Additional diagnostic value of CMR to the European Society of Cardiology (ESC) position statement criteria in a large clinical population of patients with suspected myocarditis

Additional diagnostic value of CMR to the European Society of Cardiology (ESC) position statement... Abstract Aims To determine the diagnostic yield of tissue characterization by cardiovascular magnetic resonance (CMR) in a large clinical population of patients with suspected acute myocarditis (AM) and to establish its diagnostic value within the 2013 European Society of Cardiology position statement criteria (ESC-PSC) for clinically suspected myocarditis. Methods and results In this retrospective study, CMR examinations of 303 hospitalized patients referred for work-up of suspected AM in two tertiary referral centres were analysed. CMR was performed at median 7 days (interquartile range 4–20 days) after clinical presentation and included cine imaging, T2-weighted imaging, and late gadolinium enhancement. CMR images were evaluated to assign each patient to a diagnosis. By using non-CMR criteria only, the 2013 ESC-PSC were positive for suspected myocarditis in 151 patients and negative in 30. In the remaining 122 patients, there was insufficient information available for ESC-PSC assessment, mostly due to lack of coronary angiography (CAG) before the CMR examination (n = 116, 95%). There were no in-hospital deaths. CMR provided a diagnosis in 158 patients (52%), including myocarditis in 104 (34%), myocardial infarction in 44 (15%), and other pathology in 10 patients (3%). Non-urgent CAG (>24 h after presentation) was performed before the CMR examination in 85 patients, of which 20 (24%) were done in patients with subsequently confirmed AM, which could potentially have been avoided if CMR was performed first. ESC-PSC was correct in diagnosing AM before the CMR in 50 of the 151 patients (33%) and was correct in ruling out AM in all the 30 patients (100%). However, ESC-PSC provided an incorrect diagnosis of AM in 27 of the 151 patients (18%), which was corrected by CMR through the identification of new cardiac disease that could explain the clinical syndrome. Patients with insufficient ESC-PSC information had a relatively low pre-test probability of coronary artery disease. In this group, CMR confirmed the diagnosis of AM in a relatively high percentage (44%) but still revealed myocardial infarction in 8% of them. Conclusion Tissue characterization by CMR provided a good diagnostic yield in this large clinical population of patients with suspected AM. CMR provided incremental diagnostic value to the ESC-PSC by ruling out the diagnosis of AM on one hand and by potentially sparing AM patients from CAG on the other. cardiovascular magnetic resonance, myocarditis, diagnostic value, clinical presentation, ESC position statement criteria Introduction Recognition of myocarditis in clinical practice represents a challenge for physicians, because patients may present with a wide range of symptoms and in various disease stages. Electrocardiography (ECG), echocardiography, and coronary angiography (CAG) can be used to support the suspicion of myocarditis, but findings are relatively non-specific and overlap with other cardiac diseases.1 To improve its recognition in clinical practice and to aid the selection of patients that require further diagnostic evaluation by endomyocardial biopsy (EMB), the 2013 European Society of Cardiology (ESC) position statement2 proposed new criteria for clinically suspected myocarditis, which include a combination of clinical and diagnostic features. Tissue characterization by cardiovascular magnetic resonance (CMR) is one of the components of the ESC position statement criteria (ESC-PSC) and enables the detection of myocardial oedema and myocardial injury in the setting of acute myocarditis (AM). Currently available CMR studies in patients with suspected AM have shown the ability of CMR to diagnose myocarditis, but most are relatively small and single centre, with highly selected patient populations.3–10 In this context, some studies only included patients who presented with chest pain, while others included patients with any symptom suggestive of myocarditis. In addition, several studies incorporated additional inclusion criteria such as the presence of elevated cardiac troponin, elevated C-reactive protein (CRP) or flu-like symptoms. As a result of these differing inclusion criteria, and thus heterogeneous patient populations, studies have reported widely varying rates of abnormal CMR results, and therefore the diagnostic yield of CMR in a clinical routine population with suspected AM is not well defined. Furthermore, the diagnostic importance of CMR remains to be validated in larger cohorts. The aim of this retrospective study was to assess the diagnostic yield of CMR tissue characterization in a large clinical population with suspected AM. Second, the additional value of CMR tissue characterization above non-CMR diagnostic methods within the ESC-PSC was investigated. Methods Patient population This retrospective two-centre study consisted of 303 patients who were admitted to the hospital and referred for CMR work-up of clinically suspected AM in two tertiary referral centres in Amsterdam, The Netherlands [200 patients from the VU University Medical Center (VUmc) between January 2003 and August 2016 and 103 patients from the Academic Medical Center (AMC) between January 2009 and August 2016]. The CMR referral for suspected myocarditis was left to the discretion of the treating physician, reflecting usual clinical practice patterns in those centres. Patients were identified in our local electronic databases (Microsoft Office Access in the VUmc and SPSS in the AMC) by searching for ‘suspected myocarditis’ in the reason for request field. Only patients who had been hospitalized for their clinical condition with recent onset of symptoms (days up to 3 months) and scheduled for an initial CMR examination were included. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local institutional review board (VUmc, Amsterdam, The Netherlands), who waived the requirement for informed consent due to the retrospective nature of the study. CMR protocol CMR imaging was performed on a 1.5-T whole body clinical MR system (Avanto or Sonata, Siemens Healthcare, Erlangen, Germany). Functional imaging was performed using a segmented, balanced steady-state free precession cine imaging with breath holding. Myocardial oedema was identified using a T2-weighted (T2W) triple inversion recovery sequence. Late gadolinium enhancement (LGE) images were acquired 10–15 min after the administration of 0.2 mmol/kg of gadolinium-based contrast agent using an inversion-recovery gradient-echo pulse sequence with continued adjustment of inversion time to null normal myocardium. Cine and LGE images were acquired in four-, three, and two-chamber long-axis views and short-axis orientations covering the entire left ventricle. T2W imaging was performed at least in three short-axis slices (basal, mid, and apical) or three long-axis slices (four-, three-, and two chambers) to allow oedema visualisation of all myocardial segments. CMR analysis and diagnosis All CMR images were evaluated by experienced CMR readers. For any disagreement in the CMR evaluation, consensus agreement was reached between the two readers (A.H. and R.N.). T2W images were considered to demonstrate myocardial oedema when focal areas of visually apparent high signal intensity were present. Hyperenhancement (HE) was considered to be present on the LGE images when focal areas of high signal intensity were found on both short-axis and matching long-axis views. The pattern of HE was visually assessed and categorized as subendocardial, transmural, mid-myocardial patchy, mid-myocardial striae, subepicardial, pericardial, or at the right ventricular (RV) insertion points. T2W images were used to determine whether HE lesions were acute, which was not possible in CMR studies that only included LGE imaging. After reviewing all the CMR images, each patient was assigned to a diagnosis. Myocarditis was diagnosed in the presence of subepicardial or mid-wall patchy HE with or without regionally matched oedema.11 Myocardial infarction required subendocardial/transmural HE in a coronary artery territory with or without regionally matched oedema. Coronary artery disease (CAD) on CAG was not required, because myocardial infarction can also be the result of coronary spasm or resolved thrombus.12 Dilated non-ischaemic cardiomyopathy with mid-wall fibrosis (NIDCM-MWF) was defined in the presence of a longitudinal striae of mid-wall HE within the septum in combination with left ventricular (LV) dilatation and systolic LV dysfunction.13 Takotsubo cardiomyopathy was diagnosed when a typical takotsubo pattern of akinesia/ballooning was present with or without patchy HE and/or oedema. The revised task force criteria were used to define the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).14 Hypertrophic cardiomyopathy (HCM) required a hypertrophied, non-dilated LV with a maximal wall thickness of ≥15 mm in the absence of a pressure overloading condition (i.e. hypertension and aortic stenosis) severe enough to cause the observed hypertrophy.15 CMR studies were classified as inconclusive in case of doubt between two or more diagnosis, for example ARVC and myocarditis or multiple coronary thrombi and myocarditis. These inconclusive CMR scans had good image quality, but the oedema and/or HE findings were ambiguous and one diagnosis could not be made with reasonable certainty. CMR scans without specific tissue characteristics (tissue negative) had absence of oedema, absence of HE, and absence of morphological and/or functional criteria for HCM, ARVC, and takotsubo. These tissue-negative cases were allowed to show decreased ejection fraction (LVEF) and/or increased LV dilatation, as long as none of the above-mentioned diagnostic criteria were fulfilled. Commercially available softwares (QMass, Medis, Leiden, The Netherlands; MASS, Medis, Leiden, The Netherlands; or Argus, Siemens Healthcare, Erlangen, Germany) were used to determine LV end-diastolic volume (EDV), LV end-systolic volume (ESV), and LVEF after manually tracing the endocardial borders on the cine short-axis stacks, according to SCMR (2013) guidelines on CMR image post-processing.16 Clinical assessment Patient demographics, medical history, cardiovascular risk profile, and clinical presentation were obtained from medical records. C-reactive protein was measured on admission and a value of more than 5 mg/L was defined as elevated. Cardiac troponin T concentration was considered elevated if the value exceeded 0.3 µg/L. Cardiac troponin T levels were determined approximately every 6–12 h until there was a peak and decline in serum concentration. The presence of unobstructed (<50% diameter stenosis) coronary arteries was assessed by invasive CAG. Twelve-lead ECGs were recorded on entry and were reviewed by an experienced reader who was blinded to the CMR results (P.S.B.). ECGs were scored for arrhythmias, conduction disturbances, ST-segment deviation, negative T waves, pathological Q waves, and PR segment depression, according to previously published criteria.17,18 A detailed description of the ECG criteria are provided in the Supplementary Data S1. Echocardiographic measurements of LV dimensions and function were extracted