Special Feature VANDERBILT CARDIOLOGY GRAND ROUNDS
Eosinophilic Myocarditis—An Unusual Cause of Left Ventricular Hypertrophy
Authors Samuel T. Coffin, MD, Stewart M. Benton, Jr, MD, Daniel J. Lenihan, MD, Allen J. Naftilan, MD, PhD and Lisa A. Mendes, MD Editor Daniel J. Lenihan, MD
Abstract: Eosinophilic myocarditis is a rare condition in which inflammation of the heart results in an infiltrative cardiomyopathy that is often difficult to diagnose in the acute setting. It sometimes presents as left ventricular hypertrophy. The authors present a case of a 79-yearold woman with a history of Non-Hodgkin’s lymphoma who presented with acute heart failure with marked left ventricular hypertrophy. Echocardiography demonstrated abnormalities consistent with an infiltrative cardiomyopathy, and endomyocardial biopsy showed findings consistent with eosinophilic myocarditis. The patient was managed with diuresis and glucocorticoid therapy, and within 4 weeks of her admission, her clinical status had improved and her echocardiogram normalized. The prompt diagnosis and treatment of this patient’s myocarditis likely resulted in her favorable outcome. This illustrates the need for a broad consideration of all the potential causes of hypertrophy and the necessary diagnostic strategies and therapeutic options. Key Indexing Terms: Left ventricular hypertrophy; Eosinophilia; Myocarditis; Glucocorticoids. [Am J Med Sci 2015;349(4):358–362.]
L
eft ventricular hypertrophy (LVH) denotes an increase in ventricular wall mass and is commonly described as concentric or eccentric thickening of the myocardium. Concentric hypertrophy typically occurs in the setting of chronic pressure overload. The left ventricular wall thickness is increased; however, the diameter of the ventricle is commonly unchanged or even reduced. Histologically, newly laid sarcomeres are added in parallel to the existing functional units.1 Eccentric hypertrophy, however, occurs in the setting of chronic volume overload of the ventricle. The ventricular wall thickness is increased, as is the diameter of the ventricle. Histologically, sarcomeres are added in series.1
From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Submitted January 14, 2014; accepted in revised form April 25, 2014. The authors have no financial or other conflicts of interest to disclose. Correspondence: Samuel T. Coffin, MD, Division of Cardiovascular Medicine, 383 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6300 (E-mail: samuel.t.coffi[email protected]).
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LVH is typically noted on echocardiogram by the 2-dimensional (2-D) measurement of the septal and posterior walls of the left ventricle. There are multiple etiologies of LVH, and the causative factor is not always readily apparent. Concentric hypertrophy is commonly associated with longstanding hypertension or aortic stenosis, whereas eccentric hypertrophy is often the result of aortic or mitral insufficiency and ischemic or idiopathic cardiomyopathies. Infiltrative cardiomyopathies, such as amyloidosis, result from the abnormal deposition of substances within the ventricular walls and may cause both concentric and eccentric thickening patterns on echocardiography. Although rare, hypertrophic cardiomyopathy, mucopolysaccharidoses, cardiac oxalosis, Friedreich’s ataxia, Danon’s disease, Fabry’s disease and inflammatory cardiomyopathies including eosinophilic myocarditis (EM) often result in increased left ventricular wall mass and wall thickening.2 Alternatively, cardiac sarcoidosis, hemochromatosis and Wegener’s disease are infiltrative processes that typically result in a dilated left ventricular cavity with eccentric ventricular hypertrophy.2 Myocardial biopsy is often required to establish a diagnosis in these patients. We present a case of a 79-year-old woman with a history of Non-Hodgkin’s lymphoma who presented with significant congestive heart failure and marked LVH. The case outlined illustrates the need for a broad consideration of all the potential causes of LVH and the necessary diagnostic strategies and therapeutic options.
