MR imaging in suspected acute myocarditis

MR imaging in suspected acute myocarditis Poster No.: C-1954 Congress: ECR 2012 Type: Educational Exhibit Authors: C. Lacroix, D. Bélanger, P. Martin, P. Farand, F. Belzile, G. Gahide; Sherbrooke, QC/CA Keywords: Infection, Hemodynamics / Flow dynamics, Acute, Contrast agentintravenous, MR, Echocardiography, CT, Cardiovascular system, Cardiac DOI: 10.1594/ecr2012/C-1954 Any information contained in this pdf file is automatically generated from digital material submitted to EPOS by third parties in the form of scientific presentations. References to any names, marks, products, or services of third parties or hypertext links to thirdparty sites or information are provided solely as a convenience to you and do not in any way constitute or imply ECR's endorsement, sponsorship or recommendation of the third party, information, product or service. ECR is not responsible for the content of these pages and does not make any representations regarding the content or accuracy of material in this file. As per copyright regulations, any unauthorised use of the material or parts thereof as well as commercial reproduction or multiple distribution by any traditional or electronically based reproduction/publication method ist strictly prohibited. You agree to defend, indemnify, and hold ECR harmless from and against any and all claims, damages, costs, and expenses, including attorneys' fees, arising from or related to your use of these pages. Please note: Links to movies, ppt slideshows and any other multimedia files are not available in the pdf version of presentations. www.myesr.org Page 1 of 30

Learning objectives 1. 2. 3. 4. Review the definition and epidemiology of myocarditis. Present the respective values of complementary non-imaging examinations. Define and illustrate MR scan capabilities in diagnosing acute myocarditis. Discuss the clinical interest of systematic MR scan examination. Background Myocarditis : definition Inflammation of the myocardium [1] Acute, subacute, or chronic Focal or diffuse Dallas pathological criteria (1986) = first attempt to standardize the histopathological classification of myocarditis. [1] Active myocarditis = inflammatory cellular infiltrate with evidence of myocyte necrosis Inflammatory infiltrate predominantly lymphocytic (55%) Incidence and symptoms Autopsy series have reported myocarditis in up to 22% of young adults presenting with sudden death. [1, 2] Important underlying etiology of dilated cardiomyopathy (9%) [2] Extreme diversity of clinical manifestations ranging from non specific systemic symptoms to fulminant hemodynamic collapse and sudden death. [3] Challenges of establishing the diagnosis in standard clinical settings makes true incidence of non-fatal myocarditis difficult to determine, likely higher than actually diagnosed. [2] Etiologies Multiple triggers for myocardial inflammation are possible: infection, toxic, ischemic or mechanical injury, immune reactions. [3] Infectious disease accounts for the majority of cases Viral Coxsackie A and B, HHV-6, parvovirus B19, adenoviruses and echoviruses most common [1] Page 2 of 30

Bacterial: mycobacterial, Streptococcal species, Mycoplasma pneumoniae Fungal: Aspergillus, Candida, Coccidiodes, Cryptococcus Parasitic: Schistosomiasis, Larva migrans, Toxins: anthracyclines, cocaine, interleukin-2 Immunologic syndromes: Churg-Strauss, inflammatory bowel disease, giant cell myocarditis, sarcoidosis, systemic lupus erythematosus Natural History The natural history of myocarditis is as varied as its clinical presentations. May progress to dilated cardiomyopathy in up to 10% of patients. Previously healthy adults that present with myocarditis mimicking myocardial infarction almost always fully recover their cardiovascular status. Patients who present with heart failure: Mild left ventricular dysfunction (LVEF of 40% to 50%): typically improve within weeks to months. Advanced left ventricular dysfunction (LVEF 35%, left ventricle (LV) end-diastolic dimension > 60 mm): 50% of patients will develop chronic ventricular dysfunction, and 25% of patients will progress to transplantation or death, the remaining 25% of patients will have spontaneous improvement in their ventricular function Endomyocardial biopsy (EMB) EMB is the gold standard for unequivocally establishing the diagnosis. [1] Performed via central venous access (more often the right internal jugular vein). Myocarditis more often localized at the left ventricular free wall; however, because of increased risks associated with biopsy of the left ventricle, samples are usually taken from the right ventricle (RV) or right side of interventricular septum (right ventricular free wall and pulmonary outflow track are too thin to biopsy). Weaknesses Sampling error limits its sensitivity. [1, 2] A minimum of 5 samples taken to improve sensitivity: - 1 sample sensitivity = 20%, - 5 samples sensitivity = 66% EMB is also limited by a large interobserver variation. [2] Page 3 of 30

