International Journal of Cardiology 178 (2015) 82–84
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Modern day management of giant cell myocarditis Muhammad A. Chaudhry a, Adrian Correa b, Christopher Lee c, Andrew Yoon a, Luanda Grazette a, Farhood Saremi c, Michael W. Fong a,⁎ a b c
Division of Cardiovascular Medicine, University of Southern California, United States Department of Pathology, University of Southern California, United States Department of Radiology, University of Southern California, United States
a r t i c l e
i n f o
Article history: Received 26 August 2014 Accepted 21 October 2014 Available online 23 October 2014 Keywords: Giant cell myocarditis Myocarditis Cardiomyopathy Cardiac magnetic resonance imaging Heart failure Immunosuppression
Giant cell myocarditis (GCM) is a rare, often fatal, idiopathic disorder mediated by T lymphocytes with a mean age at onset of 42.6 ± 12.7 years, without a gender predominance [1–3]. The clinical presentation is marked by sudden-onset, progressive heart failure, often with ventricular arrhythmias, advanced atrio-ventricular block and sudden death [4]. The diagnosis was historically made only at autopsy, but with the advent of the bioptome in the 1980's the diagnosis became more commonly made with endomyocardial biopsy [3]. We had a case of a twenty-two year old woman who was initially admitted at an outside hospital with a one month history of worsening dyspnea, orthopnea, lower extremity edema, palpitations, and leftsided chest pain lasting up to 20 min. The initial workup included a transthoracic echocardiogram which showed a left ventricular ejection fraction (LVEF) of 35%. A coronary angiogram was performed which showed no evidence of coronary artery disease. She was diuresed, started on a low dose heart failure regimen and discharged home only to be readmitted a week later with worsening symptoms. An electrocardiogram demonstrated ST-elevation in the anterior and inferior leads with poor R-wave progression across the precordium. Troponin I was mildly elevated at 0.3 ng/mL. In view of her worsening condition, she was ultimately transferred to our hospital for a higher level of care. ⁎ Corresponding author at: 1510 San Pablo Street, Suite 322, Los Angeles, CA 90069, United States. E-mail address: [email protected] (M.W. Fong).
http://dx.doi.org/10.1016/j.ijcard.2014.10.131 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
On physical examination, the patient was pale and ill-appearing with a blood pressure of 96/64 mm Hg, body temperature of 36 °C, heart rate of 95 beats/min, and respiratory rate of 17 breaths/min. There was jugular venous distension of 9 cm of water and hepatojugular reflux. On chest auscultation, there was a 2/6 systolic murmur along the right upper sternal border. There was no lower extremity edema. Chest X-ray was suggestive of left atrial and right ventricular enlargement. ECG revealed normal sinus rhythm with extreme right axis deviation and mild persistent ST elevation in the anterior and inferior leads with Q waves in the inferior and lateral leads (Fig. 1). Laboratory studies were significant for a white blood cell count of 4200/mm3, hemoglobin of 10.2 g/dL, sodium of 139 meq/L, creatinine of 0.98 mg/dl, and troponin of 0.381 ng/mL. An outpatient cardiac MRI performed a few days prior to admission showed extensive delayed enhancement with predominantly epicardial involvement (Fig. 2A). Right heart catheterization showed a right atrial pressure of 10 mm Hg, mean pulmonary artery pressure of 20 mm Hg, pulmonary capillary wedge pressure of 13 mm Hg, cardiac index of 1.7 L/min/m2, and systemic vascular resistance of 1300 dynes∙s/cm−5. Right ventricular biopsy showed inflammatory infiltrate including giant cells and scattered eosinophils suggestive of GCM (Fig. 2B). Immunohistochemistry for C4d was negative as were Gram, Giemsa and AFB stains. No amyloid or iron deposition was identified. Immunosuppressive therapy with rabbit antithymocyte globulin (rATG) dosed at 1.5 mg/kg was initiated for a total of seven days along with pulse steroid therapy with 1 g intravenous Solu-medrol for three days. Steroid therapy was transitioned to oral prednisone at 60 mg daily with a 10 mg weekly taper. After completion of rATG, she was started on tacrolimus and mycophenolate mofetil with target tacrolimus levels of 8–10 ng/mL. With immunosuppressive therapy, her condition improved significantly and the patient was discharged home on low dose beta blockers, amiodarone and a Life Vest. Repeat endomyocardial biopsies at one, two and three months were negative for lymphocytes or giant cells, but showed a moderate amount of myocardial fibrosis with myocyte hypertrophy by month three. Repeat cardiac MRIs were performed to assess for disease recurrence, as the patient had several admissions for recurrent symptomatic ventricular and supraventricular tachycardia. MRI showed progressive resolution of delayed enhancement and edema with myocardial wall thinning and transmural fibrosis in the inferolateral wall. The patient ultimately underwent implanted cardioverter defibrillator placement. Three months after her diagnosis, the patient developed
M.A. Chaudhry et al. / International Journal of Cardiology 178 (2015) 82–84
83
Fig. 1. Electrocardiogram showing mild ST elevation in the inferior and lateral leads.