CASE PRESENTATION A 79-year-old woman with a history of non-Hodgkin’s lymphoma and hypertension presented to our institution with progressive shortness of breath, orthopnea and chest pain. She had recently completed 3 cycles of bendamustine and rituximab approximately 2 months before her presentation. Her initial physical examination revealed a blood pressure of 91/59 mm Hg, a pulse of 106 bpm, a respiratory rate of 24 per minute and an oxygen saturation of 96% on room air. The patient had jugular venous distention of 12 cm of water, a S3 gallop and a holosystolic murmur auscultated at the left lower sternal border. Inspiratory crackles were present at the lung bases. The
The American Journal of the Medical Sciences
Volume 349, Number 4, April 2015
Eosinophilic Myocarditis as Hypertrophy
FIGURE 1. Electrocardiogram at presentation shows sinus tachycardia, right bundle branch block, left anterior fascicular block and nonspecific repolarization abnormalities.
initial laboratory evaluation was remarkable for white blood cells count: 16,000 cells per microliter (reference: 3.9–10.7), absolute eosinophil count: 480 cells per microliter (reference: 30–510), creatine phosphokinase (CK): 123 U/L (reference: 30–300), CK-MB: 16.72 ng/mL (reference: ,6), troponin I: 2.94 ng/mL (reference: ,0.05) and B-type natriuretic peptide: 9,046 pg/mL (reference: ,100), all of which were significantly abnormal. Additionally, her creatinine was 1.53 mg/dL (reference: 0.7–1.5), and her liver transaminases were mildly elevated. Her calcium was 10.4 mg/dL, the upper limit of normal. Blood and urine bacterial cultures were negative throughout the hospital course. The patient’s baseline electrocardiogram (ECG) was notable for sinus tachycardia (100 beats per minute), right bundle branch block, left anterior fascicular block, nonspecific repolarization abnormalities and low voltage across the precordial leads
FIGURE 2. A surface echocardiogram at presentation shows moderate concentric LVH and speckling of the myocardium concerning for an infiltrative process. LVH, left ventricular hypertrophy. Copyright © 2014 by the Southern Society for Clinical Investigation.
(Figure 1). There were no prior ECG tracings available for comparison. Chest radiography revealed bibasilar opacities consistent with prior scarring without other acute abnormalities. A transthoracic echocardiogram showed severe global left ventricular systolic dysfunction with a left ventricular ejection fraction estimated at 20% to 30%. There was moderate concentric LVH with speckling of the myocardium consistent with an infiltrative process (Figure 2). Stage 1 diastolic dysfunction was present, and a small pericardial effusion and dilated inferior vena cava were evident, suggesting markedly elevated right-sided filling pressures (Figures 3 and 4). The valves were structurally and functionally normal. An infiltrative process was suspected given the clinical picture, and a right ventricular endomyocardial biopsy was performed. Histologic findings included focal myocyte necrosis, diffuse inflammation with lymphocytes, eosinophils and neutrophils and interstitial edema (Figure 5) consistent with a diagnosis of EM. Repeat measurements of peripheral eosinophil count remained within the normal range. Her initial treatment included diuresis with intravenous loop diuretics and a transient milrinone infusion due to evidence of cardiogenic shock. Ultimately, she was initiated on an angiotensin-converting enzyme inhibitor and a beta-blocker when hemodynamic stability was achieved. After tissue diagnosis, the patient was started on intravenous methylprednisolone 250 mg intravenously every 12 hours for a total of 48 hours. Her regimen was then decreased to prednisone 30 mg orally twice daily for 2 days followed by a gradual taper over the following 3 weeks. Twenty days after hospital discharge, she was symptom free and without signs of volume overload. A transthoracic echocardiogram at that time demonstrated normal left ventricular ejection fraction of 65%, normal wall thickness, no pericardial effusion and normal inferior vena cava diameter (Figure 6). An additional echocardiogram 5 months later confirmed these findings. She is now asymptomatic after over 1-year follow-up.
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FIGURE 3. Mitral inflow velocities (left) show E to A reversal consistent with stage 1 diastolic dysfunction. Tissue Doppler of the lateral wall of the left ventricle (right) shows low e¢ velocity. The E/e¢ ratio is 10, consistent with stage 1 or 2 diastolic dysfunction.
