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J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 0 , N O . 1 6 , 2 0 1 7

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Cardiac MR With Late GadoliniumEnhancement in Acute MyocarditisWith Preserved Systolic FunctionITAMY Study

Giovanni Donato Aquaro, MD,a Matteo Perfetti, MD,a Giovanni Camastra, MD,b Lorenzo Monti, MD,c

Santo Dellegrottaglie, MD,d,e Claudio Moro, MD,f Alessia Pepe, MD,a Giancarlo Todiere, MD,a Chiara Lanzillo, MD,g

Alessandra Scatteia, MD,h Mauro Di Roma, MD,i Gianluca Pontone, MD,j Martina Perazzolo Marra, MD, PHD,k

Andrea Barison, MD,a Gianluca Di Bella, MD, PHD,l on behalf of the Cardiac Magnetic Resonance Working Group ofthe Italian Society of Cardiology

ABSTRACT

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BACKGROUND The prognostic role of cardiac magnetic resonance (CMR) and late gadolinium enhancement (LGE)

has not been clarified in acute myocarditis (AM) with preserved left ventricular (LV) ejection fraction (EF).

OBJECTIVES This study sought to evaluate the role of CMR and LGE in the prognosis of AM with preserved LVEF.

METHODS This study analyzed data from ITAMY (ITalian multicenter study on Acute MYocarditis) and

evaluated CMR results from 386 patients (299 male; mean age 35 � 15 years) with AM and preserved LVEF.

Clinical follow-up was performed for a median of 1,572 days. A clinical combined endpoint of cardiac

death, appropriate implantable cardioverter-defibrillator firing, resuscitated cardiac arrest, and hospitalization

for heart failure was used.

RESULTS Among the 374 patients with suitable images, LGE involved the subepicardial layer inferior and

lateral wall in 154 patients (41%; IL group), the midwall layer of the anteroseptal wall in 135 patients

(36%; AS [anteroseptal] group), and other segments in 59 patients (16%; other-LGE group), and it was absent in

26 patients (no-LGE group). The AS group had a greater extent of LGE and a higher LV end-diastolic volume index

than other groups, but levels of inflammatory markers were lower than in the other groups. Kaplan-Meier curve

analysis indicated that the AS group had a worse prognosis than the other groups (p < 0.0001). Finally, in

multivariable analysis, AS LGE was the best independent CMR predictor of the combined endpoint (odds ratio: 2.73;

95% confidence interval: 1.2 to 5.9; p ¼ 0.01).

CONCLUSIONS In patients with AM and preserved LVEF, LGE in the midwall layer of the AS myocardial segment is

associated with a worse prognosis than other patterns of presentation. (J Am Coll Cardiol 2017;70:1977–87)

© 2017 by the American College of Cardiology Foundation.

m the aGabriele Monasterio Foundation, Tuscan Region, Pisa, Italy; bCardiac Department, Vannini Hospital Rome, Rome, Italy;

diology Department, Humanitas Research Hospital, Hospital Care and Research Institution (IRCCS), Rozzano, Milan, Italy;

ivision of Cardiology, Villa dei Fiori, Acerra, Naples, Italy; eMount Sinai School of Medicine, New York, New York; fDepartment

Cardiology and Coronary Intensive CareUnit, ASST Monza, Desio Hospital, Desio Monza e Brianza, Italy; gCardiology Depart-

nt, Casilino Polyclinic, Rome, Italy; hDepartment of Advanced Biomedical Sciences, Federico II University, Naples, Italy; iRa-

logical Department, European Hospital, Rome, Italy; jCardiac Department, Monzino Cardiology Center, Milano, Italy; kDivision

Cardiology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padua, Italy; and the lClinical and

perimental Department of Medicine, University of Messina, Messina, Italy. Dr. Pontone has received institutional grants and

s from GE Healthcare, Medtronic, Bracco, Bayer, and Heartflow. All other authors have reported that they have no relationships

evant to the contents of this paper to disclose.

nuscript received May 11, 2017; revised manuscript received July 19, 2017, accepted August 8, 2017.