Of note, multiple investigators have described strong clinical, ventriculographic, and laboratory evidence of myocarditis among patients with negative biopsies. # 0,5% of complications (ex : perforation) [1, 2] Indications Recent societal consensus recommends biopsies only in patients with heart failure or myocardial disorders with specific treatment recommendations. [1, 2] Therefore, EMB is not recommended in many patients with myocarditis. With the actual recommendations, only 10% of patients with suspected myocarditis are sent for endomyocardial biopsy. [2] Myocardial biopsy optimization Mahrholdt et al. (Circulation, 2004) used cardiac magnetic resonance (CMR) imaging to guide endomyocardial biopsies (EMB): Foci were most frequently located in the lateral free wall of the left ventricle Improved EMB sensitivity to 90%: histopathologic analysis revealed active myocarditis in 19 of the 21 patients in whom biopsy was obtained from the region of contrast enhancement, patients (parvovirus B19, n=12; HHV-6, n=5). Electrocardiogram (ECG) findings in myocarditis [2, 3] Diagnostic value limited: low specificity Sensitivity of ECG for myocarditis is low: abnormalities are observed in less than 50% of patients. [2, 3] Biomarkers Increased levels of creatinine kinase and troponin can be observed (related to inflammatory injury); troponin I is more commonly increased than CK-MB in myocarditis. [3] Elevated levels of troponin I is associated with a 34% sensitivity and a 89% specificity for myocarditis. [3] Prevalence of an increased troponin T in biopsy-proven myocarditis is 35-45% [2] conferring this finding a low sensitivity and high specificity. Page 4 of 30

Lauer et al. using troponin T (>0.1 ng/ml) obtained: sensitivity 53%; specificity 94%; PPV 93%; NPV 56% for myocarditis. [4] Ultrasonography Provides excellent anatomical and functional assessment. Wall thickness and presence of pericardial effusion can be assessed. [2] The highly variable echocardiographic findings in myocarditis lack specificity; diagnostic value also limited by the fact that many patients have a normal echocardiogram. Nuclear medicine [2] 111 67 Indium antimyosin antibody and Gallium nuclear imaging have been used to diagnose myocarditis in the past. Findings had low specificity. Limited availability of the tracers Poor spatial resolution Radiation issues Imaging findings OR Procedure details Cardiac Magnetic Resonance (CMR) First description of T2-weighted CMR findings in children with myocarditis by Gagliardi et al in 1991 [2] Offers anatomical visualization, quantitative accuracy with interobserver consistency and myocardial tissue analysis. Sensitivity of cardiac magnetic resonance is best within the first 2 weeks of disease onset. [5] Indications (CMR) Consensus for performing CMR if: [2] symptomatic new or persisting symptoms suggestive of myocarditis (dyspnea, orthopnea, palpitations, effort intolerance, malaise, chest pain) clinical evidence for myocarditis Page 5 of 30

Evidence for recent/ongoing myocardial injury (ie, ventricular dysfunction, new or persisting ECG abnormalities, elevated troponin Unknown etiology of symptoms (i.e. recent systemic viral disease or previous myocarditis, absence of risk factors for coronary artery disease or age 35 years, symptoms unexplained by stenosis on coronary angiogram, recent negative ischemic stress test) the CMR result will likely affect clinical management MR findings in myocarditis Multiples findings are reported at CMR in cases of myocarditis: functional abnormalities morphological abnormalities pericardial effusions myocardial edema myocardial hyperperfusion (early gadolinium enhancement (EGE)) myocardial necrosis/fibrosis (late gadolinium enhancement (LGE)) The latest CMR diagnosis criteria for myocarditis, the Lake Louise Consensus criteria, were introduced in 2009 and are summarized below : [2] Diagnostic CMR criteria for myocarditis : Lake Louise Consensus Criteria (adapted from Friedrich et al.) In the setting of clinically suspected myocarditis, CMR findings are consistent with myocardial inflammation, if at least 2 of the following criteria are present : regional or global myocardial SI increase in T2-weighted images* (edema) increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images* (hyperemia) there is at least one focal lesion with non-ischemic regional distribution in IR-prepared gadolinium-enhanced T1-weighted images (late gadolinium enhancement)* (necrosis, fibrosis) * these criteria being further specified in the Cardiovascular Magnetic Resonance in Myocarditis : A JACC White Paper article A CMR study is consistent with myocyte injury and/or scar caused by myocardial inflammation if : criterion 3 is present Page 6 of 30