from clinical reports of echocardiography and were determined by visual assessment or by using 2D or M-mode measurements. Because of the retrospective nature of the study, the following variables had missing data: 12-lead ECG findings (14%), CRP measurement (12%), troponin T measurement (10%), and echocardiography findings (7%). Missing data for all other variables were ≤ 5%. ESC-PSC Patients were classified into those fulfilling and those not fulfilling the 2013 ESC-PSC, by using non-CMR criteria only. The 2013 ESC-PSC, without the CMR tissue characterization criterion, are summarized in Table 1 and are described in detail elsewhere.2 A reclassification between the ESC-PSC groups was defined as present when (i) CMR detected new cardiac disease that could explain the clinical in patients who fulfilled the 2013 ESC-PSC or when (ii) CMR detected myocarditis in patients who did not fulfil the 2013 ESC-PSC. NIDCM-MWF on CMR was not deemed to be a new cardiac disease, as myocarditis is one of the possible causes of DCM.2 Table 1 ESC position statement criteria for clinically suspected myocarditis without the CMR tissue characterization criterion (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome Table 1 ESC position statement criteria for clinically suspected myocarditis without the CMR tissue characterization criterion (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome Statistical analysis Data are presented as mean ± SD for normally distributed continuous variables, median and interquartile range (IQR) for non-normally distributed continuous variables, and as number/total number (%) for categorical variables. Histograms were used to determine if continuous variables were normally distributed. Mean values were compared between subgroups of patients using an independent-samples t-test or Mann–Whitney U test for, respectively, normally distributed and non-normally distributed continuous variables. Categorical values were compared between subgroups of patients using a χ2 test. Univariate binary logistic regression analyses were used to identify variables that were significantly associated with CMR results. Variables with a P-value <0.10 in univariate analyses were subsequently included in a multivariate regression using forward selection. All statistical analyses were performed using SPSS statistics (IBM SPSS Statistics 22, Chicago, IL, USA). A P-value of < 0.05 was considered statistically significant. Results A total of 303 hospitalized patients referred for CMR because of suspected AM were included in this study. Mean age of the population was 46 ± 17 years and 67% were male (Table 2). Chest pain was the most common presenting symptom (60%), followed by new-onset or worsening of dyspnoea (29%), palpitations (7%), and collapse (4%). Thirty-five patients (12%) presented to the hospital because of out of hospital cardiac arrest. Arrhythmias were documented at presentation in 62 patients (20%), including ventricular fibrillation or sustained ventricular tachycardia in 44, supraventricular tachycardia in 14, third-degree atrioventricular block in three, and asystole in one patient. There were no in-hospital deaths. Table 2 Patient demographic and clinical characteristics overall and in relation to the diagnosis on CMR Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Values are mean ± standard deviation, median (interquartile range), or n/N (%). a Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S1. b A negative result was allowed to show morphological and/or functional abnormalities, as long as none of the diagnostic criteria were fulfilled. c Values were compared in patients with elevated levels. d PR segment depression could not be scored in some patients due to atrial arrhythmias. STE, ST-segment elevation; HIV: human immunodeficiency virus. Table 2 Patient demographic and clinical characteristics overall and in relation to the diagnosis on CMR Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Values are mean ± standard deviation, median (interquartile range), or n/N (%). a Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S1. b A negative result was allowed to show morphological and/or functional abnormalities, as long as none of the diagnostic criteria were fulfilled. c Values were compared in patients with elevated levels. d PR segment depression could not be scored in some patients due to atrial arrhythmias. STE, ST-segment elevation; HIV: human immunodeficiency virus. Diagnostic yield of tissue characterization by CMR The CMR findings are summarized in Table 3. Median time from presentation to CMR was 7 days (IQR 4–20 days). LGE and T2W imaging were performed in, respectively, 100% and 87% of the CMR examinations. Mean LVEF was 48 ± 13% and was impaired (i.e. lower than 55%) in 179 patients (59%). Table 3 Cardiovascular magnetic resonance results Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Values are mean ± standard deviation, median (interquartile range), or n/N (%). Table 3 Cardiovascular magnetic resonance results Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Values are mean ± standard deviation, median (interquartile range), or n/N (%). Of the 264 examinations that included T2W imaging, oedema could not be defined due to insufficient image quality in 13 (5%). Myocardial oedema was found in 102 (41%) of the remaining 251 studies. Image quality of the LGE images was clinically useful in all the studies. There was definite HE in 168 studies (55%) and possible HE (i.e. possibility of artefact could not be excluded) in 4 (1%), which was scored as inconclusive HE. T2W imaging was performed in 149 of the 168 studies with HE (89%) and demonstrated regionally matched oedema in 96 of them (64%). T2W imaging was performed in 113 of the 131 (86%) examinations without HE on the LGE images. Of these 113 CMR scans, T2W images were of insufficient image quality in 5 (4%), demonstrated normal findings in 102 (90%), and showed oedema in 6 (5%). The predominant pattern of HE was myocarditic (subepicardial/mid-myocardial patchy) in 110 patients (65%), myocardial infarction (subendocardial/transmural) in 45 (27%), mid-myocardial striae in 5 (3%) as seen in NIDCM-MWF, and at the RV insertion points in four patients (2%). Three patients showed pericardial HE, and one patient demonstrated HE of the RV free wall. Additionally, seven patients had microvascular injury, as indicated by the presence of hypointense cores in T2w and LGE images within transmural infarction (see Supplementary data online, Figure S1). Of those seven patients, three had non-obstructive coronaries on CAG. Based on the T2W and LGE findings, a definite diagnosis was made in 158 patients (52%). The most common diagnoses were myocarditis in 104 (34%) (Figure 1) and myocardial infarction in 44 (15%) (Figure 2). Other diagnoses were takotsubo cardiomyopathy in three, ARVC in two, NIDCM-MWF in four, and HCM in one (see Supplementary data online, Figure S2). In the three patients with takotsubo, myocardial infarction was ruled out by CAG in one and was considered unlikely in the other two because of a complete normalization of LV function at follow-up echocardiography. CMR findings were inconclusive in 22 patients (7%) due to artefacts or unspecific findings. The CMR examination was interpreted as tissue negative in 123 patients (41%). In the aforementioned six patients with myocardial oedema but no HE, the diagnoses were takotsubo cardiomyopathy in two and inconclusive in three patients. In the last patient, the myocardial oedema was believed to be due to a myocardial infarction, because the oedema was transmural and clearly limited to one coronary artery territory. In the three inconclusive scans, there was only a very small area of oedema found, which made it challenging to distinguish between myocarditis and myocardial infarction (e.g. due to embolus). Supplementary data online, Table S1, describes the LV volumes and function according to the CMR diagnoses. The final diagnosis in the patient group that presented with out of hospital cardiac arrest was as follows: myocardial infarction in 6 (17%), myocarditis in 5 (14%), and ARVC in 1 (3%). CMR examinations were classified as negative for a diagnosis in 23 patients (66%). Figure 1 View largeDownload slide A 36-year-old man who presented with chest pain since 4 weeks. Cardiac troponin T level was elevated. The electrocardiogram (upper left panel), echocardiogram, and coronary angiogram (lower left panel) did not show any abnormalities. CMR demonstrated subepicardial hyperenhancement in the inferior and inferolateral basal walls, with matching high signal intensity on the T2W images, consistent with an acute myocarditis (right panel). Figure 1 View largeDownload slide A 36-year-old man who presented with chest pain since 4 weeks. Cardiac troponin T level was elevated. The electrocardiogram (upper left panel), echocardiogram, and coronary angiogram (lower left panel) did not show any abnormalities. CMR demonstrated subepicardial hyperenhancement in the inferior and inferolateral basal walls, with matching high signal intensity on the T2W images, consistent with an acute myocarditis (right panel). Figure 2 View largeDownload slide A 43-year-old man with a history of human immunodeficiency virus infection who presented with acute chest pain, cardiac troponin elevation, ST-segment elevation in multiple leads/territories (upper right panel), and non-obstructive coronary arteries on the coronary angiogram (left panel). CMR with LGE showed transmural hyperenhancement in the apical inferior and septal walls, with matching hyperintensity on the T2W images, consistent with acute myocardial infarction (lower left panel). RCA, right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending. Figure 2 View largeDownload slide A 43-year-old man with a history of human immunodeficiency virus infection who presented with acute chest pain, cardiac troponin elevation, ST-segment elevation in multiple leads/territories (upper right panel), and non-obstructive coronary arteries on the coronary angiogram (left panel). CMR with LGE showed transmural hyperenhancement in the apical inferior and septal walls, with matching hyperintensity on the T2W images, consistent with acute myocardial infarction (lower left panel). RCA, right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending. Of the 180 CAGs that were performed before the CMR examination, 65 (36%) were emergent/urgent (≤24 h after presentation), 85 (47%) were non-urgent (>24 h after presentation), and 6 (3%) were performed before the clinical presentation (outpatient setting or during a previous admission). The exact time from presentation to CAG could not be obtained in 24 patients (13%). CMR confirmed the diagnosis of AM in 20 of the 85 patients (24%) who had undergone non-urgent CAG before the CMR examination, which could potentially have been avoided if CMR was performed first. Differences in clinical presentation between groups based on CMR findings and predictors of diagnosis We compared characteristics of patients with a tissue-negative CMR result to those with a diagnosis on CMR (i.e. myocarditis, myocardial infarction, or other). Table 2 reports the differences between patients with a tissue-negative CMR result, patients with myocarditis, and patients with myocardial infarction. Compared with the tissue-negative group, the myocarditis group was significantly younger (39 ± 16 vs. 49 ± 17 year, P < 0.01) and had a significantly lower proportion of heart-failure-like presentations (19% vs. 34%, P = 0.01). Both the myocarditis and the myocardial infarction groups had a significantly higher cardiac troponin T concentration and a higher proportion of regional wall motion abnormalities (RWMA) on echocardiography when compared with the tissue-negative CMR group (median troponin T values: 0.92, 0.92, and 0.22 µg/L, respectively; proportion of RWMA: 40%, 52%, and 25%, respectively). Differences in peak troponin T concentrations between the CMR groups are illustrated in Figure 3. Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S2. (Figure 3). Figure 3 View largeDownload slide Peak cardiac troponin T concentrations between groups stratified according to CMR findings. The y-axis is on a log scale. Squares and error bars represent median and interquartile range. Double and triple asterisks indicate P-values <0.01 and 0.001. Inconc, inconclusive result; other, other pathology. Figure 3 View largeDownload slide Peak cardiac troponin T concentrations between groups stratified according to CMR findings. The y-axis is on a log scale. Squares and error bars represent median and interquartile range. Double and triple asterisks indicate P-values <0.01 and 0.001. Inconc, inconclusive result; other, other pathology. To identify patients in whom CMR examination will likely result in a diagnosis, we determined clinical predictors of a diagnosis on CMR. As demonstrated in Table 4, peak troponin T concentration was independently associated with any diagnosis on CMR [odds ratio (OR) 1.24 per 1 μg/L increase, P = 0.04], as were elevated troponin T (OR 2.51, P = 0.03), chest pain (OR 2.37, P < 0.01), absence of hypertension (OR 2.22, P = 0.02), and RWMA on echocardiography (OR 1.96, P = 0.03) [area under the curve (AUC) = 0.76]. To identify clinical parameters that can predict the diagnosis on CMR, we determined independent sets of predictors for myocarditis and for myocardial infarction in a multivariate analysis (see Supplementary data online, Table S3). Multivariate regression analyses showed age under 40 years (OR 2.24, P = 0.03), elevated CRP (5.12, P < 0.01), absence of dyspnoea (OR 2.50, P = 0.04), and presence of ST-segment elevation (OR 2.03, P = 0.048) to be independently associated with myocarditis on CMR (AUC = 0.74). Age above 40 years (OR 2.56, P = 0.04), current or former smoking (OR 2.37, P = 0.02), absence of a recent infection (OR 2.94, P = 0.04), RWMA on echocardiography (OR 2.28, P = 0.03), and peak troponin T concentration (OR 1.24, P = 0.01) were found to be independently associated with myocardial infarction on CMR (AUC = 0.60). Table 4 Univariate and multivariate analysis for predictors of any diagnosis on CMR Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Only variables with a P-value <0.10 in univariate analyses are shown. CI, confidence interval. Table 4 Univariate and multivariate analysis for predictors of any diagnosis on CMR Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Only variables with a P-value <0.10 in univariate analyses are shown. CI, confidence interval. Additional diagnostic value of CMR within the ESC-PSC To determine the additional diagnostic value of CMR in the work-up of suspected AM, we explored the impact of findings from CMR on the classification of patients according to the 2013 ESC-PSC. By using non-CMR criteria only, the 2013 ESC-PSC were positive for suspected myocarditis in 151 patients and negative in 30. Figure 4 shows the CMR results stratified according to the non-CMR diagnostic work-up, to evaluate the number of patients with reclassified diagnosis. In the ESC-PSC-negative group, none of the patients had myocarditis on CMR, but 10 patients (33%) had myocardial infarction, and two patients (7%) takotsubo cardiomyopathy. In the ESC-PSC-positive group, 50 patients (33%) showed evidence of myocarditis on CMR. CMR additionally identified alternative cardiac disease that could explain the clinical syndrome in 27 patients (18%) (i.e. myocardial infarction in 24, ARVC in two, and HCM in one patient), thereby reclassifying them to the negative ESC-PSC group. Figure 4 View largeDownload slide CMR results stratified according to the pre-CMR diagnostic work-up. Cath, catheterization; Takotsubo, takotsubo cardiomyopathy. Figure 4 View largeDownload slide CMR results stratified according to the pre-CMR diagnostic work-up. Cath, catheterization; Takotsubo, takotsubo cardiomyopathy. In the remaining 122 patients, there was insufficient information available for ESC-PSC assessment. In this group, CMR confirmed the diagnosis of myocarditis in 54 (44%) and revealed myocardial infarction in 10 (8%), NIDCM-MWF in 1 (1%) and takotsubo in 1 (1%) of the patients. In 116 of the 122 (95%) patients, ESC-PSC could not be assessed because CAG was not performed before the CMR examination to exclude obstructive CAD. These 116 patients were more likely to have a history of recent infection (45% vs. 20%, P < 0.01) and more often had CRP elevation (71% vs. 49%, P < 0.01), suggesting a higher clinical suspicion of myocarditis. Furthermore, they were significantly younger (41 ± 18 vs. 50 ± 15, P < 0.01), less often had hypertension (17% vs. 29%, P = 0.03), and tended to have a lower rate of diabetes mellitus (5% vs. 11%, P = 0.07), suggesting a lower pre-test probability of CAD. In the same subgroup of 116 patients, CAG was performed after CMR in 7 of 52 patients with myocarditis (13%), 8 of 10 with myocardial infarction (80%), 13 of 46 with a tissue-negative result (28%), and in the patient with NIDCM-WMF (100%), showing obstructed CAD in, respectively, 0%, 50%, 15%, and 100% of the patients (see Supplementary data online, Figure S3). Coronary intervention was deemed necessary in three patients with myocardial infarction, one with a tissue-negative CMR result, and in one patient with NIDCM-MWF. Discussion This study was conducted to establish the diagnostic yield of tissue characterization by CMR in a large clinical patient population with suspected AM and in relation to non-CMR diagnostic methods. The main findings of this study are that (i) tissue characterization by CMR provided a diagnosis in the majority of hospitalized patients referred for CMR with AM suspicion; (ii) troponin T, chest pain, RWMA on echocardiography, and absence of hypertension were independent predictors of a diagnosis on the CMR (i.e. myocarditis, myocardial infarction, or other); and (iii) CMR reclassified 18% of the patients who were positive for suspected AM according to the 2013 ESC-PSC to a new unexpected cardiac disease that could explain the clinical syndrome. Diagnostic yield of CMR in suspected AM In previous studies, rates of abnormal CMR findings in the setting of clinically suspected AM varied greatly among studies, ranging from 35% to 100% for LGE4–10,19–21 and 45% to 84% for T2W imaging.6,8,9,19,20,22 Rather than selecting only patients presenting with chest-pain syndromes, with heart-failure-like symptoms, or with symptoms that are accompanied by elevated CRP or viral history, this retrospective study includes a less-selected patient cohort presenting with suspected myocarditis and assesses the additional diagnostic value of CMR to the 2013 ESC PSC for myocarditis. We found that CMR was able to provide a diagnosis in approximately half of the patients. In particular, CMR confirmed the clinical suspicion of myocarditis in one-third and diagnosed alternative cardiac disease in 54 patients (18%). The proportion of patients with myocarditis in our study is lower than in most previous studies. These studies, however, have included patients on the basis of flu-like symptoms, CRP status, troponin level, ECG changes, or echocardiographic abnormalities. In contrast, we have included all patients referred for CMR work-up of suspected AM. As a result, pre-test likelihood of finding myocarditis on the CMR might have been lower in our study. In this context, we have shown that clinical parameters such as troponin T, chest pain, RWMA and absence of hypertension are independently associated with an abnormal CMR result. The diagnostic yield of CMR will thus increase when patients are selected according these clinical variables. Correlation between clinical presentation and CMR findings In this study, peak troponin T concentration was a strong predictor of a diagnosis on CMR. This predictive value of troponin T most likely reflects the inability of CMR to pick-up small areas of myocardial necrosis because of the relatively large image voxel size. This is supported by findings from a previous study, in which a small group of patients with suspected AM underwent both CMR and EMB.23 In this study, the sensitivity of CMR correlated well with the extent of cell necrosis found in the biopsy specimens. Interestingly, the authors also observed a higher sensitivity of CMR in patients with infarct-like presentations (i.e. chest pain, ST-segment elevation, and troponin elevation) than in those presenting with heart failure or life-threatening arrhythmias. This is in line with our results, in which chest pain and troponin elevation were independent predictors of a diagnostic CMR. There may be several explanations for this finding. First, some of the non-infarct-like presentations might have been caused by cardiac diseases that do not affect the myocardium, such as arrhythmias occurring solely on an electrophysiological basis or LBBB-induced heart failure. Second, patients with chest pain may present earlier after the onset of symptoms than patients with heart failure, who usually have a more gradual increase of symptoms. Previous investigations have shown that the diagnostic performance of CMR is relatively low in the chronic stage of myocarditis.6,10 Third, the pattern of myocardial damage may be different in non-infarct-like presentations as suggested by findings from a previous investigation.4 T2W imaging and LGE show regional differences in contrast between affected and non-affected tissue if there is focal disease, whereas global myocardial disease may not always be identified, especially if skeletal muscle is also inflamed.24 This explains the predictive value of RWMA on echocardiography for a diagnostic CMR. Newer CMR techniques, such as parametric tissue mapping, provide a quantitative characterization of the myocardium per voxel and do not depend on these regional differences. Therefore, tissue mapping has been demonstrated to improve the diagnostic performance of CMR in the setting of suspected myocarditis, especially in patients presenting with heart failure.25,26 We acknowledge the lack of T1- and T2-mapping as a limitation of our study. These methods are predominantly used for scientific purposes to date, and before they can be translated to the clinical routine practice, several issues will still need to be addressed. In particular, there is currently a lack of normal T1 and T2 values across vendors and techniques. Also, the ability of T1- and T2-mapping to differentiate between myocarditis and other cardiac diseases (and not just myocarditis and normal myocardium) has yet to be determined. In addition, although T1- and T2-mapping are becoming increasingly available, they are not yet available in many CMR centres. Importance of CMR within the ESC-PSC To the best of our knowledge, this is the first study to investigate the diagnostic importance of tissue characterization