated with hypersensitivity myocarditis which has been reported in 2.4 to 23 percent (Spear, 1995; Takkenberg et al., 2004). Cocaine also rarely produce a hypersensitivity myocarditis, unlike the hypereosinophilic syndrome, peripheral eosinophilia is typically absent (Isner & Chokshi, 1991).

Clinically, the presentation often heralded by fever, peripheral eosinophilia and a drug rash that occurs days to weeks after administration of a previously well-tolerated agent. Electrocardiographic abnormalities show nonspecific ST segment changes or infarct patterns (Fenoglio et al., 1981). Myocardial involvement varies but usually does not result in fulminant heart failure or hemodynamic collapse. However, some patients present with sudden death or rapidly progressive heart failure (Burke et al., 1991; Galiuto et al., 1997). Eosinophilic myocarditis can be a manifestation of eosinophilia-myalgia syndrome, which is a multisystem disease caused by ingestion of contaminants in L-tryptophan containing products (Belongia et al., 1990), characterized by peripheral eosinophilia and generalized disabling myalgias (Martin et al., 1990). Eosinophils, lymphocytes, macrophages, and fibroblasts accumulate in the affected tissues, but their role in pathogenesis is unclear. The disease is frequently evolves into a chronic course but can be fatal in up to 5% of patients.

#### **7.8 Giant cell myocarditis**

Idiopathic giant cell myocarditis is a rare inflammatory disease that often affects previously healthy young adults and frequently fatal type of myocarditis (Cooper et al., 2008). The pathogenesis of this disorder is not known. It is identified by the presence of multinucleated giant cells associated with eosinophils and myocyte destruction in the absence of granulomas on endomyocardial biopsy. It is thought to be primarily autoimmune in nature because of the reported comorbidity with a variety of autoimmune disorders (Cooper et al., 1997), thymoma, (Kilgallen et al., 1998) and drug hypersensitivity (Daniels et al., 2000).

Idiopathic giant cell myocarditis is usually a fulminant form of myocarditis and characterised by a history of rapid progression of severe heart failure associated with refractory sustained ventricular arrhythmias. Giant-cell myocarditis is sometimes distinguished from the much more common postviral myocarditis by the presence of

fibrosis leading to regurgitation, and formation of endocardial thrombi. Clinical awareness warranted when presentation may mimics acute myocardial infarction, with ischemic chest

Hypersensitivity myocarditis is a form of eosinophilic myocarditis due to autoimmune reaction affecting the heart muscle, often induced by drug. It is often first discovered at postmortem examination. In one series, the prevalence of clinically undetected hypersensitivity myocarditis in explanted hearts ranged from 2.4 to 7 percent (Wu et al.,

Numerous drugs have been implicated in hypersensitivity myocarditis including, antibiotics (Burke et al., 1991) like penicillins, cephalosporins and sulfonamides; antipsychotics (Killian et al., 1999) like clozapine and tricyclic antidepressants (Ansari et al., 2003; Burke et al., 1991; Kounis et al., 1989); others like methyldopa, hydrochlorothiazide, furosemide, tetracycline, azithromycin, aminophylline, phenytoin and benzodiazepines (Ben m'rad et al., 2009; Pursnani et al., 2009; Taliercio et al., 1985). Hypersensitivity myocarditis not constantly develop early in the course of medication. Patients taking the antipsychotic agent clozapine have been reported to develop myocarditis more than two years after the drug was started (Haas et al., 2007). Prolonged continuous infusion of dobutamine has also been associated with hypersensitivity myocarditis which has been reported in 2.4 to 23 percent (Spear, 1995; Takkenberg et al., 2004). Cocaine also rarely produce a hypersensitivity myocarditis, unlike the hypereosinophilic syndrome, peripheral eosinophilia is typically absent (Isner &

Clinically, the presentation often heralded by fever, peripheral eosinophilia and a drug rash that occurs days to weeks after administration of a previously well-tolerated agent. Electrocardiographic abnormalities show nonspecific ST segment changes or infarct patterns (Fenoglio et al., 1981). Myocardial involvement varies but usually does not result in fulminant heart failure or hemodynamic collapse. However, some patients present with sudden death or rapidly progressive heart failure (Burke et al., 1991; Galiuto et al., 1997). Eosinophilic myocarditis can be a manifestation of eosinophilia-myalgia syndrome, which is a multisystem disease caused by ingestion of contaminants in L-tryptophan containing products (Belongia et al., 1990), characterized by peripheral eosinophilia and generalized disabling myalgias (Martin et al., 1990). Eosinophils, lymphocytes, macrophages, and fibroblasts accumulate in the affected tissues, but their role in pathogenesis is unclear. The disease is frequently evolves into a chronic course but can be fatal in up to 5% of patients.