recurrent hypotension and heart failure symptoms and was found to be in cardiogenic shock without recurrence of GCM. At that point, the decision was made to list the patient for heart transplantation, which she ultimately received. Historically, management of GCM has included the use of muromonab-CD3, pulse steroids, and varying combinations of azathioprine, cyclosporine, and prednisone monitored with surveillance
endomyocardial biopsy [3]. Major limitations included side effects and toxicity, such as the cytokine release syndrome with muromonabCD3. There are case reports detailing the use of newer less toxic agents such as rATG, tacrolimus and mycophenolate mofetil [5], as is now common in heart transplantation, but no reports that we could find detailing the use of this therapy in combination as an initial strategy, as was used in this case. In a prospective trial of 20 patients over a six year period, 11
Fig. 2. A: Cardiac MRI showing a mid-ventricular short axis view using phase sensitive delayed enhancement. Epicardial enhancement (indicated by arrows) is seen in the anterolateral, inferolateral and inferior walls of the left ventricle. B: Right ventricular biopsy showing inflammatory infiltrate with multinucleated giant cells (indicated by arrow) and scattered eosinophils typical of giant cell myocarditis (hematoxylin and eosin, 400×).
84
M.A. Chaudhry et al. / International Journal of Cardiology 178 (2015) 82–84
patients were treated with high dose steroids and azathioprine and 9 with muromonab-CD3. There was a 5% mortality rate at 1 year and 2 patients were transplanted, but the overall survival rate was 95% at 1 year with immunosuppression [6]. The prognosis of GCM depends largely on aggressive immunosuppression and early cardiac transplantation. In a retrospective review of 63 patients with GCM, it was shown that without immunosuppression, mean survival was 3 months as compared to 12 month survival with immunosuppression. There was a 14.7% mortality rate at 1 month and 26% at 3.7 year follow-up. The rate of recurrence post-transplant was 26% but the pattern of involvement was generally less aggressive in the background of long term immunosuppression [3]. In a review by Davies et al., 7 patients were found to have GCM unexpectedly out of 340 cardiac transplantation cases over an 18 year period. One patient died 6 months post-transplant secondary to allograft vasculopathy, and the remainder survived between 1 and 9 years. There was asymptomatic recurrence in 3 patients at 5–13 months, while one patient had recurrence at 30 months post-transplant and responded well to uptitration of immunosuppression [7]. This case demonstrates successful treatment of GCM with modern day immunosuppressive therapy and monitoring with cardiac MRI, and serial endomyocardial biopsies.
References [1] G.M. Goldberg, Myocarditis of giant-cell type in an infant, Am. J. Clin. Pathol. 25 (1955) 510–513. [2] M.J. Davies, A. Pomerance, R.D. Teare, Idiopathic giant cell myocarditis — a distinctive clinico-pathological entity, Br. Heart J. 37 (1975) 192–195. [3] Leslie T. Cooper Jr., Gerald J. Berry, Ralph Shabetai, for the Multicenter Giant Cell Myocarditis Study Group Investigators, Idiopathic giant-cell myocarditis — natural history and treatment, N. Engl. J. Med. 336 (1997) 1860–1866. [4] Riina Kandolin, Jukka Lehtonen, Markku Kupari, Cardiac sarcoidosis and giant cell myocarditis as causes of atrioventricular block in young and middle-aged adults, Circ. Arrhythm. Electrophysiol. 4 (2011) 303–309. [5] U. Grabmaier, C. Brenner, M. Heiko, I. Kaczmarek, R. Schramm, K. Klingel, C. Hagi, W. Franz, An alternative immunosuppressive regimen to prolong transplant free survival in a patient with giant cell myocarditis, Int. J. Cardiol. 168 (1) (2013) e27–e28. [6] Leslie T. Cooper Jr., Joshua M. Hare, Henry D. Tazelaar, William D. Edwards, Randall C. Starling, Mario C. Deng, Santosh Menon, G. Martin Mullen, Brian Jaski, Kent R. Bailey, Madeleine W. Cunningham, G. William Dec, Giant Cell Myocarditis Treatment Trial Investigators, Usefulness of immunosuppression for giant cell myocarditis, Am. J. Cardiol. 102 (11) (1 December 2008) 1535–1539. [7] R.A. Davies, J.P. Veinot, S. Smith, C. Struthers, P. Hendry, R. Masters, Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome, J. Heart Lung Transplant. 21 (6) (2002 Jun) 674–679.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Modern day management of giant cell myocarditis Muhammad A. Chaudhry a, Adrian Correa b, Christopher Lee c, Andrew Yoon a, Luanda Grazette a, Farhood Saremi c, Michael W. Fong a,⁎ a b c
Division of Cardiovascular Medicine, University of Southern California, United States Department of Pathology, University of Southern California, United States Department of Radiology, University of Southern California, United States