ABBR EV I A T I ON S

AND ACRONYMS

AM = acute myocarditis

AS = anteroseptal

CMR = cardiac magnetic

resonance

CRP = C-reactive protein

ECG = electrocardiographic

EDV = end-diastolic volume

EDVi = end-diastolic volume

index

EF = ejection fraction

ESR = erythrocyte

sedimentation rate

ICD = implantable

cardioverter-defibrillator

IL = inferolateral

LGE = late gadolinium

enhancement

LV = left ventricular

RV = right ventricular

SSFP = steady-state free

precession

Aquaro et al. J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7

1978

I n the last 10 years, cardiac magneticresonance (CMR) has significantlyimproved diagnosis in patients with sus-

pected acute myocarditis (AM). The clinicalpresentation of AM is heterogeneous, and itmay begin as recent-onset heart failure,with arrhythmic events, or with infarct-likesymptoms (1–3). Systolic function is usuallypreserved in patients with infarct-like pre-sentation, who are considered to have agood prognosis. In the subsets of hemody-namically stable AM with preserved systolicfunction, endomyocardial biopsy may notbe indicated (4), and CMR is considered thebest noninvasive imaging modality for a def-inite diagnosis of AM.

CMR can detect signs of myocardial dam-age such as myocardial edema, hyperemia,and late gadolinium enhancement (LGE) inpatients with preserved left ventricular (LV)ejection fraction (EF) (5). Preserved systolicfunction is a good predictor of survival in allcardiac disease, and previous studiesdemonstrated that impairment of EF in AM is

the strongest predictor of worse prognosis (6,7). Inmany heart diseases, the presence of myocardial LGEis associated with an increased risk for adverse car-diovascular events in patients with preserved systolicfunction (8,9), but in AM, most patients have positiveLGE (10).

SEE PAGE 1988

In nonselected patients with AM, Mahrholdt et al.(11) demonstrated 2 main patterns of LGE presenta-tion: 1 involving the subepicardial layer of the lateralwall and 1 involving the midwall layer of the ante-roseptal wall. The latter was associated with ven-tricular remodeling and EF impairment at follow-upCMR. The main indication for CMR in AM is inhemodynamically stable patients with preservedEF. The aim of this multicenter study was to evaluatethe prognostic role of LGE in a large sample ofpatients with hemodynamically stable AM and pre-served EF.

METHODS

ITAMY (ITalian multicenter study on Acute MYocar-ditis) is a multicenter investigation of the prognosticvalue of CMR in AM of the Cardiac Magnetic Reso-nance Working Group of the Italian Society of Cardi-ology. The ITAMY registry includes 415 consecutiveinpatients with a definite CMR diagnosis of AM whowere enrolled from January 2006 to January 2013

in 10 Italian hospitals. CMR was performed inpatients with suspected AM and different clinicalpresentations: new onset of chest pain, dyspnea, orventricular arrhythmic events (ventricular tachy-cardia, resuscitated cardiac arrest, or new-onsetthird-degree atrioventricular block).

In the current study, we excluded patients withheart failure or arrhythmic events at presentation,decreased systolic function (EF <50%), and hemo-dynamic instability (Figure 1). For the diagnosis ofAM, we applied the diagnostic algorithm reported inFigure 2, which was modified from the algorithm ofthe European Society of Cardiology guidelines (3).Briefly, clinically suspected AM was diagnosedwhen symptomatic patients with chest pain (peri-carditis or pseudoischemic pain) fulfilled 1 or morediagnostic criteria (new electrocardiographic [ECG]modification, elevated troponin, wall motion ab-normalities with preserved LVEF at echocardiogra-phy) or in asymptomatic patients with 2 or morediagnostic criteria. A definite diagnosis of AM wasthen made in the event of 2 or more CMR LakeLouise criteria (myocardial edema, hyperemia, andLGE) (5).