Idiopathic giant cell myocarditis is a rare inflammatory disease that often affects previously healthy young adults and frequently fatal type of myocarditis (Cooper et al., 2008). The pathogenesis of this disorder is not known. It is identified by the presence of multinucleated giant cells associated with eosinophils and myocyte destruction in the absence of granulomas on endomyocardial biopsy. It is thought to be primarily autoimmune in nature because of the reported comorbidity with a variety of autoimmune disorders (Cooper et al., 1997), thymoma, (Kilgallen et al., 1998) and drug hypersensitivity (Daniels et al., 2000). Idiopathic giant cell myocarditis is usually a fulminant form of myocarditis and characterised by a history of rapid progression of severe heart failure associated with refractory sustained ventricular arrhythmias. Giant-cell myocarditis is sometimes distinguished from the much more common postviral myocarditis by the presence of

pain and ST-segment elevation on electrocardiography (Galiuto et al., 1997).

2002).

Chokshi, 1991).

**7.8 Giant cell myocarditis** 

ventricular tachycardia, heart block, and a downhill clinical course, despite optimal clinical care. In the series of 63 patients with giant cell myocarditis enrolled in the multicenter Giant Cell Myocarditis Treatment Trial, 75 percent identified with heart failure symptoms as the primary presentation, 14 percent with ventricular arrhythmia and heart block in 5 percent (Cooper et al., 1997). Most patients will require cardiac transplantation, the median survival from the onset of symptoms of less than 6 months and has an 89 percent rate of death or transplantation. This represents a significantly worse outcome compared to lymphocytic or viral myocarditis. Despite a 25 percent incidence of post-transplantation recurrence of giant cell myocarditis detected by biopsy, the 5-year survival after transplantation is about 71 percent which is comparable to survival after transplantation for cardiomyopathy.

### **7.9 Systemic lupus erythematosus myocarditis**

Acute myocarditis is an uncommon manifestation of systemic lupus erythematosus (SLE), with a prevalence of 8 to 25 percent in different studies (Apte et al., 2008; Mandell, 1987). Myocarditis frequently asymptomatic but less often may accompany other manifestations of acute SLE. In particular pericarditis, commonly occur in about two-thirds of patients, and generally follows a benign course, however tamponade or constriction may occur infrequently.

Myocarditis generally parallels the activity of the disease and, although common histologically, rarely results in clinical heart failure unless associated with hypertension. African American ethnicity is associated with a higher risk of myocarditis compared with Hispanic and Caucasian ethnicity (Apte et al., 2008). Myocarditis should be suspected if there is resting tachycardia disproportionate to body temperature, ST and T wave electrocardiographic abnormalities and unexplained cardiomegaly. The cardiomegaly may be associated with symptoms and signs of heart failure, conduction abnormalities or arrhythmias (Moder et al., 1999). Patients with SLE are at increased risk for myocardial ischemia due to accelerated atherosclerosis or coronary arteritis. Endocardial involvement with fibrinous endocarditis (Libman & Sachs, 1924) is another serious manifestation can lead to valvular insufficiencies or embolic events. Likewise patients with the antiphospholipid syndrome have a higher incidence of valvular disease, a variety of thrombotic disorders, myocardial infarction, pulmonary hypertension, and cardiomyopathy. Myocardial biopsy reveal mononuclear cells infiltration distinguish active myocarditis from fibrosis and other causes of cardiomyopathy (Schattner & Liang, 2003) or rarely cardiotoxicity induced by hydroxychloroquine (Keating et al., 2005). Inflammation may lead to fibrosis that may be manifested clinically as dilated cardiomyopathy.

#### **7.10 Sarcoid myocarditis**

It is a granulomatous form of myocarditis. The clinical evidence of myocardial involvement is present in approximately 5 percent of patients with sarcoidosis. However, an autopsy series have reported higher rates of about 25 percent of subclinical cardiac involvement (Chapelon-Abric et al., 2004; Kim et al., 2009; Thomsen & Eriksson et al., 1999). The clinical manifestations of cardiac sarcoidosis are largely nonspecific and may precede, follow, or occur concurrently with involvement of other organs. Sarcoid heart disease should be considered in the evaluation of an otherwise healthy young or middle aged person with cardiac symptoms or in a patient with known sarcoidosis who develops arrhythmias, conduction disease, or heart failure. Patients who present with apparently chronic dilated