a r t i c l e
i n f o
Article history: Received 26 August 2014 Accepted 21 October 2014 Available online 23 October 2014 Keywords: Giant cell myocarditis Myocarditis Cardiomyopathy Cardiac magnetic resonance imaging Heart failure Immunosuppression
Giant cell myocarditis (GCM) is a rare, often fatal, idiopathic disorder mediated by T lymphocytes with a mean age at onset of 42.6 ± 12.7 years, without a gender predominance [1–3]. The clinical presentation is marked by sudden-onset, progressive heart failure, often with ventricular arrhythmias, advanced atrio-ventricular block and sudden death [4]. The diagnosis was historically made only at autopsy, but with the advent of the bioptome in the 1980's the diagnosis became more commonly made with endomyocardial biopsy [3]. We had a case of a twenty-two year old woman who was initially admitted at an outside hospital with a one month history of worsening dyspnea, orthopnea, lower extremity edema, palpitations, and leftsided chest pain lasting up to 20 min. The initial workup included a transthoracic echocardiogram which showed a left ventricular ejection fraction (LVEF) of 35%. A coronary angiogram was performed which showed no evidence of coronary artery disease. She was diuresed, started on a low dose heart failure regimen and discharged home only to be readmitted a week later with worsening symptoms. An electrocardiogram demonstrated ST-elevation in the anterior and inferior leads with poor R-wave progression across the precordium. Troponin I was mildly elevated at 0.3 ng/mL. In view of her worsening condition, she was ultimately transferred to our hospital for a higher level of care. ⁎ Corresponding author at: 1510 San Pablo Street, Suite 322, Los Angeles, CA 90069, United States. E-mail address: [email protected] (M.W. Fong).
http://dx.doi.org/10.1016/j.ijcard.2014.10.131 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
On physical examination, the patient was pale and ill-appearing with a blood pressure of 96/64 mm Hg, body temperature of 36 °C, heart rate of 95 beats/min, and respiratory rate of 17 breaths/min. There was jugular venous distension of 9 cm of water and hepatojugular reflux. On chest auscultation, there was a 2/6 systolic murmur along the right upper sternal border. There was no lower extremity edema. Chest X-ray was suggestive of left atrial and right ventricular enlargement. ECG revealed normal sinus rhythm with extreme right axis deviation and mild persistent ST elevation in the anterior and inferior leads with Q waves in the inferior and lateral leads (Fig. 1). Laboratory studies were significant for a white blood cell count of 4200/mm3, hemoglobin of 10.2 g/dL, sodium of 139 meq/L, creatinine of 0.98 mg/dl, and troponin of 0.381 ng/mL. An outpatient cardiac MRI performed a few days prior to admission showed extensive delayed enhancement with predominantly epicardial involvement (Fig. 2A). Right heart catheterization showed a right atrial pressure of 10 mm Hg, mean pulmonary artery pressure of 20 mm Hg, pulmonary capillary wedge pressure of 13 mm Hg, cardiac index of 1.7 L/min/m2, and systemic vascular resistance of 1300 dynes∙s/cm−5. Right ventricular biopsy showed inflammatory infiltrate including giant cells and scattered eosinophils suggestive of GCM (Fig. 2B). Immunohistochemistry for C4d was negative as were Gram, Giemsa and AFB stains. No amyloid or iron deposition was identified. Immunosuppressive therapy with rabbit antithymocyte globulin (rATG) dosed at 1.5 mg/kg was initiated for a total of seven days along with pulse steroid therapy with 1 g intravenous Solu-medrol for three days. Steroid therapy was transitioned to oral prednisone at 60 mg daily with a 10 mg weekly taper. After completion of rATG, she was started on tacrolimus and mycophenolate mofetil with target tacrolimus levels of 8–10 ng/mL. With immunosuppressive therapy, her condition improved significantly and the patient was discharged home on low dose beta blockers, amiodarone and a Life Vest. Repeat endomyocardial biopsies at one, two and three months were negative for lymphocytes or giant cells, but showed a moderate amount of myocardial fibrosis with myocyte hypertrophy by month three. Repeat cardiac MRIs were performed to assess for disease recurrence, as the patient had several admissions for recurrent symptomatic ventricular and supraventricular tachycardia. MRI showed progressive resolution of delayed enhancement and edema with myocardial wall thinning and transmural fibrosis in the inferolateral wall. The patient ultimately underwent implanted cardioverter defibrillator placement. Three months after her diagnosis, the patient developed
M.A. Chaudhry et al. / International Journal of Cardiology 178 (2015) 82–84
83
Fig. 1. Electrocardiogram showing mild ST elevation in the inferior and lateral leads.