Endomyocardial biopsy was performed when CMRresults were inconclusive (#1 CMR criterion). Toexclude obstructive coronary artery disease, coronaryartery angiography was performed on all patientswith the exception of those younger than 30 years ofage with a low risk of coronary artery disease. Thefinal population included 386 patients (299 male;mean age 35 � 15 years) with a CMR diagnosis ofstable AM and preserved systolic function (LVEF>50%). At hospital admission, all patients underwentclinical evaluation and laboratory testing, includingleukocytes, C-reactive protein (CRP), erythrocytesedimentation rate (ESR), and troponin T. Informedconsent was obtained from all patients at the time ofCMR examination.

CMR ACQUISITION PROTOCOL. CMR imaging wasperformed with 1.5-T systems (CVi, HD release, GEHealthcare,Milwaukee,Wisconsin; MagnetomAvanto,Siemens Medical Systems, Erlangen, Germany;Gyroscan NT, Philips Healthcare, Amsterdam, theNetherlands) using dedicated cardiac software, aphased-array surface receiver coil, and vectocardio-gram triggering. According to the protocols recom-mended by the Society for Cardiovascular MagneticResonance, we acquired cine steady-state free preces-sion (cine-SSFP) images, T2-weighted imaging, andLGE at 10 min after gadolinium injection in theshort-axis (9 to 13 images covering the entire LV),2-chamber, and 4-chamber planes. Short-axis

FIGURE 1 Study Population

n = 462 patients with Clinically Suspected Acute Myocarditis

n = 16 excluded for claustrophobia,contraindications, no Gd injection

n = 31 other diagnosis by CMR

n = 415 patients with CMR and definite diagnosis of myocarditis

n = 386 patients with definite diagnosis of myocarditis and preserved LVEF

n = 374 patients with acute myocarditis and LVEF >50%

n = 154 Infero-Lateral LGE n = 26 no LGE

n = 135 Anteroseptal LGE n = 59 other LGE

n = 29 excluded for LVEF <50%

n = 12 excluded for sub-optimal LGE images

Flow chart visualizing the derivation of the study population. CMR ¼ cardiac magnetic

resonance; Gd ¼ gadolinium; LGE ¼ late gadolinium enhancement; LVEF ¼ left

ventricular ejection fraction.

FIGURE 2 Diagnostic Algorithm

In clinically suspected myocarditis

In presence of ≤1 CMR tissue abnormality, diagnosis confirmed byendomyocardial biopsy

≥2 tissue abnormalities at CMR(edema, hyperemia, LGE)

Definite diagnosis of acute myocarditis:

• In patients with acute chest pain (pericarditic or pseudo-ischemic) and ≥1 Diagnostic Criteria:- New ECG abnormalities (ST elevation or non ST elevation, T wave inversion, new I-III degree AV-block)- Myocardiocytolysis markers (elevated Troponin T/I)- Wall motion abnormalities at echocardiography (with preserved LVEF)

Absence of angiographically detectable coronary artery disease (or age <30 yand low risk of CAD) and absence of known pre-existing cardiovasculardisease or secondary conditions

Clinically suspected acute myocarditis:

• In patients with no chest pain and ≥2 diagnostic criteria Plus

+

Diagnostic algorithm for the diagnosis of acute myocarditis used in the current study.

AV ¼ atrioventricular; CAD ¼ coronary artery disease; ECG ¼ electrocardiographic; other

abbreviations as in Figure 1.

J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7 Aquaro et al.O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

1979

cine-SSFP images were acquired immediately aftergadolinium injection for hyperemia assessment.

CMR ANALYSIS. All CMR studies were analyzed off-line using a workstation with dedicated cardiac soft-ware with consensus among 3 experienced observerswho were blinded to the clinical presentation results.To evaluate LV global and regional function andcalculate LV mass, the endocardial and epicardialborders were manually drawn in the end-diastolicand end-systolic short-axis cine-SSFP images. Papil-lary muscles and trabeculae were not included in themyocardium. LV end-diastolic volume (EDV), LVend-systolic volume, LVEF, and LV mass weredetermined.