The presence of LV dysfunction or pericardial effusion provides additional, supportive evidence for myocarditis Inflammation can be predicted or ruled out with diagnostic accuracy of 78% if #2 criteria present (only 68% of diagnostic accuracy if only LGE imaging is performed). [2] Functional abnormalities [2] Very reproducible assessment of right and left ventricular (LV) function Even mild functional abnormalities can be identified, quantified, and followed Global LV dysfunction is frequently seen in patients with more severe myocarditis. Regional or less severe LV wall motion abnormalities have a low specificity for the underlying pathophysiology of myocarditis. [2] Morphological abnormalities A transient increase of wall thickness can be seen in myocarditis; can be used as a supportive finding. [2] Transient subtle increase of LV volume can be observed in the course of myocarditis and can also serve as a retrospective, supportive evidence for myocarditis (Fig. 1). [2, 5] Decrease of LV mass during the recovery of uncomplicated myocarditis found to be associated with edema as assessed by T2-weighted CMR (retrospective). [2] Fig. 1: Transient increase in LV volume found in the course of myocarditis, with subsequent decrease (return to normal) of the LV volume during the recovery phase. Page 7 of 30

Pericardial effusions [2] Reported in 32% to 57% of patients with myocarditis (Fig. 2) [2] Not specific but supportive for inflammation Distribution, extent and hemodynamic significance assessed in short and long axis steady-state free precession (SSFP) images (inherent T2 sensitivity) to differentiate from epicardial fat, seen around coronary vessels or in the atrioventricular (AV) groove. In SSFP images, fat typically separated from effusion by a single-pixel thin chemical shift artifact layer (fine line without signal) fluid will demonstrate hypersignal Low signal on T1-weighted images Page 8 of 30

Fig. 2: Short-axis view of a patient with myocarditis showing pericardial effusion (high signal intensity) surrounding mostly the lateral wall of the LV. Page 9 of 30

EDEMA Edema is not specific for myocarditis but implies acute injury Edema itself can cause harm : increased interstitial hydrostatic pressure # capillary compression # necrosis # cardiac function impaired [1] Edema visible in 36% of patients with histologically "active myocarditis" Limited sensitivity in less severe inflammation Edema Imaging Principles [2] Early imaging is best since edema can be present for 2-3 weeks Increased permeability of cellular membranes when inflammatory cell injury (Fig. 3) From intracellular edema (Na+ influx) to efflux of water + leakage of large molecules (troponin) [2] Fig. 3: Myocardial cells with increased membrane permeability (red rectangular cells) secondary to inflammatory injury. T2-weighted imaging detects tissue edema (contrast-generating mechanism: long T2 of water-bound protons) (Fig. 4) [2] Short-axis views often provide better image quality than long-axis views [2] Page 10 of 30

Fig. 4: Short-axis T2 sequence showing hypersignal corresponding to edema, mostly located in the anterolateral mid left ventricular wall. Page 11 of 30

Artifacts related to intraventricular blood signal in apical slices limit their utility (Fig. 5). Black blood preparation aims at suppressing this slow blood flow hypersignal (predominant at LV apex). Fig. 5: Axial view of a T2 sequence showing slow blood flow at LV apex, manifested as high signal area. Useful sequences Triple IR-T2: Black Blood Preparation + Fat suppression preferably used [1, 2] Myocardium: isosignal Fat: no signal Cavity: no signal Suppress fat signal (STIR) (Fig. 6) Increase edema visualization Lower SNR, which depends on motion artifacts Page 12 of 30

