Iatrogenic myocarditis—biomarkers, cardiovascular MRI and the need for early diagnosis

Iatrogenic myocarditis—biomarkers, cardiovascular MRI and the need for early diagnosis Oxford Medical Case Reports, 2018;1, 15–17 doi: 10.1093/omcr/omx096 Editorial EDITORIAL Iatrogenic myocarditis—biomarkers, cardiovascular MRI and the need for early diagnosis 1 1 1,2, Amrit S. Lota , Brian P. Halliday and Vassilios S Vassiliou * National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK, and Norwich Medical School, University of East Anglia Norfolk, Norfolk and Norwich University Hospital, Norwich, UK *Correspondence address. National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel: +020-73-52-8121, Ext. 2920; Fax: +020-73-51-8146; E-mail: v.vassiliou@rbht.nhs.uk Myocarditis remains a challenging diagnosis that arises from a At present, the gold standard for diagnosis of myocarditis range of potential insults that can result in cardiac inflamma- remains an endomyocardial biopsy [11]. Histopathological ana- tion, immune activation and functional impairment [1]. Acute lysis with immunostaining confirms the presence and charac- viral infection represents the leading aetiology followed by drug- terizes the nature of acute inflammatory infiltrates. However, induced hypersensitivity, giant cell myocarditis and cardiac the limitations of endomyocardial biopsy are many and include involvement in systemic autoimmune disease [2]. Due to hetero- high rates of sampling error, interobserver variability and peri- geneity in clinical presentation and disease severity, accurate procedural risks of cardiac tamponade and death. For these epidemiological assessment is limited but overall prevalence is reasons, endomyocardial biopsy is rarely a practical first step in estimated at 22 cases per 100 000 patients annually [3]. Clozapine the diagnosis of myocarditis in the majority of centres. is the cornerstone of therapy in refractory schizophrenia and sig- Cardiovascular magnetic resonance imaging (CMR) has nificantly reduces suicide rates further than other antipsychotic emerged as an important diagnostic tool for the non-invasive agents [4]. However, cardiotoxicity resulting in myocarditis can assessment of acute myocarditis. Standard myocardial tissue occur in 1–3% of patients and can result in complications includ- characterization techniques can detect myocardial oedema, ing sudden cardiac death and heart failure [5, 6]. reactive hyperaemia and replacement fibrosis from myocyte The case report by Datta and Solomon [7] describes a young cell death [12]. Diagnostic accuracy is further enhanced with patient presenting acutely with chest pain, ST segment elevation novel T1 and T2 mapping approaches as shown in Fig. 1 [13]. and mild troponin level elevation. Following the demonstration CMR also plays an equally important role in the exclusion of of unobstructed coronary arteries on invasive angiography and other causes of troponin-positive chest pain and unobstructed impaired left ventricular function on transthoracic echocardi- coronary arteries, such as infarction due to recanalisation, ography, a diagnosis of myocarditis likely secondary to cloza- spasm or embolism [14]. However, access to CMR is often lim- pine was reached. This report emphasizes the need for prompt ited and may be impractical as a screening test in all patients. recognition of myocarditis and immediate withdrawal of ther- Circulating biomarkers of myocardial injury, such as troponin, apy where clozapine-induced myocarditis is suspected. These represent a more feasible initial investigation and possible features appeared 2 days after starting clozapine therapy. approach for routine interval screening, which is relevant given However, it should be noted that symptoms are often non- that clinical presentation can be non-specific[9]. specific with chest pain occurring in only half of all cases and Multiple potential mechanisms have been proposed for clinical presentation varying between Days 14 and 21 after clozapine-induced myocarditis [5]. Hypersensitivity eosino- therapy initiation [8, 9]. In some cases, presentations may philic myocarditis