recurrent hypotension and heart failure symptoms and was found to be in cardiogenic shock without recurrence of GCM. At that point, the decision was made to list the patient for heart transplantation, which she ultimately received. Historically, management of GCM has included the use of muromonab-CD3, pulse steroids, and varying combinations of azathioprine, cyclosporine, and prednisone monitored with surveillance
endomyocardial biopsy [3]. Major limitations included side effects and toxicity, such as the cytokine release syndrome with muromonabCD3. There are case reports detailing the use of newer less toxic agents such as rATG, tacrolimus and mycophenolate mofetil [5], as is now common in heart transplantation, but no reports that we could find detailing the use of this therapy in combination as an initial strategy, as was used in this case. In a prospective trial of 20 patients over a six year period, 11
Fig. 2. A: Cardiac MRI showing a mid-ventricular short axis view using phase sensitive delayed enhancement. Epicardial enhancement (indicated by arrows) is seen in the anterolateral, inferolateral and inferior walls of the left ventricle. B: Right ventricular biopsy showing inflammatory infiltrate with multinucleated giant cells (indicated by arrow) and scattered eosinophils typical of giant cell myocarditis (hematoxylin and eosin, 400×).
84
M.A. Chaudhry et al. / International Journal of Cardiology 178 (2015) 82–84
patients were treated with high dose steroids and azathioprine and 9 with muromonab-CD3. There was a 5% mortality rate at 1 year and 2 patients were transplanted, but the overall survival rate was 95% at 1 year with immunosuppression [6]. The prognosis of GCM depends largely on aggressive immunosuppression and early cardiac transplantation. In a retrospective review of 63 patients with GCM, it was shown that without immunosuppression, mean survival was 3 months as compared to 12 month survival with immunosuppression. There was a 14.7% mortality rate at 1 month and 26% at 3.7 year follow-up. The rate of recurrence post-transplant was 26% but the pattern of involvement was generally less aggressive in the background of long term immunosuppression [3]. In a review by Davies et al., 7 patients were found to have GCM unexpectedly out of 340 cardiac transplantation cases over an 18 year period. One patient died 6 months post-transplant secondary to allograft vasculopathy, and the remainder survived between 1 and 9 years. There was asymptomatic recurrence in 3 patients at 5–13 months, while one patient had recurrence at 30 months post-transplant and responded well to uptitration of immunosuppression [7]. This case demonstrates successful treatment of GCM with modern day immunosuppressive therapy and monitoring with cardiac MRI, and serial endomyocardial biopsies.
References [1] G.M. Goldberg, Myocarditis of giant-cell type in an infant, Am. J. Clin. Pathol. 25 (1955) 510–513. [2] M.J. Davies, A. Pomerance, R.D. Teare, Idiopathic giant cell myocarditis — a distinctive clinico-pathological entity, Br. Heart J. 37 (1975) 192–195. [3] Leslie T. Cooper Jr., Gerald J. Berry, Ralph Shabetai, for the Multicenter Giant Cell Myocarditis Study Group Investigators, Idiopathic giant-cell myocarditis — natural history and treatment, N. Engl. J. Med. 336 (1997) 1860–1866. [4] Riina Kandolin, Jukka Lehtonen, Markku Kupari, Cardiac sarcoidosis and giant cell myocarditis as causes of atrioventricular block in young and middle-aged adults, Circ. Arrhythm. Electrophysiol. 4 (2011) 303–309. [5] U. Grabmaier, C. Brenner, M. Heiko, I. Kaczmarek, R. Schramm, K. Klingel, C. Hagi, W. Franz, An alternative immunosuppressive regimen to prolong transplant free survival in a patient with giant cell myocarditis, Int. J. Cardiol. 168 (1) (2013) e27–e28. [6] Leslie T. Cooper Jr., Joshua M. Hare, Henry D. Tazelaar, William D. Edwards, Randall C. Starling, Mario C. Deng, Santosh Menon, G. Martin Mullen, Brian Jaski, Kent R. Bailey, Madeleine W. Cunningham, G. William Dec, Giant Cell Myocarditis Treatment Trial Investigators, Usefulness of immunosuppression for giant cell myocarditis, Am. J. Cardiol. 102 (11) (1 December 2008) 1535–1539. [7] R.A. Davies, J.P. Veinot, S. Smith, C. Struthers, P. Hendry, R. Masters, Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome, J. Heart Lung Transplant. 21 (6) (2002 Jun) 674–679.