Fig. 6: Axial STIR showing increased signal corresponding to edema in the apical and septal regions of the LV. Double IR-T2: Black Blood Preparation Myocardium: isosignal Fat: hypersignal Cavity: no signal higher SNR Possible global myocardial distribution of edema in myocarditis warrants a quantitative signal intensity analysis of the entire myocardium, since it may be more difficult to recognize otherwise. [2] Normalizing the signal intensity of the myocardium to that of skeletal muscle is recommended [1] : (SI myocardium/ SI skeletal muscle) with T2 ratio # 1.9 as cutoff value for myocarditis [2] Page 13 of 30

SNR of T2-weighted images limits their ability to identify small regions of edema and involvement of skeletal muscles (systemic inflammation) may decrease sensitivity of this finding. HYPEREMIA Hyperemia imaging principle - early gadolinium enhancement (EGE) Presently regarded as the best CMR related predictor in patients with suspected myocarditis. Tissue inflammation is associated with regional vasodilatation : increased blood volume leads to increased uptake of contrast agents during the early vascular phase. [2] Increased signal intensity results, especially within the first 2 minutes [1] ; washout predominates after a 3-4 minutes steady state. [1] The purpose of myocardial early gadolinium enhancement ratio (EGEr) is to detect an overall increased volume of gadolinium distribution into the intravascular and interstitial spaces during the early washout period. [2] Can be seen up to 4-6 weeks after onset of disease. [1, 5] Useful sequences for early gadolinium enhancement - Contrast-enhanced fast spin echo T1-weighted MR - Black blood preparation (Double IR - T1) Myocardium: Isosignal Fat: Hypersignal Cavity: No signal Gadolinium sensitivity Fast spin-echo sequences vulnerable to varying heart rate and irregular breathing patterns - Good SNR Quantitative evaluation of myocardial EGEr [1] Normalization of the myocardial signal intensity in T1-weighted images to that of skeletal muscle to obtain the EGEr Abnormally increased EGE ratio if # 4 [1] May be hampered in patients with evidence for skeletal muscle involvement (signal intensity increase of 20% or higher) Page 14 of 30

an absolute myocardial signal intensity increase between pregadolinium and post-gadolinium images of more than 45% should be used as a threshold consistent with myocarditis instead of the normalized myocardial early gadolinium enhancement ratio. [2] LATE GADOLINIUM ENHANCEMENT (LGE) LGE reflects early and late myocardial irreversible injury (necrosis and fibrosis). [2, 6, 7] Early stage: visualization of myocardial necrosis (in severe acute myocarditis) by gadolinium entering the cells through acutely injured membrane (volume of distribution is increased) (Fig. 7). [2] Fig. 7: In severe acute myocarditis, visualization of myocardial necrosis is explained by gadolinium entering the cells through acutely injured membrane (volume of distribution is increased). Later stage: visualization of fibrosis ; clearance of necrotic regions replaced by fibrocytes with a large interstitial component (also increasing the volume of distribution for gadolinium). [2] Patterns of LGE in active myocarditis Multiple focal hypersignal foci are typically localized to the subepicardial regions [7] of the left ventricle (Fig. 8-9) mostly in the inferolateral and less frequently in the anteroseptal segments. Can also be diffuse or regional. [6] Page 15 of 30

Fig. 8: Short-axis delayed-enhancement in the same patient as in Figure 4, showing abnormal enhancement (increased signal intensity) involving the areas of T2 hypersignal (seen in Figure 4), mostly in the anterolateral mid left ventricular wall. Page 16 of 30

Fig. 9: Short-axis delayed-enhancement showing subepicardial nodular foci of enhancement in the septal and lateral left ventricular wall.!!! Left ventricular outflow tract (LVOT) and membranous septum may mimic LGE in the basal septum in short axis. Page 17 of 30

!!! A line of increased signal intensity may appear in the basal septum on transverse, long axis or short axis images which may not represent pathologic LGE but may be related to the fusion of the right ventricular moderator band to the right ventricular portion of the interventricular septum. Topography of LGE is crucial and allows differentiation between ischemic (typical subendocardial involvement) and non-ischemic injury. There is typical subepicardium involvement in myocarditis (Fig. 10), clearly distinguishing this injury pattern from ischemia-mediated injury, where mandatory subendocardium involvement is seen (Fig. 11). [2, 6] Page 18 of 30