is well documented with antibiotics (37%), indeed be delayed by several months requiring a high degree central nervous system agents (21%, primarily clozapine fol- of clinical suspicion for diagnosis [10]. lowed by carbamazepine), vaccines (8%) and a range of other Received: November 13, 2017. Accepted: November 17, 2017 © The Author 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx096/4799002 by Ed 'DeepDyve' Gillespie user on 16 March 2018 16 A.S. Lota et al. Figure 1: Short axis image of the left ventricle for a patient with acute myocarditis using four different imaging sequences for detailed myocardial tissue characteriza- tion. (A) T2-STIR showing myocardial oedema in the mid-wall region of the inferoseptum (area of high signal intensity indicated by white arrow). (B) Late gadolinium enhancement showing replacement fibrosis in the same region, importantly, with absence of sub-endocardial enhancement that would suggest myocardial infarc- tion. (C) T2 map for accurate quantification of myocardial oedema. (D) Post-contrast T1 map for diffuse interstitial fibrosis assessment. agents in 33% [15]. An alternative mechanism may be linked to FUNDING increased circulating noradrenaline levels, which may result in Dr Lota is supported by BHF CRTF (FS/17/21/32712) and the cardiac dysfunction [16]. This form of acute ‘catecholaminergic’ Alexander Jansons Foundation; Dr Halliday is supported by BHF myocarditis is difficult to distinguish from Takotsubo cardio- CRTF (FS/15/29/31492). myopathy but are still considered distinct entities [17]. However, it should be remembered that aetiology may be confounded by concomitant illicit drug use, and that both external insults may REFERENCES act synergistically to cause myocarditis. 1. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet 2012;379: Clozapine re-challenge after an episode of acute myocarditis 738–47. remains an unanswered question. Given the limited alternative 2. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr. The quest therapeutic options in this group of patients, further investiga- for new approaches in myocarditis and inflammatory car- tion may be helpful alongside approaches at more intensive diomyopathy. J Am Coll Cardiol 2016;68:2348–64. monitoring when initiating clozapine therapy that may include 3. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, high-sensitivity troponin assays and CMR, although under- Bolliger I, et al. Global, regional, and national incidence, standably many physicians and psychiatrists are hesitant. prevalence, and years lived with disability for 301 acute and In summary, clozapine-induced myocarditis remains a rare chronic diseases and injuries in 188 countries, 1990–2013: a but potentially fatal complication and this case emphasizes the systematic analysis for the Global Burden of Disease Study need for pharmaco-vigilance, early recognition of myocarditis 2013. Lancet 2015;386:743–800. and the need for definitive diagnosis by endomyocardial biopsy 4. Hennen J, Baldessarini RJ. Suicidal risk during treatment with or CMR. clozapine: a meta-analysis. Schizophr Res 2005;73:139–45. 5. Khan AA, Ashraf A, Baker D, Al-Omary MS, Savage L, Ekmejian A, et al. Clozapine and incidence of myocarditis CONFLICT OF INTEREST STATEMENT and sudden death—long term Australian experience. Int J No conflicts of interest. Cardiol 2017;238:136–9. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx096/4799002 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Iatrogenic myocarditis—biomarkers, cardiovascular MRI 17 6. Haas SJ, Hill R, Krum H, Liew D, Tonkin A, Demos L, et al. 12. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Clozapine-associated myocarditis: a review of 116 cases of Alakija P, Cooper LT, et al. Cardiovascular magnetic reson- suspected myocarditis associated with the use of cloza- ance in myocarditis: a JACC White Paper. J Am Coll Cardiol pine in Australia during 1993-2003. Drug Safety 2007;30: 2009;53:1475–87. 47–57. 13. Lurz P, Luecke C, Eitel I, Föhrenbach F, Frank C, Grothoff M, 7. Datta T, Solomon A. Clozapine induced myocarditis. Oxf et al. Comprehensive cardiac magnetic resonance imaging Med Case Rep 2017. (in press). in patients with suspected myocarditis: the MyoRacer-Trial. 