DISCUSSION EM or hypersensitivity myocarditis is a rare condition in which inflammation of the heart is characterized by a variable myocardial inflammatory cell infiltrate that includes eosinophils.3 Frequently, the underlying cause of EM is unknown; however, identified precipitants include medication reactions, immunization reactions or various hypereosinophilic syndromes.4 Eosinophils play a particularly active role in the inflammatory response, which is postulated to be a result of the unique chemotactive interleukin milieu expressed from damaged myocytes. Eosinophils cause damage through the release of major basic protein and other cationic proteins resulting in necrosis due to increased membrane permeability and decreased mitochondrial respiration in the cardiac myocytes.5 The actual increase in wall thickness is caused by interstitial edema, rather than a change in myocyte diameter.6 The location of infiltration may range from localized to multifocal and widespread. Glucocorticoids may decrease the inflammatory reaction by decreasing the levels of inflammatory factors that attract eosinophils to the myocardium.7 Specific to this case, chemotherapeutic agents have not been shown to be definitively associated with EM. Rituximab has been associated with hypersensitivity reactions including hypersensitivity pneumonitis and acute infusional hypersensitivity reactions but not specifically EM. Bendamustine has not been shown to cause significant hypersensitivity in the literature.
The clinical presentation of EM is quite variable, and patients may present with chest pain consistent with acute coronary syndrome, new onset heart failure and even cardiogenic shock.3,8 A preceding viral syndrome may be present in some cases.9 Various diagnostic modalities have utility in the evaluation of patients with suspected EM (Table 1). Laboratory findings may include peripheral eosinophilia and elevation in cardiac enzymes. ECG findings include various rhythm disturbances ranging from sinus tachycardia to atrial arrhythmias. Premature ventricular contractions and ST segment abnormalities including ST elevation may be observed. Echocardiographic findings may include left ventricular dilation, wall motion abnormalities and a speckled appearance of the myocardium. Furthermore, focal or diffuse wall motion abnormalities may be present. Typical findings on cardiac MRI are consistent with myocarditis and may show areas of inflammation and edema in a patchy distribution.10 Endomyocardial biopsy is generally the gold standard for the diagnosis of EM. Infiltrates can vary in location and are typically perivascular or interstitial. The histopathology can vary from small foci of inflammatory cells with few eosinophils to a near global infiltration with necrosis of the cardiac myocytes.3 Because of the often variable distribution of infiltrates in EM, the sensitivity of biopsy is estimated at only 50%.11 For this reason, if a biopsy is negative in a patient with a high clinical suspicion for EM, a repeat biopsy is indicated. ACC/AHA guidelines recommend myocardial biopsy in
FIGURE 4. Surface echocardiogram of the inferior vena cava shows dilation to greater than 2 cm with minimal variation with respiration (thin line), consistent with markedly elevated rightsided filling pressures.
FIGURE 5. Hematoxylin and eosin staining of myocardial biopsy shows inflammation with eosinophils, lymphocytes, and neutrophils, as well as myocyte necrosis.
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Eosinophilic Myocarditis as Hypertrophy
FIGURE 6. Surface echocardiograms of the patient at presentation (left) and 2 days after discharge (right) show the decrease in posterior wall thickness from presentation to posttreatment.