Fig. 10: Focal and multifocal patterns of late gadolinium enhancement in myocarditis : focal hypersignals are typically localized to the subepicardial regions, more commonly at the inferolateral segments. Page 19 of 30

Fig. 11: Short-axis LGE MR showing subendocardial late enhancement related to ischemia-mediated injury. Involvement of subepicardium more important than subepicardial predominance 16% of patients with suspected acute myocarditis have myocardial infarction (chest pain, troponin elevation, normal coronary angiogram) (Gahide et al. European radiology 2010). Useful sequences : Inversion-recovery sequence principle and value Inversion pulse serves to decrease signal response from normal myocardium, thereby highlighting areas with increased accumulation of gadolinium as bright regions. (Fig. 12) Page 20 of 30

Fig. 12: Inversion pulse to decrease signal response from normal myocardium, highlighting areas of enhancement. LGE imaging is the gold standard for in vivo detection of irreversible myocardial injury associated with myocardial infarction. [2] Does not differentiate acute from chronic inflammatory myocardial injury. [1] High specificity in myocarditis demonstrated in many previous studies. [2, 6] Variable sensitivity; LGE may be insensitive for the detection of symptomatic myocarditis with limited or non-focal irreversible injury. [2] Using the Dallas criteria, De Cobelli et al (J Am Coll Cardiol, 2006)found: LGE sensitivity = 84% in active myocarditis less sensitive in "borderline" myocarditis (44%) [1, 2] Time delay after gadolinium perfusion Found to be reliable from 5 minutes to up to 30 minutes after gadolinium perfusion in myocardial infarction (MI) [8] (Fig.13) Page 21 of 30

Fig. 13: Findings of delayed-enhancement were found to be reliable from 5 minutes to up to 30 minutes after gadolinium injection in myocardial infarction (MI). Differences in gadolinium kinetics in myocarditis and acute myocardial infarction : [9] volume of blood decreases in the core of a myocardial infarct volume of blood increases in acute myocarditis. In myocarditis, the contrast between enhanced and normal myocardium (Cenhanced-normal) is higher and image quality has been recently demonstrated better 5 minutes after injection of gadolinium compared with the 10 and 15 minutes time-points used for myocardial infarction. [9] Gadolinium-Enhanced Cine MR : a newly proposed approach Based upon unpublished personal results: 68 patients (29 women; mean age 38.5 ± 14.4 years) Myocardial enhancement assessed on both contrast-enhanced (CE) Cine MR done shortly after gadolinium injection and delayed-enhancement (DE) imaging CE Cine MR confirmed positive DE imaging findings in 96.6% (n=28/29), located in the same segments with a Pearson's correlation coefficient of enhanced surfaces of 0.91 (Fig. 14-18) CE Cine MR increased the detection of myocardial lesions by 27.6% CE Cine MR seems more sensitive than DE imaging Page 22 of 30

Fig. 14: Correlation of findings of myocardial enhancement on CE Cine MR and DE MRI. Page 23 of 30

Fig. 15: Single-shot delayed-enhancement short-axis view showing increased signal involving the subepicardium of the mid and apical anterolateral wall in a 20 y.o. male patient with myocarditis. Page 24 of 30

Fig. 16: Cine MR short-axis view in the same 20. y.o. patient as in Figure 15 showing increased signal intensity involving the subepicardium of the mid and apical anterolateral wall of the LV, that correlates with the myocardial enhancement seen on the single-shot delayed-enhancement sequence also done in that patient. Page 25 of 30

Fig. 17: Delayed-enhancement short-axis view in a 40 y.o. patient with myocarditis (that proved to be related to streptococcal A infection - rheumatic fever) showing increased signal intensity in the basal mostly anterolateral (but almost circumferential) LV wall involving 25-50% of the myocardial thickness. Page 26 of 30

Fig. 18: CE cine short-axis view in the same 40 y.o. patient with myocarditis as in Figure 17 showing increased signal intensity also affecting the anterolateral basal LV wall and involving 25-50% of the myocardial thickness. Proposed protocol in suspected acute myocarditis (Fig. 19) Page 27 of 30