8. Pieroni M, Cavallaro R, Chimenti C, Smeraldi E, Frustaci A. J Am Coll Cardiol 2016;67:1800–11. Clozapine-induced hypersensitivity myocarditis. Chest 2004; 14. Assomull RG, Lyne JC, Keenan N, Gulati A, Bunce NH, Davies 126:1703–5. SW, et al. The role of cardiovascular magnetic resonance in 9. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. patients presenting with chest pain, raised troponin, and A new monitoring protocol for clozapine-induced myocar- unobstructed coronary arteries. Eur Heart J 2007;28:1242–9. ditis based on an analysis of 75 cases and 94 controls. Aust 15. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, N Z J Psychiatry 2011;45:458–65. Ammirati E. Eosinophilic myocarditis: characteristics, treat- 10. Lang UE, Willbring M, von Golitschek R, Schmeisser A, ment, and outcomes. J Am Coll Cardiol 2017;70:2363–75. Matschke K, Malte Tugtekin S. Clozapine-induced myocar- 16. ElmanI,Goldstein DS,EisenhoferG,Folio J, Malhotra AK, ditis after long-term treatment: case presentation and clin- Adler CM, et al. Mechanism of peripheral noradrenergic stimu- ical perspectives. J Psychopharmacol 2008;22:576–80. lation by clozapine. Neuropsychopharmacology 1999;20:29–34. 11. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno- 17. Lyon AR, Bossone E, Schneider B, Sechtem U, Citro R, Blanes J, Felix SB, et al. Current state of knowledge on aeti- Underwood SR, et al. Current state of knowledge on ology, diagnosis, management, and therapy of myocarditis: Takotsubo syndrome: a position statement from the task- a position statement of the European Society of Cardiology force on Takotsubo Syndrome of the Heart Failure Working Group on Myocardial and Pericardial Diseases. Eur Association of the European Society of Cardiology. Eur J Heart J 2013;34:2636–48. 2648a–2648d. Heart Fail 2016;18:8–27. 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Iatrogenic myocarditis—biomarkers, cardiovascular MRI and the need for early diagnosis

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Abstract

Oxford Medical Case Reports, 2018;1, 15–17 doi: 10.1093/omcr/omx096 Editorial EDITORIAL Iatrogenic myocarditis—biomarkers, cardiovascular MRI and the need for early diagnosis 1 1 1,2, Amrit S. Lota , Brian P. Halliday and Vassilios S Vassiliou * National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK, and Norwich Medical School, University of East Anglia Norfolk, Norfolk and Norwich University Hospital, Norwich, UK *Correspondence address. National Heart & Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Tel: +020-73-52-8121, Ext. 2920; Fax: +020-73-51-8146; E-mail: v.vassiliou@rbht.nhs.uk Myocarditis remains a challenging diagnosis that arises from a At present, the gold standard for diagnosis of myocarditis range of potential insults that can result in cardiac inflamma- remains an endomyocardial biopsy [11]. Histopathological ana- tion, immune activation and functional impairment [1]. Acute lysis with immunostaining confirms the presence and charac- viral infection represents the leading aetiology followed by drug- terizes the nature of acute inflammatory infiltrates. However, induced hypersensitivity, giant cell myocarditis and cardiac the limitations of endomyocardial biopsy are many and include involvement in systemic autoimmune disease [2]. Due to hetero- high rates of sampling error, interobserver variability and peri- geneity in clinical presentation and disease severity, accurate procedural risks of cardiac tamponade and death. For these epidemiological assessment is limited but overall prevalence is reasons, endomyocardial biopsy is rarely a practical first step in estimated at 22 cases per 100 000 patients annually [3]. Clozapine the diagnosis of myocarditis in the majority of centres. is the cornerstone of therapy in refractory schizophrenia and sig- Cardiovascular magnetic resonance imaging (CMR) has nificantly reduces suicide rates further than other antipsychotic emerged as an important diagnostic tool for the non-invasive agents [4]. However, cardiotoxicity resulting