by CMR within the ESC-PSC. In our study, none of the patients who were negative for the ESC-PSC showed evidence of myocarditis on CMR, suggesting that CMR has limited additional diagnostic value in these patients. However, in the ESC-PSC-positive group, CMR identified alternative cardiac disease in a substantial number of patients, thereby reclassifying them to the negative group. The most prevalent alternative cardiac disease was myocardial infarction, as indicated by subendocardial/transmural HE. We found smoking to be independently associated with myocardial infarction on the CMR, which supports the ischaemic aetiology of the subendocardial/transmural HE. It is known that cigarette smoking increases the risk of acute thrombosis and coronary vasospasm.27 We also found older age to be independently associated with myocardial infarction on the CMR, which also favours the ischaemic aetiology. Myocarditis, in contrast to myocardial infarction, predominantly affects young and middle-aged adults.28,29 Nonetheless, the precise mechanisms responsible for the myocardial infarction remain undetermined in this study (embolism or coronary spasm). Considering that the ESC Working Group on myocardial and pericardial diseases currently recommends EMB analysis in ESC-PSC-positive patients, an unnecessary EMB can potentially be avoided by first performing a CMR.2 Nevertheless, in life-threatening presentations where EMB is urgently indicated, CMR should not delay the diagnosis. One hundred and sixteen patients in the insufficient ESC-PSC group did not undergo CAG prior to the CMR examination, most likely due to a high clinical suspicion of myocarditis. In this subgroup, CMR confirmed the suspicion of myocarditis in approximately half of the patients, which may spare them from invasive CAG. CMR also revealed myocardial infarction in this group, despite the low pre-test probability of CAD. Clinical implications By showing the overall good diagnostic yield of CMR, and the substantial number of newly identified alternative cardiac diseases, our study provides strong support for the routine use of CMR in the work-up of suspected AM. Even in patients who fulfilled the 2013 ESC-PSC for clinically suspected myocarditis, CMR reclassified 18% to an alternative cardiac disease. Hence, the number needed to scan to reclassify one person is five. In these patients, CMR findings are likely to affect decision-making regarding subsequent diagnostic testing and therapy, such as referral for CAG or EMB, initiation of antiplatelet therapy, and screening of family members. However, whether this will translate into improved clinical outcomes merits future research. From another perspective, CMR examinations were negative for a diagnosis in about half of the patients, and especially in those without chest pain, without RWMA and with only minimal troponin release. These observations stress the importance of newer T1- and T2-mapping techniques that may provide a more detailed tissue characterization. This is particularly important in myocarditis patients who present with heart failure, as their prognosis is generally worse,28 yet may improve with adequate therapy.30 Study limitations Inherent to the retrospective design of the study, there were some missing data, and selection bias might have occurred. In this context, some cases of suspected myocarditis might have been missed by only using the keywords ‘suspected myocarditis’ as search terms for cases. Nonetheless, this retrospective collection allowed to evaluate the diagnostic yield and incremental value of CMR tissue characterization in a large clinical population with suspected AM. Second, patients with suspected myocarditis are not routinely subjected to EMB at our institution, and therefore we could not corroborate the CMR T1/T2 signals to histopathology. Third, this retrospective study reports the diagnostic yield and incremental value of CMR protocols that were in practice at the two centres during those years, which differs from the current CMR protocol for myocarditis. T2W imaging was, for example, not available in all studies and was mostly performed in three slices instead of whole heart coverage. In addition, small variations in T2w imaging protocols (i.e. sequences parameters, cardiac phased array coils, and image prescan normalization filters) did not allow reliable T2 SI ratio assessment. It can be argued that this may account for some of the CMR tissue-negative cases in which only cine imaging and LGE were performed. Also, in cases with LGE only, we cannot confirm that the HE lesions are acute, although the acute onset of symptoms makes it plausible. Furthermore, in the patient with HCM, the rare possibility of severe global oedema as cause of the hypertrophy cannot be ruled out without follow-up imaging.31 Nevertheless, the acquisition of good-quality T2w images remains challenging as this method is sensitive to cardiac motion, surface coil intensity inhomogeneity and inadequate suppression of blood, especially in sick patients with high or irregular heart rate or pericardial effusion.32 These technical difficulties may explain why T2W imaging was not performed in all patients. Our CMR protocol did not include early gadolinium enhancement (EGE) or, as mentioned above, T1- and T2-mapping. EGE is, however, sensitive to respiratory artefacts and dramatically increases scan time, which hampers its use in clinical practice. Furthermore, removal of EGE from the CMR protocol does not change the diagnostic overall accuracy of CMR, although it does reduce some if its sensitivity.33 Also, EGE is considered optional according to the SCMR board of trustees task force on standardized protocols.34 Despite the modified CMR protocol, we still found CMR to provide a good diagnostic yield and incremental diagnostic value in patients with suspected AM. Fourth, CMR reader was not blinded to the clinical parameters, which might have introduced some bias in the evaluation of the CMR images. Conclusion Tissue characterization by CMR provided a good diagnostic yield in our large clinical population of patients who were referred for work-up of suspected AM. CMR added diagnostic information in patients who met the ESC-PSC and reclassified a substantial number of to an alternative cardiac disease. Our study provides strong support for the routine use of CMR in the work-up of suspected AM. Large-scale multicentre cohorts are, however, needed to investigate prognostic implications of CMR findings, preferably including the use of parametric tissue mapping. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: None declared. References 1 Biesbroek PS , Beek AM , Germans T , Niessen HW , van Rossum AC. Diagnosis of myocarditis: current state and future perspectives . Int J Cardiol 2015 ; 191 : 211 – 9 . Google Scholar Crossref Search ADS PubMed 2 Caforio AL , Pankuweit S , Arbustini E , Basso C , Gimeno-Blanes J , Felix SB et al. 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Variability and homogeneity of cardiovascular magnetic resonance myocardial T2-mapping in volunteers compared to patients with edema . J Cardiovasc Magn Reson 2013 ; 15 : 27. Google Scholar Crossref Search ADS PubMed 33 Chu GC , Flewitt JA , Mikami Y , Vermes E , Friedrich MG. Assessment of acute myocarditis by cardiovascular MR: diagnostic performance of shortened protocols . Int J Cardiovasc Imaging 2013 ; 29 : 1077 – 83 . Google Scholar Crossref Search ADS PubMed 34 Kramer CM , Barkhausen J , Flamm SD , Kim RJ , Nagel E ; Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols . Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update . J Cardiovasc Magn Reson 2013 ; 15 : 91 . Google Scholar Crossref Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. 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Additional diagnostic value of CMR to the European Society of Cardiology (ESC) position statement criteria in a large clinical population of patients with suspected myocarditis

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Abstract

Abstract Aims To determine the diagnostic yield of tissue characterization by cardiovascular magnetic resonance (CMR) in a large clinical population of patients with suspected acute myocarditis (AM) and to establish its diagnostic value within the 2013 European Society of Cardiology position statement criteria (ESC-PSC) for clinically suspected myocarditis. Methods and results In this retrospective study, CMR examinations of 303 hospitalized patients referred for work-up of suspected AM in two tertiary referral centres were analysed. CMR was performed at median 7 days (interquartile range 4–20 days) after clinical presentation and included cine imaging, T2-weighted imaging, and late gadolinium enhancement. CMR images were evaluated to assign each patient to a diagnosis. By using non-CMR criteria only, the 2013 ESC-PSC were positive for suspected myocarditis in 151 patients and negative in 30. In the remaining 122 patients, there was insufficient information available for ESC-PSC assessment, mostly due to lack of coronary angiography (CAG) before the CMR examination (n = 116, 95%). There were no in-hospital deaths. CMR provided a diagnosis in 158 patients (52%), including myocarditis in 104 (34%), myocardial infarction in 44 (15%), and other pathology in 10 patients (3%). Non-urgent CAG (>24 h after presentation) was performed before the CMR examination in 85 patients, of which 20 (24%) were done in patients with subsequently confirmed AM, which could potentially have been avoided if CMR was performed first. ESC-PSC was correct in diagnosing AM before the CMR in 50 of the 151 patients (33%) and was correct in ruling out AM in all the 30 patients (100%). However, ESC-PSC provided an incorrect diagnosis of AM in 27 of the 151 patients (18%), which was corrected by CMR through the identification of new cardiac disease that could explain the clinical syndrome. Patients with insufficient ESC-PSC information had a relatively low pre-test probability of coronary artery disease. In this group, CMR confirmed the diagnosis of AM in a relatively high percentage (44%) but still revealed myocardial infarction in 8% of them. Conclusion Tissue characterization by CMR provided a good diagnostic yield in this large clinical population of patients with suspected AM. CMR provided incremental diagnostic value to the ESC-PSC by ruling out the diagnosis of AM on one hand and by potentially sparing AM patients from CAG on the other. cardiovascular magnetic resonance, myocarditis, diagnostic value, clinical presentation, ESC position statement criteria Introduction Recognition of myocarditis in clinical practice represents a challenge for physicians, because patients may present with a wide range of symptoms and in various disease stages. Electrocardiography (ECG), echocardiography, and coronary angiography (CAG) can be used to support the suspicion of myocarditis, but findings are relatively non-specific and overlap with other cardiac diseases.1 To improve its recognition in clinical practice and to aid the selection of patients that require further diagnostic evaluation by endomyocardial biopsy (EMB), the 2013 European Society of Cardiology (ESC) position statement2 proposed new criteria for clinically suspected myocarditis, which include a combination of clinical and diagnostic features. Tissue characterization by cardiovascular magnetic resonance (CMR) is one of the components