On T2-weighted images, edema was consideredpresent when the ratio of signal intensity between themyocardium and the mean signal intensity of theskeletal muscle was $2 (5,12). LGE was qualitativelyevaluated and manifested as a nonischemic pattern ofdistribution (i.e., subepicardial or midventricularenhancement) (13,14). Myocardial hyperemia wasevaluated, as previously reported (13), using the post-contrast SSFP cine images. The occurrence of edema,hyperemia, or LGE was evaluated in each of the 17 LVsegments (13,14). Furthermore, each LV wall (septal,anterior, inferior, and lateral) was considered tobe involved if at least 1 segment with LGE wasobserved (15).

CLINICAL FOLLOW-UP. After the CMR examination,follow-up was performed for all patients by the in-vestigators of the 10 Italian hospitals in the registry. Aclinical questionnaire was compiled by a clinicalphysician during periodic ambulatory visitations ineach hospital, by contacting the patients’ relatives bytelephone, by a general practitioner, or by consultingthe office of vital statistics at a patient’s place ofresidence. The clinical questionnaire included thedefinition of the following major events: cardiacdeath, resuscitated cardiac arrest, ventricular assistdevice, transplantation, and appropriate implantablecardioverter-defibrillator (ICD) shock, as well as mi-nor events (heart failure hospitalization). A completeanalysis of the ICD was performed by the referringphysician to confirm the appropriateness of theshock.

STATISTICAL ANALYSIS. Values are presented as themean � SD or as the median (interquartile range[IQR]) for variables with normal and non-normaldistributions, respectively. Values with non-normaldistribution according to the Kolmogorov-Smirnovtest were logarithmically transformed for parametricanalysis. Qualitative data are expressed aspercentages.

TABLE 1 Patient Characteristics

Males 299 (73)

Age, yrs 35 � 15

Height, cm 175 � 10

Weight, kg 76 � 14

Hypertension 44 (11)

Hyperlipidemia 15 (4)

Diabetes 9 (4)

Smoking 55 (13)

Family history of CAD 48 (12)

Obesity 19 (5)

Pericardial effusion 48 (12)

Chest pain 368 (95)

Fever (2 weeks from symptoms onset) 225 (58)

Palpitations 20 (5)

ECG abnormalities 371 (96)

Wall motion abnormalities at echocardiography 82 (21)

Coronary artery angiography performed 365 (95)

Endomyocardial biopsy performed 18 (5)

Laboratory tests

Leukocytes, 103cells/ml 10.7 � 3.8

ERS, mm/h 21 � 19

CRP, ng/ml 5.5 (1.8–15.5)

Abnormal ERS and/or CRP 385 (99)

Troponin T, peak ng/ml 1.85 (0.002–7.6)

Elevated troponin T 386 (100)

CMR parameters

LVEDVi, ml/m2 83 � 23

LVEF, % 61 � 9

LV mass index, g/m2 73 � 16

WMSI 1.07 � 0.27

RVEDVi, ml/m2 82 � 17

RVEF, % 52 � 21

Wall motion abnormalities 92 (24)

No. of segments with edema 2 (1–4)

No. of segments with hyperemia 2 (0–3)

No. of segments with LGE 2 (1–4)

Values are n (%), mean � SD, or median (interquartile range). The data refer to the entire pop-ulation of 386 patients.

CAD ¼ coronary artery disease; CMR ¼ cardiac magnetic resonance; CRP ¼ C-reactive protein;ECG ¼ electrocardiographic; ERS ¼ erythrocyte sedimentation rate; LGE ¼ late gadoliniumenhancement; LV ¼ left ventricular; LVEDVi ¼ left ventricular end-diastolic volume index;LVEF ¼ left ventricular ejection fraction; RVEDVi ¼ right ventricular end-diastolic volume index;RVEF ¼ right ventricular ejection fraction; WMSI ¼ wall motion score index.