Performing Cine MR after gadolinium perfusion # Shortens the examination time by 5 to 10 minutes # Increases the sensitivity in depicting myocardial lesions Fig. 19: Proposed CMR protocol for suspected acute myocarditis, with CE cine MR performed after gadolinium injection before LGE at 5 minutes. A recent study in 18 patients with suspected myocarditis [10] also showed that CE cine sequences were as accurate as LGE in detecting acute myocarditis. They found good correlation between : Locations of the abnormalities Surface areas of the abnormalities observed SNR and CNR of acute myocarditis lesions were significantly higher on CE cine images than on late gadolinium-enhanced images. [10] # Suggest that CE Cine sequences can be used to detect the lesions of acute myocarditis rapidly and efficiently, a few minutes after gadolinium injection (compared with use of the standard late gadolinium-enhanced sequence). Conclusion Page 28 of 30

Cardiac magnetic resonance imaging has become a powerful tool in evaluation of patients with suspected acute myocarditis, by being able to identify the presence of edema, hyperemia, necrosis and fibrosis, and by assessing functional and morphological status. Its sensitivity is best within the first two weeks of disease onset. To achieve best diagnostic accuracy for identifying presence of inflammation, systematic use of the Diagnostic CMR Lake Louise Consensus Criteria for myocarditis (presence of # 2 criteria) is recommended. Since some of the abnormalities are typically only present for a certain time, MR imaging is also useful to assess recovery after treatment. Personal Information Caroline Lacroix, MD is currently a third-year resident in diagnostic radiology at Centre Hospitalier Universitaire de Sherbrooke. Danny Bélanger, MD, M.Sc is currently a fourth-year resident in diagnostic radiology at Centre Hospitalier Universitaire de Sherbrooke. Philippe Martin, MD is currently a third-year resident in infectious diseases at Centre Hospitalier Universitaire de Sherbrooke. Paul Farand, MD, M.Sc is a cardiologist and an assistant professor at Centre Hospitalier Universitaire de Sherbrooke. François Belzile, MD, is an interventional radiologist, an assistant professor and the director of the Diagnostic Radiology residency program at Centre Hospitalier Universitaire de Sherbrooke. Gerald Gahide, MD, Ph.D is an interventional radiologist and an assistant professor at Centre Hospitalier Universitaire de Sherbrooke. References 1. Childs, H. and M.G. Friedrich, Cardiovascular magnetic resonance imaging in myocarditis. Prog Cardiovasc Dis, 2011. 54(3): p. 266-75. Page 29 of 30

2. Friedrich, M.G., et al., Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol, 2009. 53(17): p. 1475-87. 3. Cooper, L.T., Jr., Myocarditis. N Engl J Med, 2009. 360(15): p. 1526-38. 4. Lauer, B., et al., Cardiac troponin T in patients with clinically suspected myocarditis. J Am Coll Cardiol, 1997. 30(5): p. 1354-9. 5. Wassmuth, R. and J. Schulz-Menger, Cardiovascular magnetic resonance imaging of myocardial inflammation. Expert Rev Cardiovasc Ther, 2011. 9(9): p. 1193-201. 6. Ordovas, K.G. and C.B. Higgins, Delayed contrast enhancement on MR images of myocardium: past, present, future. Radiology, 2011. 261(2): p. 358-74. 7. Bohl, S. and J. Schulz-Menger, Cardiovascular magnetic resonance imaging of nonischaemic heart disease: established and emerging applications. Heart Lung Circ, 2010. 19(3): p. 117-32. 8. Wagner, A., et al., Effects of time, dose, and inversion time for acute myocardial infarct size measurements based on magnetic resonance imaging-delayed contrast enhancement. J Am Coll Cardiol, 2006. 47(10): p. 2027-33. 9. Jacquier, A., et al., Gadolinium chelate kinetics in cardiac MR imaging of myocarditis: comparison to acute myocardial infarction and impact on late gadolinium enhancement. Invest Radiol, 2011. 46(11): p. 705-10. 10. Deux, J.F., et al., Acute myocarditis: diagnostic value of contrast-enhanced cine steady-state free precession MRI sequences. AJR Am J Roentgenol, 2011. 197(5): p. 1081-7. Page 30 of 30