of the ESC position statement criteria (ESC-PSC) and enables the detection of myocardial oedema and myocardial injury in the setting of acute myocarditis (AM). Currently available CMR studies in patients with suspected AM have shown the ability of CMR to diagnose myocarditis, but most are relatively small and single centre, with highly selected patient populations.3–10 In this context, some studies only included patients who presented with chest pain, while others included patients with any symptom suggestive of myocarditis. In addition, several studies incorporated additional inclusion criteria such as the presence of elevated cardiac troponin, elevated C-reactive protein (CRP) or flu-like symptoms. As a result of these differing inclusion criteria, and thus heterogeneous patient populations, studies have reported widely varying rates of abnormal CMR results, and therefore the diagnostic yield of CMR in a clinical routine population with suspected AM is not well defined. Furthermore, the diagnostic importance of CMR remains to be validated in larger cohorts. The aim of this retrospective study was to assess the diagnostic yield of CMR tissue characterization in a large clinical population with suspected AM. Second, the additional value of CMR tissue characterization above non-CMR diagnostic methods within the ESC-PSC was investigated. Methods Patient population This retrospective two-centre study consisted of 303 patients who were admitted to the hospital and referred for CMR work-up of clinically suspected AM in two tertiary referral centres in Amsterdam, The Netherlands [200 patients from the VU University Medical Center (VUmc) between January 2003 and August 2016 and 103 patients from the Academic Medical Center (AMC) between January 2009 and August 2016]. The CMR referral for suspected myocarditis was left to the discretion of the treating physician, reflecting usual clinical practice patterns in those centres. Patients were identified in our local electronic databases (Microsoft Office Access in the VUmc and SPSS in the AMC) by searching for ‘suspected myocarditis’ in the reason for request field. Only patients who had been hospitalized for their clinical condition with recent onset of symptoms (days up to 3 months) and scheduled for an initial CMR examination were included. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local institutional review board (VUmc, Amsterdam, The Netherlands), who waived the requirement for informed consent due to the retrospective nature of the study. CMR protocol CMR imaging was performed on a 1.5-T whole body clinical MR system (Avanto or Sonata, Siemens Healthcare, Erlangen, Germany). Functional imaging was performed using a segmented, balanced steady-state free precession cine imaging with breath holding. Myocardial oedema was identified using a T2-weighted (T2W) triple inversion recovery sequence. Late gadolinium enhancement (LGE) images were acquired 10–15 min after the administration of 0.2 mmol/kg of gadolinium-based contrast agent using an inversion-recovery gradient-echo pulse sequence with continued adjustment of inversion time to null normal myocardium. Cine and LGE images were acquired in four-, three, and two-chamber long-axis views and short-axis orientations covering the entire left ventricle. T2W imaging was performed at least in three short-axis slices (basal, mid, and apical) or three long-axis slices (four-, three-, and two chambers) to allow oedema visualisation of all myocardial segments. CMR analysis and diagnosis All CMR images were evaluated by experienced CMR readers. For any disagreement in the CMR evaluation, consensus agreement was reached between the two readers (A.H. and R.N.). T2W images were considered to demonstrate myocardial oedema when focal areas of visually apparent high signal intensity were present. Hyperenhancement (HE) was considered to be present on the LGE images when focal areas of high signal intensity were found on both short-axis and matching long-axis views. The pattern of HE was visually assessed and categorized as subendocardial, transmural, mid-myocardial patchy, mid-myocardial striae, subepicardial, pericardial, or at the right ventricular (RV) insertion points. T2W images were used to determine whether HE lesions were acute, which was not possible in CMR studies that only included LGE imaging. After reviewing all the CMR images, each patient was assigned to a diagnosis. Myocarditis was diagnosed in the presence of subepicardial or mid-wall patchy HE with or without regionally matched oedema.11 Myocardial infarction required subendocardial/transmural HE in a coronary artery territory with or without regionally matched oedema. Coronary artery disease (CAD) on CAG was not required, because myocardial infarction can also be the result of coronary spasm or resolved thrombus.12 Dilated non-ischaemic cardiomyopathy with mid-wall fibrosis (NIDCM-MWF) was defined in the presence of a longitudinal striae of mid-wall HE within the septum in combination with left ventricular (LV) dilatation and systolic LV dysfunction.13 Takotsubo cardiomyopathy was diagnosed when a typical takotsubo pattern of akinesia/ballooning was present with or without patchy HE and/or oedema. The revised task force criteria were used to define the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC).14 Hypertrophic cardiomyopathy (HCM) required a hypertrophied, non-dilated LV with a maximal wall thickness of ≥15 mm in the absence of a pressure overloading condition (i.e. hypertension and aortic stenosis) severe enough to cause the observed hypertrophy.15 CMR studies were classified as inconclusive in case of doubt between two or more diagnosis, for example ARVC and myocarditis or multiple coronary thrombi and myocarditis. These inconclusive CMR scans had good image quality, but the oedema and/or HE findings were ambiguous and one diagnosis could not be made with reasonable certainty. CMR scans without specific tissue characteristics (tissue negative) had absence of oedema, absence of HE, and absence of morphological and/or functional criteria for HCM, ARVC, and takotsubo. These tissue-negative cases were allowed to show decreased ejection fraction (LVEF) and/or increased LV dilatation, as long as none of the above-mentioned diagnostic criteria were fulfilled. Commercially available softwares (QMass, Medis, Leiden, The Netherlands; MASS, Medis, Leiden, The Netherlands; or Argus, Siemens Healthcare, Erlangen, Germany) were used to determine LV end-diastolic volume (EDV), LV end-systolic volume (ESV), and LVEF after manually tracing the endocardial borders on the cine short-axis stacks, according to SCMR (2013) guidelines on CMR image post-processing.16 Clinical assessment Patient demographics, medical history, cardiovascular risk profile, and clinical presentation were obtained from medical records. C-reactive protein was measured on admission and a value of more than 5 mg/L was defined as elevated. Cardiac troponin T concentration was considered elevated if the value exceeded 0.3 µg/L. Cardiac troponin T levels were determined approximately every 6–12 h until there was a peak and decline in serum concentration. The presence of unobstructed (<50% diameter stenosis) coronary arteries was assessed by invasive CAG. Twelve-lead ECGs were recorded on entry and were reviewed by an experienced reader who was blinded to the CMR results (P.S.B.). ECGs were scored for arrhythmias, conduction disturbances, ST-segment deviation, negative T waves, pathological Q waves, and PR segment depression, according to previously published criteria.17,18 A detailed description of the ECG criteria are provided in the Supplementary Data S1. Echocardiographic measurements of LV dimensions and function were extracted from clinical reports of echocardiography and were determined by visual assessment or by using 2D or M-mode measurements. Because of the retrospective nature of the study, the following variables had missing data: 12-lead ECG findings (14%), CRP measurement (12%), troponin T measurement (10%), and echocardiography findings (7%). Missing data for all other variables were ≤ 5%. ESC-PSC Patients were classified into those fulfilling and those not fulfilling the 2013 ESC-PSC, by using non-CMR criteria only. The 2013 ESC-PSC, without the CMR tissue characterization criterion, are summarized in Table 1 and are described in detail elsewhere.2 A reclassification between the ESC-PSC groups was defined as present when (i) CMR detected new cardiac disease that could explain the clinical in patients who fulfilled the 2013 ESC-PSC or when (ii) CMR detected myocarditis in patients who did not fulfil the 2013 ESC-PSC. NIDCM-MWF on CMR was not deemed to be a new cardiac disease, as myocarditis is one of the possible causes of DCM.2 Table 1 ESC position statement criteria for clinically suspected myocarditis without the CMR tissue characterization criterion (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome Table 1 ESC position statement criteria for clinically suspected myocarditis without the CMR tissue characterization criterion (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome (1) One or more of the clinical presentation criteria acute chest pain new-onset or worsening of dyspnoea at rest or exercise subacute/chronic or worsening of dyspnoea at rest or exercise palpitations, unexplained arrhythmia symptoms, syncope, aborted sudden cardiac death, and unexplained cardiogenic shock (2) One or more of the diagnostic criteria new abnormalities on 12-lead electrocardiogram or 24 h rhythm registration elevated levels of cardiac troponin T functional or structural abnormalities on cardiac imaging (echo/angio) (3) Absence of significant (>50%) obstructive coronary artery disease on coronary angiography (4) Absence of known pre-existing cardiovascular disease or extra-cardiac causes that could explain the syndrome Statistical analysis Data are presented as mean ± SD for normally distributed continuous variables, median and interquartile range (IQR) for non-normally distributed continuous variables, and as number/total number (%) for categorical variables. Histograms were used to determine if continuous variables were normally distributed. Mean values were compared between subgroups of patients using an independent-samples t-test or Mann–Whitney U test for, respectively, normally distributed and non-normally distributed continuous variables. Categorical values were compared between subgroups of patients using a χ2 test. Univariate binary logistic regression analyses were used to identify variables that were significantly associated with CMR results. Variables with a P-value <0.10 in univariate analyses were subsequently included in a multivariate regression using forward selection. All statistical analyses were performed using SPSS statistics (IBM SPSS Statistics 22, Chicago, IL, USA). A P-value of < 0.05 was considered statistically significant. Results A total of 303 hospitalized patients referred for CMR because of suspected AM were included in this study. Mean age of the population was 46 ± 17 years and 67% were male (Table 2). Chest pain was the most common presenting symptom (60%), followed by new-onset or worsening of dyspnoea (29%), palpitations (7%), and collapse (4%). Thirty-five patients (12%) presented to the hospital because of out of hospital cardiac arrest. Arrhythmias were documented at presentation in 62 patients (20%), including ventricular fibrillation or sustained ventricular tachycardia in 44, supraventricular tachycardia in 14, third-degree atrioventricular block in three, and asystole in one patient. There were no in-hospital deaths. Table 2 Patient demographic and clinical characteristics overall and in relation to the diagnosis on CMR Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Values are mean ± standard deviation, median (interquartile range), or n/N (%). a Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S1. b A negative result was allowed to show morphological and/or functional abnormalities, as long as none of the diagnostic criteria were fulfilled. c Values were compared in patients with elevated levels. d PR segment depression could not be scored in some patients due to atrial arrhythmias. STE, ST-segment elevation; HIV: human immunodeficiency virus. Table 2 Patient demographic and clinical characteristics overall and in relation to the diagnosis on CMR Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Total cohort Subgroups according to CMR resulta All patients (N = 303) Myocarditis (N = 104) Myocardial infarction (N = 44) Tissue-negative resultb (N = 123) P-value, myocarditis vs. tissue negative P-value, infarction vs. tissue negative Age (years) 46 ± 17 39 ± 16 51 ± 16 49 ± 17 <0.001 0.60 Age under 40 years 113/303 (37) 61/104 (59) 10/44 (23) 35/12 (29) <0.001 0.46 Male 204/303 (67) 81/104 (78) 29/44 (66) 75/123 (61) 0.006 0.56 Cardiovascular risk factors  Hypertension 70/290 (24) 14/99 (14) 12/43 (28) 32/117 (27) 0.018 0.94  Hypercholesterolemia 21/290 (7) 7/99 (7) 4/43 (9) 7/117 (6) 0.75 0.44  Diabetes mellitus 24/290 (8) 1/99 (1) 6/43 (14) 15/117 (13) 0.001 0.85  Current or former smoking 98/290 (34) 29/99 (29) 22/43 (51) 35/117 (30) 0.92 0.013 Presenting symptoms  Chest pain 179/299 (60) 77/101 (76) 26/44 (59) 60/122 (49) <0.001 0.26  Dyspnoea 88/299 (29) 19/101 (19) 15/44 (34) 41/122 (34) 0.013 0.95  Palpitations 20/299 (7) 5/101 (5) 2/44 (5) 8/122 (7) 0.61 0.63  Collapse 13/299 (4) 4/101 (4) 1/44 (2) 5/122 (4) 0.96 0.58 Out-of-hospital cardiac arrest 35/299 (12) 5/101(5) 6/44 (14) 23/122 (19) 0.002 0.44 History of a recent infection 85/290 (29) 49/99 (50) 6/43 (14) 28/117 (24) <0.001 0.17 History of rheumatic/autoimmune disease 13/290 (5) 3/99 (3) 1/43 (2) 7/117 (6) 0.30 0.35 HIV infection 5/290 (2) 4/99 (4) 1/43 (2) 0/117 (0) 0.028 0.098 Blood results  Elevated CRP, >5 mg/L 154/268 (58) 76/94 (81) 19/39 (49) 46/109 (42) <0.001 0.48   CRP (mg/L)c 30.5 (12.0–100.5) 43.5 (20.4–129.7) 48.0 (17.0–161.0) 20.8 (8.9–80.0) 0.047 0.16  Elevated troponin T, >0.03 µg/L 224/272 (82) 83/94 (88) 40/42 (95) 77/108 (71) 0.003 0.001   Peak troponin T (µg/L)c 0.49 (0.14–1.25) 0.92 (0.27–1.72) 0.92 (0.37–1.74) 0.22 (0.08–0.50) <0.001 <0.001 Electrocardiogram  Left bundle branch block 22/261 (8) 3/85 (4) 4/41 (10) 14/110 (13) 0.024 0.62  Right bundle branch block 9/261 (3) 0/85 (0) 2/41 (5) 7/110 (6) 0.018 0.73  Left ventricular hypertrophy 9/261 (3) 1/85 (1) 1/41 (2) 6/110 (6) 0.11 0.43  Low QRS voltages 5/261 (2) 1/85 (1) 1/41 (2) 2/110 (2) 0.72 0.81  PR-segment depressiond 25/248 (10) 12/81 (15) 2/37 (5) 9/105 (9) 0.18 0.54  Pathological Q wave 41/261 (16) 14/85 (17) 11/41 (27) 11/110 (10) 0.18 0.009  STE 83/261 (32) 46/85 (54) 12/41 (29) 21/110 (19) <0.001 0.18   Number of leads with STE 4 (2–6) 5 (3–6) 4 (1–5) 2 (2–5) 0.007 0.93   Sum of STE (mm) 5.0 (3.0–8.0) 5.5 (3.5–8.6) 5.3 (1.8–9.1) 4.3 (4.0–6.5) 0.08 0.45   Average STE per lead (mm) 1.3 (1.0–1.7) 1.2 (1.0–1.5) 1.9 (1.0–2.0) 1.3 (1.0–1.6) 0.33 0.43   Reciprocal STD 48/81 (59) 24/46 (52) 9/12 (75) 15/21 (71) 0.138 0.83  Negative T wave 87/261 (33) 18/85 (21) 21/41 (51) 34/110 (31) 0.128 0.021 Echocardiography  Impaired LV systolic function 135/281 (48) 33/93 (36) 26/44 (59) 56/116 (48) 0.063 0.22  RWMA 99/281 (35) 37/93 (40) 23/44 (52) 29/116 (25) 0.017 0.001  LV dilatation 56/281 (20) 11/93 (12) 8/44 (18) 26/116 (22) 0.046 0.56  Pericardial effusion 42/281 (15) 17/93 (18) 5/44 (11) 19/116 (16) 0.72 0.43 Values are mean ± standard deviation, median (interquartile range), or n/N (%). a Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S1. b A negative result was allowed to show morphological and/or functional abnormalities, as long as none of the diagnostic criteria were fulfilled. c Values were compared in patients with elevated levels. d PR segment depression could not be scored in some patients due to atrial arrhythmias. STE, ST-segment elevation; HIV: human immunodeficiency virus. Diagnostic yield of tissue characterization by CMR The CMR findings are summarized in Table 3. Median time from presentation to CMR was 7 days (IQR 4–20 days). LGE and T2W imaging were performed in, respectively, 100% and 87% of the CMR examinations. Mean LVEF was 48 ± 13% and was impaired (i.e. lower than 55%) in 179 patients (59%). Table 3 Cardiovascular magnetic resonance results Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Values are mean ± standard deviation, median (interquartile range), or n/N (%). Table 3 Cardiovascular magnetic resonance results Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Time from presentation to CMR (days) 7 (4–20) T2W-imaging protocol 264/303 (87)  Myocardial oedema present 102/264 (39)  Insufficient quality 13/264 (5) LGE protocol 303/303 (100)  Hyperenhancement present 168/303 (55)  Hyperenhancement location   Subepicardial 81/168 (48)   Mid-myocardial patchy 29/168 (17)   Transmural 24/168 (14)   Subendocardial 21/168 (13)   Mid-myocardial striae 5/168 (3)   Pericardial 3/168 (2)   RV insertion points 4/168 (2)   RV free wall 1/168 (1)  Inconclusive 4/303 (1) Microvascular injury present 7/303 (2) LV volumes and function  EDV (mL) 194 ± 67  ESV (mL) 105 ± 65  EF (%) 48 ± 13  Systolic dysfunction (EF < 55%) 179 (59)   EF (%) 41 ± 12 CMR-based diagnosis  Myocarditis 104/303 (34)  Myocardial infarction 44/303 (15)  Other pathology   Takotsubo cardiomyopathy 3/303 (1)   ARVC 2/303 (1)   NIDCM-MWF 4/303 (1)   HCM 1/303 (0)  Inconclusive result 22/303 (7) Values are mean ± standard deviation, median (interquartile range), or n/N (%). Of the 264 examinations that included T2W imaging, oedema could not be defined due to insufficient image quality in 13 (5%). Myocardial oedema was found in 102 (41%) of the remaining 251 studies. Image quality of the LGE images was clinically useful in all the studies. There was definite HE in 168 studies (55%) and possible HE (i.e. possibility of artefact could not be excluded) in 4 (1%), which was scored as inconclusive HE. T2W imaging was performed in 149 of the 168 studies with HE (89%) and demonstrated regionally matched oedema in 96 of them (64%). T2W imaging was performed in 113 of the 131 (86%) examinations without HE on the LGE images. Of these 113 CMR scans, T2W images were of insufficient image quality in 5 (4%), demonstrated normal findings in 102 (90%), and showed oedema in 6 (5%). The predominant pattern of HE was myocarditic (subepicardial/mid-myocardial patchy) in 110 patients (65%), myocardial infarction (subendocardial/transmural) in 45 (27%), mid-myocardial striae in 5 (3%) as seen in NIDCM-MWF, and at the RV insertion points in four patients (2%). Three patients showed pericardial HE, and one patient demonstrated HE of the RV free wall. Additionally, seven patients had microvascular injury, as indicated by the presence of hypointense cores in T2w and LGE images within transmural infarction (see Supplementary data online, Figure S1). Of those seven patients, three had non-obstructive coronaries on CAG. Based on the T2W and LGE findings, a definite diagnosis was made in 158 patients (52%). The most common diagnoses were myocarditis in 104 (34%) (Figure 1) and myocardial infarction in 44 (15%) (Figure 2). Other diagnoses were takotsubo cardiomyopathy in three, ARVC in two, NIDCM-MWF in four, and HCM in one (see Supplementary data online, Figure S2). In the three patients with takotsubo, myocardial infarction was ruled out by CAG in one and was considered unlikely in the other two because of a complete normalization of LV function at follow-up echocardiography. CMR findings were inconclusive in 22 patients (7%) due to artefacts or unspecific findings. The CMR examination was interpreted as tissue negative in 123 patients (41%). In the aforementioned six patients with myocardial oedema but no HE, the diagnoses were takotsubo cardiomyopathy in two and inconclusive in three patients. In the last patient, the myocardial oedema was believed to be due to a myocardial infarction, because the oedema was transmural and clearly limited to one coronary artery territory. In the three inconclusive scans, there was only a very small area of oedema found, which made it challenging to distinguish between myocarditis and myocardial infarction (e.g. due to embolus). Supplementary data online, Table S1, describes the LV volumes and function according to the CMR diagnoses. The final diagnosis in the patient group that presented with out of hospital cardiac arrest was as follows: myocardial infarction in 6 (17%), myocarditis in 5 (14%), and ARVC in 1 (3%). CMR examinations were classified as negative for a diagnosis in 23 patients (66%). Figure 1 View largeDownload slide A 36-year-old man who presented with chest pain since 4 weeks. Cardiac troponin T level was elevated. The electrocardiogram (upper left panel), echocardiogram, and coronary angiogram (lower left panel) did not show any abnormalities. CMR demonstrated subepicardial hyperenhancement in the inferior and inferolateral basal walls, with matching high signal intensity on the T2W images, consistent with an acute myocarditis (right panel). Figure 1 View largeDownload slide A 36-year-old man who presented with chest pain since 4 weeks. Cardiac troponin T level was elevated. The electrocardiogram (upper left panel), echocardiogram, and coronary angiogram (lower left panel) did not show any abnormalities. CMR demonstrated subepicardial hyperenhancement in the inferior and inferolateral basal walls, with matching high signal intensity on the T2W images, consistent with an acute myocarditis (right panel). Figure 2 View largeDownload slide A 43-year-old man with a history of human immunodeficiency virus infection who presented with acute chest pain, cardiac troponin elevation, ST-segment elevation in multiple leads/territories (upper right panel), and non-obstructive coronary arteries on the coronary angiogram (left panel). CMR with LGE showed transmural hyperenhancement in the apical inferior and septal walls, with matching hyperintensity on the T2W images, consistent with acute myocardial infarction (lower left panel). RCA, right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending. Figure 2 View largeDownload slide A 43-year-old man with a history of human immunodeficiency virus infection who presented with acute chest pain, cardiac troponin elevation, ST-segment elevation in multiple leads/territories (upper right panel), and non-obstructive coronary arteries on the coronary angiogram (left panel). CMR with LGE showed transmural hyperenhancement in the apical inferior and septal walls, with matching hyperintensity on the T2W images, consistent with acute myocardial infarction (lower left panel). RCA, right coronary artery; LCX, left circumflex coronary artery; LAD, left anterior descending. Of the 180 CAGs that were performed before the CMR examination, 65 (36%) were emergent/urgent (≤24 h after