TABLE 2 Diagnostic Characteristics of the Population

Chest pain

Yes 368 (95)

No 18 (5)

Diagnostic criteria

Troponin elevation þ new ECG abnormalities 304 (79)

Troponin elevation þ new ECG abnormalities þwall motion abnormalities at echocardiography

67 (17)

Troponin elevation þ wall motion abnormalities atechocardiography

15 (4)

Other clinical symptoms/signs

Recent fever 225 (58)

Respiratory or GI symptoms 68 (18)

Elevated ERS/CRP 385 (99)

Pericardial effusion 48 (12)

Coronary angiography

Performed (no obstructive CAD) 365 (95)

Not performed (age <30 yrs, low risk of CAD) 21 (5)

Cardiac magnetic resonance

$2 tissue abnormalities (edema, hyperemia, LGE) 368 (95)

1 tissue abnormality 18 (5)

Edema þ hyperemia þ LGE 85 (22)

Edema þ LGE 261 (68)

Edema only 16 (4)

LGE only 2 (1)

Endomyocardial biopsy

Positive 18 (5)

Values are n (%). Data refer to the entire population of 386 patients.

GI ¼ gastrointestinal; other abbreviations as in Table 1.

Aquaro et al. J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7

1980

Categorical variables were compared by the chi-square test or the Fisher exact test when appro-priate. Continuous variables were compared by theStudent independent t test and analysis of variance orby the Wilcoxon nonparametric test when appro-priate. The Kaplan-Meier time-to-event method wasused to calculate and compare longitudinal curvesamong groups. Logistic regression analysis was usedto explore the impact of each significant variable inunivariate analysis to predict the occurrence of car-diac events evaluated as a combined endpoint (car-diac death, appropriate ICD firing, resuscitatedcardiac arrest, and hospitalization for heart failure).

A p value lower than 0.05 was considered statisticallysignificant.

RESULTS

Baseline characteristics of the entire population andgroups are summarized in Table 1. The populationwas composed of young adults with a low prevalenceof risk factors for coronary heart disease. The mostcommonly reported symptom was chest pain (95%),and fever was present in 58% of patients. All patientswere in New York Heart Association functional class Ibecause of the exclusion of patients with heart failurepresentation. ECG abnormalities were found in 371(96%) of the subjects (ST-segment elevation in 73%,ST-segment depression in 15%, and negative T-wavein 8%). Increased troponin T was found in all pa-tients, and abnormal values of ESR or increased CRPwere found in 385 patients (99%). Regional wall mo-tion abnormalities were found in 82 patients by usingechocardiography (21%).

Coronary artery angiography was performed in 365patients (95%), who all showed no obstructive coro-nary artery disease (patients with obstructive diseasewere excluded from the study). Coronary artery

FIGURE 3 Example of IL LGE

Cardiac magnetic resonance images of a case of acute myocarditis with the anteroseptal (AS) pattern of late gadolinium enhancement (LGE).

SSFP ¼ steady-state free precession; STIR ¼ short tau inversion recovery.

J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7 Aquaro et al.O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

1981

angiography was not performed in 21 patientsyounger than 30 years of age (mean age of these pa-tients was 22 � 9 years), patients who had a low riskof coronary artery disease, and patients with signs ofinflammation (fever preceding chest pain, increase ofESR and CRP, or signs of viral infection). The definitediagnosis of AM was made using endomyocardial bi-opsy in 18 patients (5%) with only 1 tissue abnor-mality in CMR. In the remaining patients, clinicallysuspected myocarditis was made confirmed by theevidence of 2 or more tissue abnormalities in CMR.The diagnostic criteria are shown in Table 2.

CMR RESULTS. LV dilation was found in 33 patients(8%; 28 male) by using recently published referencevalues of normality (16). Right ventricular (RV) dila-tion was found in 42 patients (10%). Pericardial

effusion was found in 48 patients (12%), and signs ofpericardial inflammation (post-contrast enhance-ment) were found in 11 (3%). Regional wall motionabnormalities were found in 92 patients (22%). InT2–short tau inversion recovery (STIR) images, signsof myocardial edema were detected in 362 patients(94%). Hyperemia was found in 85 patients (23%).

In 12 cases, LGE images were of suboptimal qualityas a result of artifacts. LGE images of 374 patientswere visually analyzed, among which 4 main clustersof distribution were found: in 154 patients (41%),the subepicardial layer of the inferior and lateralsegments was constantly involved with variable dis-tribution in other segments, except the anteroseptalsegments (IL cluster); in 135 patients (36%), the mid-wall layer of the basal anteroseptal wall wasconstantly involved with various other segments,

FIGURE 4 Example of AS LGE

Cardiac magnetic resonance images of a case of acute myocarditis with the inferolateral (IL) pattern of LGE. Abbreviations as

in Figures 1 and 3.