TABLE 1. Useful tests in the diagnosis of eosinophilic myocarditis Diagnostic modality Findings in eosinophilic myocarditis Chest x-ray Electrocardiogram
Peripheral eosinophil count7
Cardiac biomarkers Echocardiography
Cardiac MRI10 Endomyocardial biopsy11
Cardiomegaly, pulmonary vascular congestion and evidence of volume overload may be present Ischemic ST changes including ST elevation may be present Absence of chamber enlargement and low voltages are typically present and suggest an infiltrative process Frequent PVCs and atrial arrhythmias may be present May or may not be present Commonly present if precipitant of eosinophil stimulation is infection (helminths), drug reactions or collegen vascular disease (vasculitis) CK, CK-MB and troponin I levels are typically elevated BNP may be significantly elevated if systolic failure and volume overload are present Left ventricular hypertrophy may be present Left ventricular chamber dilation is often present Focal or diffuse wall motion abnormalities are often present A speckled appearance of the myocardium often suggests an infiltrative process Findings of inflammation and tissue edema are consistent with myocarditis (sensitivity of 80% and specificity of 73% in diagnosis of myocarditis) Inflammatory infiltrates with an eosinophilic predominance (sensitivity is ;50% due to patchy myocardial involvement; specificity is 100%)
patients with heart failure of ,2-week duration with hemodynamic compromise and/or in patients with a dilated cardiomyopathy of any duration associated with allergic reaction and eosinophilia.12 The treatment of EM includes withdrawal of any potentially offending medications and the addition of glucocorticoids to traditional medical treatment of heart failure. In cases that are clearly reactive, stopping the offending medication will often resolve the symptoms entirely. Patients with acute or particularly severe presentations may benefit from glucocorticoid therapy. The duration of therapy is determined by their clinical response, and disease recurrence is possible especially if any underlying precipitant of eosinophil activation is not clearly identified and treated. Therefore, the recommended length of therapy has not yet been established and may be variable depending on individual patients and precipitating events.3,4,13,14 Cases of complete recovery with low recurrence rates have been reported using immunosuppressant agents in combination with steroids for the treatment of EM.3,13,15
CONCLUSIONS This case represents an unusual example of EM presenting as acute heart failure with marked LVH and an infiltrative pattern on echocardiogram. Given this, a broad differential was undertaken, which led to a prompt diagnosis. Treatment was Copyright © 2014 by the Southern Society for Clinical Investigation.
started within 2 weeks of the onset of symptoms and resulted in complete clinical and sustained echocardiographic recovery within 1 month. Recognition of a potential infiltrative process on echocardiography led to early diagnosis and successful treatment of EM in this patient. REFERENCES 1. Gaasch WH, Zile MR. Left ventricular structural remodeling in health and disease with special emphasis on volume, mass, and geometry. J Am Coll Cardiol 2011;58:1733–40. 2. Seward JB, Casaclang-Verzosa G. Infiltrative cardiovascular diseases. Cardiomyopathies that look alike. J Am Coll Cardiol 2010; 55:1769–79. 3. Al Ali AM, Straatman LP, Allard MF, et al. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22: 1233–7. 4. Ginsberg F, Parrillo JE. Eosinophilic myocarditis. Heart Fail Clin 2005;1:419–29. 5. Young JD, Peterson CG, Venge P, et al. Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 1986; 321:613–6. 6. Hiramitsu S, Morimoto S, Kato S, et al. Transient ventricular wall thickening in acute myocarditis: a serial echocardiographic and histopathologic study. Jpn Circ J 2001;65:863–6.
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7. Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592–600. 8. Sohn IS, Park JC, Chung JH, et al. A case of acute eosinophilic myopericarditis presenting with cardiogenic shock and normal peripheral eosinophil count. Korean J Intern Med 2006;21:136–40. 9. Roehrl MH, Alexander MP, Hammond SB, et al. Eosinophilic myocarditis in hypereosinophilic syndrome. Am J Hematol 2011;86:607–8. 10. Kim EY, Chang SA, Lee YK, et al. Early non-invasive diagnosis and treatment of acute eosinophilic myopericarditis by cardiac magnetic resonance. J Korean Med Sci 2011;11:1522–6.
a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. 13. Corradi D, Vaglio A, Maestri R, et al. Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death. Hum Pathol 2004;35:1160–3.
11. Burke AP, Saenger J, Mullick F, et al. Hypersensitivity myocarditis. Arch Pathol Lab Med 1991;115:764–9.
14. Watanabe N, Nakagawa S, Fukunaga T, et al. Acute necrotizing eosinophilic myocarditis successfully treated by high dose methylprednisolone. Jpn Circ J 2001;65:923–6.
12. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease:
15. Aggarwal A, Bergin P, Jessup P, et al. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transpl 2001;20:1241–4.
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Volume 349, Number 4, April 2015
Eosinophilic Myocarditis—An Unusual Cause of Left Ventricular Hypertrophy
Authors Samuel T. Coffin, MD, Stewart M. Benton, Jr, MD, Daniel J. Lenihan, MD, Allen J. Naftilan, MD, PhD and Lisa A. Mendes, MD Editor Daniel J. Lenihan, MD
Abstract: Eosinophilic myocarditis is a rare condition in which inflammation of the heart results in an infiltrative cardiomyopathy that is often difficult to diagnose in the acute setting. It sometimes presents as left ventricular hypertrophy. The authors present a case of a 79-yearold woman with a history of Non-Hodgkin’s lymphoma who presented with acute heart failure with marked left ventricular hypertrophy. Echocardiography demonstrated abnormalities consistent with an infiltrative cardiomyopathy, and endomyocardial biopsy showed findings consistent with eosinophilic myocarditis. The patient was managed with diuresis and glucocorticoid therapy, and within 4 weeks of her admission, her clinical status had improved and her echocardiogram normalized. The prompt diagnosis and treatment of this patient’s myocarditis likely resulted in her favorable outcome. This illustrates the need for a broad consideration of all the potential causes of hypertrophy and the necessary diagnostic strategies and therapeutic options. Key Indexing Terms: Left ventricular hypertrophy; Eosinophilia; Myocarditis; Glucocorticoids. [Am J Med Sci 2015;349(4):358–362.]
L
eft ventricular hypertrophy (LVH) denotes an increase in ventricular wall mass and is commonly described as concentric or eccentric thickening of the myocardium. Concentric hypertrophy typically occurs in the setting of chronic pressure overload. The left ventricular wall thickness is increased; however, the diameter of the ventricle is commonly unchanged or even reduced. Histologically, newly laid sarcomeres are added in parallel to the existing functional units.1 Eccentric hypertrophy, however, occurs in the setting of chronic volume overload of the ventricle. The ventricular wall thickness is increased, as is the diameter of the ventricle. Histologically, sarcomeres are added in series.1
From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. Submitted January 14, 2014; accepted in revised form April 25, 2014. The authors have no financial or other conflicts of interest to disclose. Correspondence: Samuel T. Coffin, MD, Division of Cardiovascular Medicine, 383 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6300 (E-mail: samuel.t.coffi[email protected]).
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LVH is typically noted on echocardiogram by the 2-dimensional (2-D) measurement of the septal and posterior walls of the left ventricle. There are multiple etiologies of LVH, and the causative factor is not always readily apparent. Concentric hypertrophy is commonly associated with longstanding hypertension or aortic stenosis, whereas eccentric hypertrophy is often the result of aortic or mitral insufficiency and ischemic or idiopathic cardiomyopathies. Infiltrative cardiomyopathies, such as amyloidosis, result from the abnormal deposition of substances within the ventricular walls and may cause both concentric and eccentric thickening patterns on echocardiography. Although rare, hypertrophic cardiomyopathy, mucopolysaccharidoses, cardiac oxalosis, Friedreich’s ataxia, Danon’s disease, Fabry’s disease and inflammatory cardiomyopathies including eosinophilic myocarditis (EM) often result in increased left ventricular wall mass and wall thickening.2 Alternatively, cardiac sarcoidosis, hemochromatosis and Wegener’s disease are infiltrative processes that typically result in a dilated left ventricular cavity with eccentric ventricular hypertrophy.2 Myocardial biopsy is often required to establish a diagnosis in these patients. We present a case of a 79-year-old woman with a history of Non-Hodgkin’s lymphoma who presented with significant congestive heart failure and marked LVH. The case outlined illustrates the need for a broad consideration of all the potential causes of LVH and the necessary diagnostic strategies and therapeutic options.