presentation), 85 (47%) were non-urgent (>24 h after presentation), and 6 (3%) were performed before the clinical presentation (outpatient setting or during a previous admission). The exact time from presentation to CAG could not be obtained in 24 patients (13%). CMR confirmed the diagnosis of AM in 20 of the 85 patients (24%) who had undergone non-urgent CAG before the CMR examination, which could potentially have been avoided if CMR was performed first. Differences in clinical presentation between groups based on CMR findings and predictors of diagnosis We compared characteristics of patients with a tissue-negative CMR result to those with a diagnosis on CMR (i.e. myocarditis, myocardial infarction, or other). Table 2 reports the differences between patients with a tissue-negative CMR result, patients with myocarditis, and patients with myocardial infarction. Compared with the tissue-negative group, the myocarditis group was significantly younger (39 ± 16 vs. 49 ± 17 year, P < 0.01) and had a significantly lower proportion of heart-failure-like presentations (19% vs. 34%, P = 0.01). Both the myocarditis and the myocardial infarction groups had a significantly higher cardiac troponin T concentration and a higher proportion of regional wall motion abnormalities (RWMA) on echocardiography when compared with the tissue-negative CMR group (median troponin T values: 0.92, 0.92, and 0.22 µg/L, respectively; proportion of RWMA: 40%, 52%, and 25%, respectively). Differences in peak troponin T concentrations between the CMR groups are illustrated in Figure 3. Characteristics of patients with inconclusive CMR results and with other pathology are reported in the Supplementary data online, Table S2. (Figure 3). Figure 3 View largeDownload slide Peak cardiac troponin T concentrations between groups stratified according to CMR findings. The y-axis is on a log scale. Squares and error bars represent median and interquartile range. Double and triple asterisks indicate P-values <0.01 and 0.001. Inconc, inconclusive result; other, other pathology. Figure 3 View largeDownload slide Peak cardiac troponin T concentrations between groups stratified according to CMR findings. The y-axis is on a log scale. Squares and error bars represent median and interquartile range. Double and triple asterisks indicate P-values <0.01 and 0.001. Inconc, inconclusive result; other, other pathology. To identify patients in whom CMR examination will likely result in a diagnosis, we determined clinical predictors of a diagnosis on CMR. As demonstrated in Table 4, peak troponin T concentration was independently associated with any diagnosis on CMR [odds ratio (OR) 1.24 per 1 μg/L increase, P = 0.04], as were elevated troponin T (OR 2.51, P = 0.03), chest pain (OR 2.37, P < 0.01), absence of hypertension (OR 2.22, P = 0.02), and RWMA on echocardiography (OR 1.96, P = 0.03) [area under the curve (AUC) = 0.76]. To identify clinical parameters that can predict the diagnosis on CMR, we determined independent sets of predictors for myocarditis and for myocardial infarction in a multivariate analysis (see Supplementary data online, Table S3). Multivariate regression analyses showed age under 40 years (OR 2.24, P = 0.03), elevated CRP (5.12, P < 0.01), absence of dyspnoea (OR 2.50, P = 0.04), and presence of ST-segment elevation (OR 2.03, P = 0.048) to be independently associated with myocarditis on CMR (AUC = 0.74). Age above 40 years (OR 2.56, P = 0.04), current or former smoking (OR 2.37, P = 0.02), absence of a recent infection (OR 2.94, P = 0.04), RWMA on echocardiography (OR 2.28, P = 0.03), and peak troponin T concentration (OR 1.24, P = 0.01) were found to be independently associated with myocardial infarction on CMR (AUC = 0.60). Table 4 Univariate and multivariate analysis for predictors of any diagnosis on CMR Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Only variables with a P-value <0.10 in univariate analyses are shown. CI, confidence interval. Table 4 Univariate and multivariate analysis for predictors of any diagnosis on CMR Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Univariate analysis Multivariate analysis OR (95% CI) P-value OR (95% CI) P-value Age under 40 years 2.25 (1.40–3.64) 0.001 Male sex 1.68 (1.04–2.73) 0.035 Hypertension 0.60 (0.35–1.04) 0.067 0.45 (0.230.89) 0.021 Diabetes mellitus 0.42 (0.18–1.02) 0.056 Chest pain 2.10 (1.31–3.37) 0.002 2.37 (1.31–4.30) 0.004 Dyspnoea 0.65 (0.40–1.08) 0.094 History of a recent infection 2.19 (1.30–3.71) 0.003 Elevated troponin T, >0.03 µg/L 3.86 (1.94–7.70) <0.001 2.51 (1.08–5.80) 0.032 Peak troponin T (µg/L) 1.54 (1.18–2.01) 0.001 1.24 (1.01–1.53) 0.040 Elevated CRP, >5 mg/L 2.92 (1.76–4.83) <0.001 1.79 (1.00–3.23) 0.052 Left bundle branch block 0.41 (0.16–1.05) 0.062 ST-segment elevation 3.18 (1.80–5.63) <0.001 Pathological Q waves 2.15 (1.05–4.40) 0.035 RWMA on echocardiography 2.23 (1.35–3.70) 0.002 1.96 (1.06–3.64) 0.032 LV dilatation on echocardiography 0.58 (0.32–1.05) 0.070 Only variables with a P-value <0.10 in univariate analyses are shown. CI, confidence interval. Additional diagnostic value of CMR within the ESC-PSC To determine the additional diagnostic value of CMR in the work-up of suspected AM, we explored the impact of findings from CMR on the classification of patients according to the 2013 ESC-PSC. By using non-CMR criteria only, the 2013 ESC-PSC were positive for suspected myocarditis in 151 patients and negative in 30. Figure 4 shows the CMR results stratified according to the non-CMR diagnostic work-up, to evaluate the number of patients with reclassified diagnosis. In the ESC-PSC-negative group, none of the patients had myocarditis on CMR, but 10 patients (33%) had myocardial infarction, and two patients (7%) takotsubo cardiomyopathy. In the ESC-PSC-positive group, 50 patients (33%) showed evidence of myocarditis on CMR. CMR additionally identified alternative cardiac disease that could explain the clinical syndrome in 27 patients (18%) (i.e. myocardial infarction in 24, ARVC in two, and HCM in one patient), thereby reclassifying them to the negative ESC-PSC group. Figure 4 View largeDownload slide CMR results stratified according to the pre-CMR diagnostic work-up. Cath, catheterization; Takotsubo, takotsubo cardiomyopathy. Figure 4 View largeDownload slide CMR results stratified according to the pre-CMR diagnostic work-up. Cath, catheterization; Takotsubo, takotsubo cardiomyopathy. In the remaining 122 patients, there was insufficient information available for ESC-PSC assessment. In this group, CMR confirmed the diagnosis of myocarditis in 54 (44%) and revealed myocardial infarction in 10 (8%), NIDCM-MWF in 1 (1%) and takotsubo in 1 (1%) of the patients. In 116 of the 122 (95%) patients, ESC-PSC could not be assessed because CAG was not performed before the CMR examination to exclude obstructive CAD. These 116 patients were more likely to have a history of recent infection (45% vs. 20%, P < 0.01) and more often had CRP elevation (71% vs. 49%, P < 0.01), suggesting a higher clinical suspicion of myocarditis. Furthermore, they were significantly younger (41 ± 18 vs. 50 ± 15, P < 0.01), less often had hypertension (17% vs. 29%, P = 0.03), and tended to have a lower rate of diabetes mellitus (5% vs. 11%, P = 0.07), suggesting a lower pre-test probability of CAD. In the same subgroup of 116 patients, CAG was performed after CMR in 7 of 52 patients with myocarditis (13%), 8 of 10 with myocardial infarction (80%), 13 of 46 with a tissue-negative result (28%), and in the patient with NIDCM-WMF (100%), showing obstructed CAD in, respectively, 0%, 50%, 15%, and 100% of the patients (see Supplementary data online, Figure S3). Coronary intervention was deemed necessary in three patients with myocardial infarction, one with a tissue-negative CMR result, and in one patient with NIDCM-MWF. Discussion This study was conducted to establish the diagnostic yield of tissue characterization by CMR in a large clinical patient population with suspected AM and in relation to non-CMR diagnostic methods. The main findings of this study are that (i) tissue characterization by CMR provided a diagnosis in the majority of hospitalized patients referred for CMR with AM suspicion; (ii) troponin T, chest pain, RWMA on echocardiography, and absence of hypertension were independent predictors of a diagnosis on the CMR (i.e. myocarditis, myocardial infarction, or other); and (iii) CMR reclassified 18% of the patients who were positive for suspected AM according to the 2013 ESC-PSC to a new unexpected cardiac disease that could explain the clinical syndrome. Diagnostic yield of CMR in suspected AM In previous studies, rates of abnormal CMR findings in the setting of clinically suspected AM varied greatly among studies, ranging from 35% to 100% for LGE4–10,19–21 and 45% to 84% for T2W imaging.6,8,9,19,20,22 Rather than selecting only patients presenting with chest-pain syndromes, with heart-failure-like symptoms, or with symptoms that are accompanied by elevated CRP or viral history, this retrospective study includes a less-selected patient cohort presenting with suspected myocarditis and assesses the additional diagnostic value of CMR to the 2013 ESC PSC for myocarditis. We found that CMR was able to provide a diagnosis in approximately half of the patients. In particular, CMR confirmed the clinical suspicion of myocarditis in one-third and diagnosed alternative cardiac disease in 54 patients (18%). The proportion of patients with myocarditis in our study is lower than in most previous studies. These studies, however, have included patients on the basis of flu-like symptoms, CRP status, troponin level, ECG changes, or echocardiographic abnormalities. In contrast, we have included all patients referred for CMR work-up of suspected AM. As a result, pre-test likelihood of finding myocarditis on the CMR might have been lower in our study. In this context, we have shown that clinical parameters such as troponin T, chest pain, RWMA and absence of hypertension are independently associated with an abnormal CMR result. The diagnostic yield of CMR will thus increase when patients are selected according these clinical variables. Correlation between clinical presentation and CMR findings In this study, peak troponin T concentration was a strong predictor of a diagnosis on CMR. This predictive value of troponin T most likely reflects the inability of CMR to pick-up small areas of myocardial necrosis because of the relatively large image voxel size. This is supported by findings from a previous study, in which a small group of patients with suspected AM underwent both CMR and EMB.23 In this study, the sensitivity of CMR correlated well with the extent of cell necrosis found in the biopsy specimens. Interestingly, the authors also observed a higher sensitivity of CMR in patients with infarct-like presentations (i.e. chest pain, ST-segment elevation, and troponin elevation) than in those presenting with heart failure or life-threatening arrhythmias. This is in line with our results, in which chest pain and troponin elevation were independent predictors of a diagnostic CMR. There may be several explanations for this finding. First, some of the non-infarct-like presentations might have been caused by cardiac diseases that do not affect the myocardium, such as arrhythmias occurring solely on an electrophysiological basis or LBBB-induced heart failure. Second, patients