Clinical Presentation 27

Women present with heart failure during the peripartum period and become manifested in the last month of pregnancy or within 5 months of the delivery without apparent etiology for the heart failure can be found. The clinical scenario is challenging because many normal women in the last month of a normal pregnancy experience dyspnea, fatigue and pedal edema, symptoms can mimic early congestive cardiac failure. Physical examination can be significant for signs of right and left heart failure. Symptoms and signs that should raise the suspicion of heart failure include paroxysmal nocturnal dyspnea, chest pain, nocturnal cough, new regurgitant murmurs, pulmonary crackles, elevated jugular venous pressure and hepatomegaly. The electrocardiogram usually demonstrates a normal sinus or sinus tachycardia rhythm, but frequent ectopy and other atrial arrhythmias may also be present. Left ventricular hypertrophy, inverted T waves, Q waves, and nonspecific ST-T changes have also been reported (Brown & Bertolet, 1998). Recurrence in a subsequent pregnancy has been reported. However, significant improvement occurs in up to 50 percent of affected

The clinical signs and symptoms of myocarditis are highly variable. A thorough medical history with emphasis on possible causes is essential. A scrupulous awareness to ample clinical scenarios is essential for clinicians, particularly when the cases are lacking apparent etiologies or the presentations being similar to acute myocardial infarction, asymptomatic left ventricular systolic dysfunction, unexplained ventricular tachyarrhythmias or cardiogenic shock. Clinician need to be attentive when evidence of myocardial damage not attributable to epicardial coronary artery disease, primary valvular disease or noninflammatory causes. Usually, most cases of myocarditis are self limited and a spontaneous improvement occurs in a substantial number of patients with lymphocytic disease but is rarely, if ever, observed with granulomatous myocarditis. While routine diagnostic endomyocardial biopsy is not required in most cases of suspected acute myocarditis, the need for biopsy will depend upon the time course and severity of the

Better understanding of the clinicopathologic aberration that characterize the diverse clinical scenarios and more comprehensive understanding of the natural history of the various subtypes of myocarditis should assist clinicians for better approach and subsequently plan

The authors would like to acknowledge Sahera Khalil Al-Nnadaf (H.D.) who actively

Abrishami, B., O'Connel, C., Sharma, O. (2004). Cardiac sarcoidosis with presentation of

Akhras, F., Dubrey, S., Gazzard, B. (1994). Emerging patterns of heart disease in HIV

infected homosexual subjects with and without opportunistic infections; a prospective colour flow Doppler echocardiographic study. *Eur Heart J*, Vol.15, pp.

large left atrial mass. *Curr Opin Pulm Med*, Vol.10, p. 397.

women; others are left with a progressive dilated cardiomyopathy.

**8. Conclusion** 

clinical presentation.

**9. Acknowledgment** 

**10. References** 

68-75.

more effective therapy in the future.

contributed in preparation and assembly of this chapter.

cardiomyopathy yet with new ventricular arrhythmias or second-degree or third degree heart block or who do not have a response to optimal care are more likely to have cardiac sarcoidosis (Yazaki et al., 1998). Cardiac symptoms were reported in 101 patients, when cardiac sarcoidosis was diagnosed in 84 percent compared to 4 percent in asymptomatic patients (Smedema et al., 2005). Endomyocardial biopsy shows characteristic noncaseating granulomas. However, the diagnosis can also be inferred if there is a tissue diagnosis of sarcoidosis from an extracardiac source in the presence of a cardiomyopathy of unknown origin.

The electrocardiographic abnormalities found in nearly 70 percent of patients with sarcoidosis (Chapelon-Abric et al., 2004). Cardiac involvement with sarcoidosis may produce clinical symptoms and electrocardiographic findings simulating myocardial infarction. Conduction abnormalities in form of first-degree heart block due to disease of the atrioventricular node or bundle of His, and various types of intraventricular conduction defects, are common among patients with cardiac sarcoidosis (Chapelon-Abric et al., 2004). These lesions may initially be silent, but can progress to complete heart block and cause syncope (Yoshida et al., 1997). Sustained or nonsustained ventricular tachycardia and ventricular premature beats are the second most common presentation of cardiac sarcoidosis; electrocardiography reveals ventricular arrhythmias in as many as 22 percent of patients with sarcoidosis (Sekiguchi et al., 1980). Supraventricular arrhythmias are infrequent. Sudden death due to ventricular tachyarrhythmias or conduction block accounts for 25 to 65 percent of deaths due to cardiac sarcoidosis, however, sudden death can occur in the absence of a previous cardiac event (Reuhl et al., 1997; Soejima & Yada, 2009; Yazaki et al., 2001). Both systolic and diastolic heart failure can occur. Left ventricular aneurysms develop in patients with extensive involvement of the myocardium. Mitral incompetence may occur with cardiac sarcoidosis due to associated systolic dysfunction and left ventricular dilation or due to papillary muscle involvement by sarcoid granulomas (Sato et al., 2008). Tricuspid regurgitation with atrioventricular block secondary to infiltration of tricuspid valves and conduction system by sarcoid granulomas has been reported as well (Goyal & Aragam, 2006). A left atrial granulomatous mass resembling myxoma has been reported too (Abrishami et al., 2004).