CASE PRESENTATION A 79-year-old woman with a history of non-Hodgkin’s lymphoma and hypertension presented to our institution with progressive shortness of breath, orthopnea and chest pain. She had recently completed 3 cycles of bendamustine and rituximab approximately 2 months before her presentation. Her initial physical examination revealed a blood pressure of 91/59 mm Hg, a pulse of 106 bpm, a respiratory rate of 24 per minute and an oxygen saturation of 96% on room air. The patient had jugular venous distention of 12 cm of water, a S3 gallop and a holosystolic murmur auscultated at the left lower sternal border. Inspiratory crackles were present at the lung bases. The
The American Journal of the Medical Sciences
Volume 349, Number 4, April 2015
Eosinophilic Myocarditis as Hypertrophy
FIGURE 1. Electrocardiogram at presentation shows sinus tachycardia, right bundle branch block, left anterior fascicular block and nonspecific repolarization abnormalities.
initial laboratory evaluation was remarkable for white blood cells count: 16,000 cells per microliter (reference: 3.9–10.7), absolute eosinophil count: 480 cells per microliter (reference: 30–510), creatine phosphokinase (CK): 123 U/L (reference: 30–300), CK-MB: 16.72 ng/mL (reference: ,6), troponin I: 2.94 ng/mL (reference: ,0.05) and B-type natriuretic peptide: 9,046 pg/mL (reference: ,100), all of which were significantly abnormal. Additionally, her creatinine was 1.53 mg/dL (reference: 0.7–1.5), and her liver transaminases were mildly elevated. Her calcium was 10.4 mg/dL, the upper limit of normal. Blood and urine bacterial cultures were negative throughout the hospital course. The patient’s baseline electrocardiogram (ECG) was notable for sinus tachycardia (100 beats per minute), right bundle branch block, left anterior fascicular block, nonspecific repolarization abnormalities and low voltage across the precordial leads
FIGURE 2. A surface echocardiogram at presentation shows moderate concentric LVH and speckling of the myocardium concerning for an infiltrative process. LVH, left ventricular hypertrophy. Copyright © 2014 by the Southern Society for Clinical Investigation.
(Figure 1). There were no prior ECG tracings available for comparison. Chest radiography revealed bibasilar opacities consistent with prior scarring without other acute abnormalities. A transthoracic echocardiogram showed severe global left ventricular systolic dysfunction with a left ventricular ejection fraction estimated at 20% to 30%. There was moderate concentric LVH with speckling of the myocardium consistent with an infiltrative process (Figure 2). Stage 1 diastolic dysfunction was present, and a small pericardial effusion and dilated inferior vena cava were evident, suggesting markedly elevated right-sided filling pressures (Figures 3 and 4). The valves were structurally and functionally normal. An infiltrative process was suspected given the clinical picture, and a right ventricular endomyocardial biopsy was performed. Histologic findings included focal myocyte necrosis, diffuse inflammation with lymphocytes, eosinophils and neutrophils and interstitial edema (Figure 5) consistent with a diagnosis of EM. Repeat measurements of peripheral eosinophil count remained within the normal range. Her initial treatment included diuresis with intravenous loop diuretics and a transient milrinone infusion due to evidence of cardiogenic shock. Ultimately, she was initiated on an angiotensin-converting enzyme inhibitor and a beta-blocker when hemodynamic stability was achieved. After tissue diagnosis, the patient was started on intravenous methylprednisolone 250 mg intravenously every 12 hours for a total of 48 hours. Her regimen was then decreased to prednisone 30 mg orally twice daily for 2 days followed by a gradual taper over the following 3 weeks. Twenty days after hospital discharge, she was symptom free and without signs of volume overload. A transthoracic echocardiogram at that time demonstrated normal left ventricular ejection fraction of 65%, normal wall thickness, no pericardial effusion and normal inferior vena cava diameter (Figure 6). An additional echocardiogram 5 months later confirmed these findings. She is now asymptomatic after over 1-year follow-up.
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FIGURE 3. Mitral inflow velocities (left) show E to A reversal consistent with stage 1 diastolic dysfunction. Tissue Doppler of the lateral wall of the left ventricle (right) shows low e¢ velocity. The E/e¢ ratio is 10, consistent with stage 1 or 2 diastolic dysfunction.