with chest pain may present earlier after the onset of symptoms than patients with heart failure, who usually have a more gradual increase of symptoms. Previous investigations have shown that the diagnostic performance of CMR is relatively low in the chronic stage of myocarditis.6,10 Third, the pattern of myocardial damage may be different in non-infarct-like presentations as suggested by findings from a previous investigation.4 T2W imaging and LGE show regional differences in contrast between affected and non-affected tissue if there is focal disease, whereas global myocardial disease may not always be identified, especially if skeletal muscle is also inflamed.24 This explains the predictive value of RWMA on echocardiography for a diagnostic CMR. Newer CMR techniques, such as parametric tissue mapping, provide a quantitative characterization of the myocardium per voxel and do not depend on these regional differences. Therefore, tissue mapping has been demonstrated to improve the diagnostic performance of CMR in the setting of suspected myocarditis, especially in patients presenting with heart failure.25,26 We acknowledge the lack of T1- and T2-mapping as a limitation of our study. These methods are predominantly used for scientific purposes to date, and before they can be translated to the clinical routine practice, several issues will still need to be addressed. In particular, there is currently a lack of normal T1 and T2 values across vendors and techniques. Also, the ability of T1- and T2-mapping to differentiate between myocarditis and other cardiac diseases (and not just myocarditis and normal myocardium) has yet to be determined. In addition, although T1- and T2-mapping are becoming increasingly available, they are not yet available in many CMR centres. Importance of CMR within the ESC-PSC To the best of our knowledge, this is the first study to investigate the diagnostic importance of tissue characterization by CMR within the ESC-PSC. In our study, none of the patients who were negative for the ESC-PSC showed evidence of myocarditis on CMR, suggesting that CMR has limited additional diagnostic value in these patients. However, in the ESC-PSC-positive group, CMR identified alternative cardiac disease in a substantial number of patients, thereby reclassifying them to the negative group. The most prevalent alternative cardiac disease was myocardial infarction, as indicated by subendocardial/transmural HE. We found smoking to be independently associated with myocardial infarction on the CMR, which supports the ischaemic aetiology of the subendocardial/transmural HE. It is known that cigarette smoking increases the risk of acute thrombosis and coronary vasospasm.27 We also found older age to be independently associated with myocardial infarction on the CMR, which also favours the ischaemic aetiology. Myocarditis, in contrast to myocardial infarction, predominantly affects young and middle-aged adults.28,29 Nonetheless, the precise mechanisms responsible for the myocardial infarction remain undetermined in this study (embolism or coronary spasm). Considering that the ESC Working Group on myocardial and pericardial diseases currently recommends EMB analysis in ESC-PSC-positive patients, an unnecessary EMB can potentially be avoided by first performing a CMR.2 Nevertheless, in life-threatening presentations where EMB is urgently indicated, CMR should not delay the diagnosis. One hundred and sixteen patients in the insufficient ESC-PSC group did not undergo CAG prior to the CMR examination, most likely due to a high clinical suspicion of myocarditis. In this subgroup, CMR confirmed the suspicion of myocarditis in approximately half of the patients, which may spare them from invasive CAG. CMR also revealed myocardial infarction in this group, despite the low pre-test probability of CAD. Clinical implications By showing the overall good diagnostic yield of CMR, and the substantial number of newly identified alternative cardiac diseases, our study provides strong support for the routine use of CMR in the work-up of suspected AM. Even in patients who fulfilled the 2013 ESC-PSC for clinically suspected myocarditis, CMR reclassified 18% to an alternative cardiac disease. Hence, the number needed to scan to reclassify one person is five. In these patients, CMR findings are likely to affect decision-making regarding subsequent diagnostic testing and therapy, such as referral for CAG or EMB, initiation of antiplatelet therapy, and screening of family members. However, whether this will translate into improved clinical outcomes merits future research. From another perspective, CMR examinations were negative for a diagnosis in about half of the patients, and especially in those without chest pain, without RWMA and with only minimal troponin release. These observations stress the importance of newer T1- and T2-mapping techniques that may provide a more detailed tissue characterization. This is particularly important in myocarditis patients who present with heart failure, as their prognosis is generally worse,28 yet may improve with adequate therapy.30 Study limitations Inherent to the retrospective design of the study, there were some missing data, and selection bias might have occurred. In this context, some cases of suspected myocarditis might have been missed by only using the keywords ‘suspected myocarditis’ as search terms for cases. Nonetheless, this retrospective collection allowed to evaluate the diagnostic yield and incremental value of CMR tissue characterization in a large clinical population with suspected AM. Second, patients with suspected myocarditis are not routinely subjected to EMB at our institution, and therefore we could not corroborate the CMR T1/T2 signals to histopathology. Third, this retrospective study reports the diagnostic yield and incremental value of CMR protocols that were in practice at the two centres during those years, which differs from the current CMR protocol for myocarditis. T2W imaging was, for example, not available in all studies and was mostly performed in three slices instead of whole heart coverage. In addition, small variations in T2w imaging protocols (i.e. sequences parameters, cardiac phased array coils, and image prescan normalization filters) did not allow reliable T2 SI ratio assessment. It can be argued that this may account for some of the CMR tissue-negative cases in which only cine imaging and LGE were performed. Also, in cases with LGE only, we cannot confirm that the HE lesions are acute, although the acute onset of symptoms makes it plausible. Furthermore, in the patient with HCM, the rare possibility of severe global oedema as cause of the hypertrophy cannot be ruled out without follow-up imaging.31 Nevertheless, the acquisition of good-quality T2w images remains challenging as this method is sensitive to cardiac motion, surface coil intensity inhomogeneity and inadequate suppression of blood, especially in sick patients with high or irregular heart rate or pericardial effusion.32 These technical difficulties may explain why T2W imaging was not performed in all patients. Our CMR protocol did not include early gadolinium enhancement (EGE) or, as mentioned above, T1- and T2-mapping. EGE is, however, sensitive to respiratory artefacts and dramatically increases scan time, which hampers its use in clinical practice. Furthermore, removal of EGE from the CMR protocol does not change the diagnostic overall accuracy of CMR, although it does reduce some if its sensitivity.33 Also, EGE is considered optional according to the SCMR board of trustees task force on standardized protocols.34 Despite the modified CMR protocol, we still found CMR to provide a good diagnostic yield and incremental diagnostic value in patients with suspected AM. Fourth, CMR reader was not blinded to the clinical parameters, which might have introduced some bias in the evaluation of the CMR images. Conclusion Tissue characterization by CMR provided a good diagnostic yield in our large clinical population of patients who were referred for work-up of suspected AM. CMR added diagnostic information in patients who met the ESC-PSC and reclassified a substantial number of to an alternative cardiac disease. Our study provides strong support for the routine use of CMR in the work-up of suspected AM. Large-scale multicentre cohorts are, however, needed to investigate prognostic implications of CMR findings, preferably including the use of parametric tissue mapping. Supplementary data Supplementary data are available at European Heart Journal - Cardiovascular Imaging online. Conflict of interest: None declared. References 1 Biesbroek PS , Beek AM , Germans T , Niessen HW , van Rossum AC. Diagnosis of myocarditis: current state and future perspectives . Int J Cardiol 2015 ; 191 : 211 – 9 . Google Scholar Crossref Search ADS PubMed 2 Caforio AL , Pankuweit S , Arbustini E , Basso C , Gimeno-Blanes J , Felix SB et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases . Eur Heart J 2013 ; 34 : 2636 – 48 , 48a–d. Google Scholar Crossref Search ADS PubMed 3 Ong P , Athansiadis A , Hill S , Kispert EM , Borgulya G , Klingel K et al. Usefulness of pericardial effusion as new diagnostic criterion for noninvasive detection of myocarditis . Am J Cardiol 2011 ; 108 : 445 – 52 . Google Scholar Crossref Search ADS PubMed 4 Mahrholdt H , Wagner A , Deluigi CC , Kispert E , Hager S , Meinhardt G et al. Presentation, patterns of myocardial damage, and clinical course of viral myocarditis . Circulation 2006 ; 114 : 1581 – 90 . Google Scholar Crossref Search ADS PubMed 5 Baccouche H , Mahrholdt H , Meinhardt G , Merher R , Voehringer M , Hill S et al. 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Google Scholar Crossref Search ADS PubMed 29 Imazio M , Brucato A , Barbieri A , Ferroni F , Maestroni S , Ligabue G et al. Good prognosis for pericarditis with and without myocardial involvement: results from a multicenter, prospective cohort study . Circulation 2013 ; 128 : 42 – 9 . Google Scholar Crossref Search ADS PubMed 30 Frustaci A , Russo MA , Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study . Eur Heart J 2009 ; 30 : 1995 – 2002 . Google Scholar Crossref Search ADS PubMed 31 Ferreira VM , Piechnik SK , Firoozan S , Karamitsos TD , Neubauer S. Acute chest pain and massive LV hypertrophy in a 38-year-old man . Heart 2014 ; 100 : 347 – 51 . Google Scholar Crossref Search ADS PubMed 32 Wassmuth R , Prothmann M , Utz W , Dieringer M , von Knobelsdorff-Brenkenhoff F , Greiser A et al. Variability and homogeneity of cardiovascular magnetic resonance myocardial T2-mapping in volunteers compared to patients with edema . J Cardiovasc Magn Reson 2013 ; 15 : 27. Google Scholar Crossref Search ADS PubMed 33 Chu GC , Flewitt JA , Mikami Y , Vermes E , Friedrich MG. Assessment of acute myocarditis by cardiovascular MR: diagnostic performance of shortened protocols . Int J Cardiovasc Imaging 2013 ; 29 : 1077 – 83 . Google Scholar Crossref Search ADS PubMed 34 Kramer CM , Barkhausen J , Flamm SD , Kim RJ , Nagel E ; Society for Cardiovascular Magnetic Resonance Board of Trustees Task Force on Standardized Protocols . Standardized cardiovascular magnetic resonance (CMR) protocols 2013 update . J Cardiovasc Magn Reson 2013 ; 15 : 91 . Google Scholar Crossref Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Dec 1, 2018

References

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