in myocarditis can assessment of acute myocarditis. Standard myocardial tissue occur in 1–3% of patients and can result in complications includ- characterization techniques can detect myocardial oedema, ing sudden cardiac death and heart failure [5, 6]. reactive hyperaemia and replacement fibrosis from myocyte The case report by Datta and Solomon [7] describes a young cell death [12]. Diagnostic accuracy is further enhanced with patient presenting acutely with chest pain, ST segment elevation novel T1 and T2 mapping approaches as shown in Fig. 1 [13]. and mild troponin level elevation. Following the demonstration CMR also plays an equally important role in the exclusion of of unobstructed coronary arteries on invasive angiography and other causes of troponin-positive chest pain and unobstructed impaired left ventricular function on transthoracic echocardi- coronary arteries, such as infarction due to recanalisation, ography, a diagnosis of myocarditis likely secondary to cloza- spasm or embolism [14]. However, access to CMR is often lim- pine was reached. This report emphasizes the need for prompt ited and may be impractical as a screening test in all patients. recognition of myocarditis and immediate withdrawal of ther- Circulating biomarkers of myocardial injury, such as troponin, apy where clozapine-induced myocarditis is suspected. These represent a more feasible initial investigation and possible features appeared 2 days after starting clozapine therapy. approach for routine interval screening, which is relevant given However, it should be noted that symptoms are often non- that clinical presentation can be non-specific[9]. specific with chest pain occurring in only half of all cases and Multiple potential mechanisms have been proposed for clinical presentation varying between Days 14 and 21 after clozapine-induced myocarditis [5]. Hypersensitivity eosino- therapy initiation [8, 9]. In some cases, presentations may philic myocarditis is well documented with antibiotics (37%), indeed be delayed by several months requiring a high degree central nervous system agents (21%, primarily clozapine fol- of clinical suspicion for diagnosis [10]. lowed by carbamazepine), vaccines (8%) and a range of other Received: November 13, 2017. Accepted: November 17, 2017 © The Author 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx096/4799002 by Ed 'DeepDyve' Gillespie user on 16 March 2018 16 A.S. Lota et al. Figure 1: Short axis image of the left ventricle for a patient with acute myocarditis using four different imaging sequences for detailed myocardial tissue characteriza- tion. (A) T2-STIR showing myocardial oedema in the mid-wall region of the inferoseptum (area of high signal intensity indicated by white arrow). (B) Late gadolinium enhancement showing replacement fibrosis in the same region, importantly, with absence of sub-endocardial enhancement that would suggest myocardial infarc- tion. (C) T2 map for accurate quantification of myocardial oedema. (D) Post-contrast T1 map for diffuse interstitial fibrosis assessment. agents in 33% [15]. An alternative mechanism may be linked to FUNDING increased circulating noradrenaline levels, which may result in Dr Lota is supported by BHF CRTF (FS/17/21/32712) and the cardiac dysfunction [16]. This form of acute ‘catecholaminergic’ Alexander Jansons Foundation; Dr Halliday is supported by BHF myocarditis is difficult to distinguish from Takotsubo cardio- CRTF (FS/15/29/31492). myopathy but are still considered distinct entities [17]. However, it should be remembered that aetiology may be confounded by concomitant illicit drug use, and that both external insults may REFERENCES act synergistically to cause myocarditis. 1. Sagar S, Liu PP, Cooper LT Jr. Myocarditis. Lancet 2012;379: Clozapine re-challenge after an episode of acute myocarditis 738–47. remains an unanswered question. Given the limited alternative 2. Heymans S, Eriksson U, Lehtonen J, Cooper LT Jr. The quest therapeutic options in this group of patients, further investiga- for new approaches in myocarditis and inflammatory car- tion may be helpful alongside approaches at more intensive diomyopathy. J Am Coll Cardiol 2016;68:2348–64. monitoring when initiating clozapine therapy that may include 3. Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, high-sensitivity troponin assays and CMR, although under- Bolliger I, et al. Global, regional, and national incidence, standably many physicians and psychiatrists are hesitant. prevalence, and years lived with disability for 301 acute and In summary, clozapine-induced myocarditis remains a rare chronic diseases and injuries in 188 countries, 1990–2013: a but potentially fatal complication and this case emphasizes the systematic analysis for the Global Burden of Disease Study need for pharmaco-vigilance, early recognition of myocarditis 2013. Lancet 2015;386:743–800. and the need for definitive diagnosis by endomyocardial biopsy 4. Hennen J, Baldessarini RJ. Suicidal risk during treatment with or CMR. clozapine: a meta-analysis. Schizophr Res 2005;73:139–45. 5. Khan AA, Ashraf A, Baker D, Al-Omary MS, Savage L, Ekmejian A, et al. Clozapine and incidence of myocarditis CONFLICT OF INTEREST STATEMENT and sudden death—long term Australian experience. Int J No conflicts of interest. Cardiol 2017;238:136–9. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx096/4799002 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Iatrogenic myocarditis—biomarkers, cardiovascular MRI 17 6. Haas SJ, Hill R, Krum H, Liew D, Tonkin A, Demos L, et al. 12. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Clozapine-associated myocarditis: a review of 116 cases of Alakija P, Cooper LT, et al. Cardiovascular magnetic reson- suspected myocarditis associated with the use of cloza- ance in myocarditis: a JACC White Paper. J Am Coll Cardiol pine in Australia during 1993-2003. Drug Safety 2007;30: 2009;53:1475–87. 47–57. 13. Lurz P, Luecke C, Eitel I, Föhrenbach F, Frank C, Grothoff M, 7. Datta T, Solomon A. Clozapine induced myocarditis. Oxf et al. Comprehensive cardiac magnetic resonance imaging Med Case Rep 2017. (in press). in patients with suspected myocarditis: the MyoRacer-Trial. 8. Pieroni M, Cavallaro R, Chimenti C, Smeraldi E, Frustaci A. J Am Coll Cardiol 2016;67:1800–11. Clozapine-induced hypersensitivity myocarditis. Chest 2004; 14. Assomull RG, Lyne JC, Keenan N, Gulati A, Bunce NH, Davies 126:1703–5. SW, et al. The role of cardiovascular magnetic resonance in 9. Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ. patients presenting with chest pain, raised troponin, and A new monitoring protocol for clozapine-induced myocar- unobstructed coronary arteries. Eur Heart J 2007;28:1242–9. ditis based on an analysis of 75 cases and 94 controls. Aust 15. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, N Z J Psychiatry 2011;45:458–65. Ammirati E. Eosinophilic myocarditis: characteristics, treat- 10. Lang UE, Willbring M, von Golitschek R, Schmeisser A, ment, and outcomes. J Am Coll Cardiol 2017;70:2363–75. Matschke K, Malte Tugtekin S. Clozapine-induced myocar- 16. ElmanI,Goldstein DS,EisenhoferG,Folio J, Malhotra AK, ditis after long-term treatment: case presentation and clin- Adler CM, et al. Mechanism of peripheral noradrenergic stimu- ical perspectives. J Psychopharmacol 2008;22:576–80. lation by clozapine. Neuropsychopharmacology 1999;20:29–34. 11. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno- 17. Lyon AR, Bossone E, Schneider B, Sechtem U, Citro R, Blanes J, Felix SB, et al. Current state of knowledge on aeti- Underwood SR, et al. Current state of knowledge on ology, diagnosis, management, and therapy of myocarditis: Takotsubo syndrome: a position statement from the task- a position statement of the European Society of Cardiology force on Takotsubo Syndrome of the Heart Failure Working Group on Myocardial and Pericardial Diseases. Eur Association of the European Society of Cardiology. Eur J Heart J 2013;34:2636–48. 2648a–2648d. Heart Fail 2016;18:8–27. Downloaded from https://academic.oup.com/omcr/article-abstract/2018/1/omx096/4799002 by Ed 'DeepDyve' Gillespie user on 16 March 2018

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Published: Jan 1, 2018

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