DISCUSSION EM or hypersensitivity myocarditis is a rare condition in which inflammation of the heart is characterized by a variable myocardial inflammatory cell infiltrate that includes eosinophils.3 Frequently, the underlying cause of EM is unknown; however, identified precipitants include medication reactions, immunization reactions or various hypereosinophilic syndromes.4 Eosinophils play a particularly active role in the inflammatory response, which is postulated to be a result of the unique chemotactive interleukin milieu expressed from damaged myocytes. Eosinophils cause damage through the release of major basic protein and other cationic proteins resulting in necrosis due to increased membrane permeability and decreased mitochondrial respiration in the cardiac myocytes.5 The actual increase in wall thickness is caused by interstitial edema, rather than a change in myocyte diameter.6 The location of infiltration may range from localized to multifocal and widespread. Glucocorticoids may decrease the inflammatory reaction by decreasing the levels of inflammatory factors that attract eosinophils to the myocardium.7 Specific to this case, chemotherapeutic agents have not been shown to be definitively associated with EM. Rituximab has been associated with hypersensitivity reactions including hypersensitivity pneumonitis and acute infusional hypersensitivity reactions but not specifically EM. Bendamustine has not been shown to cause significant hypersensitivity in the literature.
The clinical presentation of EM is quite variable, and patients may present with chest pain consistent with acute coronary syndrome, new onset heart failure and even cardiogenic shock.3,8 A preceding viral syndrome may be present in some cases.9 Various diagnostic modalities have utility in the evaluation of patients with suspected EM (Table 1). Laboratory findings may include peripheral eosinophilia and elevation in cardiac enzymes. ECG findings include various rhythm disturbances ranging from sinus tachycardia to atrial arrhythmias. Premature ventricular contractions and ST segment abnormalities including ST elevation may be observed. Echocardiographic findings may include left ventricular dilation, wall motion abnormalities and a speckled appearance of the myocardium. Furthermore, focal or diffuse wall motion abnormalities may be present. Typical findings on cardiac MRI are consistent with myocarditis and may show areas of inflammation and edema in a patchy distribution.10 Endomyocardial biopsy is generally the gold standard for the diagnosis of EM. Infiltrates can vary in location and are typically perivascular or interstitial. The histopathology can vary from small foci of inflammatory cells with few eosinophils to a near global infiltration with necrosis of the cardiac myocytes.3 Because of the often variable distribution of infiltrates in EM, the sensitivity of biopsy is estimated at only 50%.11 For this reason, if a biopsy is negative in a patient with a high clinical suspicion for EM, a repeat biopsy is indicated. ACC/AHA guidelines recommend myocardial biopsy in
FIGURE 4. Surface echocardiogram of the inferior vena cava shows dilation to greater than 2 cm with minimal variation with respiration (thin line), consistent with markedly elevated rightsided filling pressures.
FIGURE 5. Hematoxylin and eosin staining of myocardial biopsy shows inflammation with eosinophils, lymphocytes, and neutrophils, as well as myocyte necrosis.
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Eosinophilic Myocarditis as Hypertrophy
FIGURE 6. Surface echocardiograms of the patient at presentation (left) and 2 days after discharge (right) show the decrease in posterior wall thickness from presentation to posttreatment.
TABLE 1. Useful tests in the diagnosis of eosinophilic myocarditis Diagnostic modality Findings in eosinophilic myocarditis Chest x-ray Electrocardiogram
Peripheral eosinophil count7
Cardiac biomarkers Echocardiography
Cardiac MRI10 Endomyocardial biopsy11
Cardiomegaly, pulmonary vascular congestion and evidence of volume overload may be present Ischemic ST changes including ST elevation may be present Absence of chamber enlargement and low voltages are typically present and suggest an infiltrative process Frequent PVCs and atrial arrhythmias may be present May or may not be present Commonly present if precipitant of eosinophil stimulation is infection (helminths), drug reactions or collegen vascular disease (vasculitis) CK, CK-MB and troponin I levels are typically elevated BNP may be significantly elevated if systolic failure and volume overload are present Left ventricular hypertrophy may be present Left ventricular chamber dilation is often present Focal or diffuse wall motion abnormalities are often present A speckled appearance of the myocardium often suggests an infiltrative process Findings of inflammation and tissue edema are consistent with myocarditis (sensitivity of 80% and specificity of 73% in diagnosis of myocarditis) Inflammatory infiltrates with an eosinophilic predominance (sensitivity is ;50% due to patchy myocardial involvement; specificity is 100%)
patients with heart failure of ,2-week duration with hemodynamic compromise and/or in patients with a dilated cardiomyopathy of any duration associated with allergic reaction and eosinophilia.12 The treatment of EM includes withdrawal of any potentially offending medications and the addition of glucocorticoids to traditional medical treatment of heart failure. In cases that are clearly reactive, stopping the offending medication will often resolve the symptoms entirely. Patients with acute or particularly severe presentations may benefit from glucocorticoid therapy. The duration of therapy is determined by their clinical response, and disease recurrence is possible especially if any underlying precipitant of eosinophil activation is not clearly identified and treated. Therefore, the recommended length of therapy has not yet been established and may be variable depending on individual patients and precipitating events.3,4,13,14 Cases of complete recovery with low recurrence rates have been reported using immunosuppressant agents in combination with steroids for the treatment of EM.3,13,15
CONCLUSIONS This case represents an unusual example of EM presenting as acute heart failure with marked LVH and an infiltrative pattern on echocardiogram. Given this, a broad differential was undertaken, which led to a prompt diagnosis. Treatment was Copyright © 2014 by the Southern Society for Clinical Investigation.
started within 2 weeks of the onset of symptoms and resulted in complete clinical and sustained echocardiographic recovery within 1 month. Recognition of a potential infiltrative process on echocardiography led to early diagnosis and successful treatment of EM in this patient. REFERENCES 1. Gaasch WH, Zile MR. Left ventricular structural remodeling in health and disease with special emphasis on volume, mass, and geometry. J Am Coll Cardiol 2011;58:1733–40. 2. Seward JB, Casaclang-Verzosa G. Infiltrative cardiovascular diseases. Cardiomyopathies that look alike. J Am Coll Cardiol 2010; 55:1769–79. 3. Al Ali AM, Straatman LP, Allard MF, et al. Eosinophilic myocarditis: case series and review of literature. Can J Cardiol 2006;22: 1233–7. 4. Ginsberg F, Parrillo JE. Eosinophilic myocarditis. Heart Fail Clin 2005;1:419–29. 5. Young JD, Peterson CG, Venge P, et al. Mechanism of membrane damage mediated by human eosinophil cationic protein. Nature 1986; 321:613–6. 6. Hiramitsu S, Morimoto S, Kato S, et al. Transient ventricular wall thickening in acute myocarditis: a serial echocardiographic and histopathologic study. Jpn Circ J 2001;65:863–6.
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7. Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592–600. 8. Sohn IS, Park JC, Chung JH, et al. A case of acute eosinophilic myopericarditis presenting with cardiogenic shock and normal peripheral eosinophil count. Korean J Intern Med 2006;21:136–40. 9. Roehrl MH, Alexander MP, Hammond SB, et al. Eosinophilic myocarditis in hypereosinophilic syndrome. Am J Hematol 2011;86:607–8. 10. Kim EY, Chang SA, Lee YK, et al. Early non-invasive diagnosis and treatment of acute eosinophilic myopericarditis by cardiac magnetic resonance. J Korean Med Sci 2011;11:1522–6.
a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol 2007;50:1914–31. 13. Corradi D, Vaglio A, Maestri R, et al. Eosinophilic myocarditis in a patient with idiopathic hypereosinophilic syndrome: insights into mechanisms of myocardial cell death. Hum Pathol 2004;35:1160–3.
11. Burke AP, Saenger J, Mullick F, et al. Hypersensitivity myocarditis. Arch Pathol Lab Med 1991;115:764–9.
14. Watanabe N, Nakagawa S, Fukunaga T, et al. Acute necrotizing eosinophilic myocarditis successfully treated by high dose methylprednisolone. Jpn Circ J 2001;65:923–6.
12. Cooper LT, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease:
15. Aggarwal A, Bergin P, Jessup P, et al. Hypersensitivity myocarditis presenting as cardiogenic shock. J Heart Lung Transpl 2001;20:1241–4.
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