Aquaro et al. J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7

1982

except the inferior or inferolateral walls (AS cluster);and in 59 cases (16%), LGE images were positive butdid not involve the inferolateral basal or the ante-roseptal walls (other-LGE cluster). Finally, in 26patients (7%), LGE images were negative (no-LGEcluster). On the basis of these clusters, the populationwas subdivided into 4 groups: the IL group, AS group,other-LGE group, and no-LGE group (Figure 1).Examples of LGE images from these groups areshown in Figures 3 and 4.

As evident in Table 3, patients in the AS group hadlower ESR and CRP values than did other groups. Inaddition, the AS group had a higher LV EDV index(LVEDVi) and more myocardial segments with LGEthan the IL group. LVEF and wall motion score indexwere not different among groups, but patients in theAS group had a lower RVEF than others. The no-LGEand other-LGE groups showed higher RVEF thanother patients. The number of myocardial segmentswith edema was higher in the AS and IL groups than

in the no-LGE and other-LGE patients. Myocardialedema and hyperemia had the same regional distri-bution of LGE.

CLINICAL FOLLOW-UP. During the median follow-upof 1,572 days (25th to 75th percentile: 1,122 to 2,923),ICDs were inserted in 6 patients (2 patients for epi-sodes of nonvasovagal syncope associated with non-sustained ventricular tachycardia during 24-h ECGHolter monitoring and in 4 patients for evidence ofsustained ventricular tachycardia during Holtermonitoring). There were 30 patients who had >5%worsening of LVEF according to echocardiographyduring follow-up. The average decrease of LVEF inthese 30 patients was 10 � 5%. In 26 of these patients,coronary angiography was repeated during follow-upand confirmed the absence of obstructive coronaryartery disease. The worsening of LV function wasmore prevalent in the AS group than in the IL group(20 vs. 10; p ¼ 0.022).

TABLE 3 Clinical Differences Among the Groups

AS Group(n ¼ 135)

IL Group(n ¼ 154)

Other-LGE Group(n ¼ 59)

No-LGE Group(n ¼ 26)

Globalp Value

Age, yrs 33 � 12 32 � 12 33 � 12 38 � 15*†‡ 0.02

Hypertension 11 (8) 23 (15) 7 (12) 3 (12) 0.50

Hyperlipidemia 5 (4) 6 (4) 1 (2) 1 (4) 0.80

Diabetes 2 (2) 2 (1) 3 (5) 2 (7) 0.09

Smoking 15 (11) 27 (17) 10 (17) 3 (12) 0.50

Family history of CAD 13 (9) 24 (15) 9 (15) 2 (7) 0.60

Obesity 7 (5) 7 (4) 3 (6) 2 (7) 0.80

ECG abnormalities 131 (97) 152 (98) 56 (95) 24 (92) 0.12

Laboratory results

Leukocytes, 103cells/ml 10.1 � 3.2 10.3 � 3.9 10.8 � 4.2 10.1 � 3.8 0.60

Troponin T, ng/ml 1.5 (1–4)‡§ 1.4 (0.9–1.8) 1.0 (0.9–1.7) 0.9 (0.4–1.2) 0.02

ERS, mm/h 12 (1–27)†‡ 20 (4–40) 23 (7–46) 12 (1–26)†‡ 0.005

CRP, mg/l 7.2 (2.9–32.2)† 8.1 (4.3–36.8) 7.7 (2.2–33) 4.7 (2.3–11)*†‡ 0.002

CMR results

LVEDVi, ml/m2 84 � 18† 79 � 16 84 � 27 81 � 19 0.004

LVEF, % 62 � 7 62 � 6 62 � 7 62 � 9 0.30

LV mass index, g/m2 74 � 17 72 � 16 72 � 15 72 � 15 0.70

WMSI 1.02 � 0.23 1.03 � 0.19 1.04 � 0.18 1.01 � 0.03 0.11

RVEDVi, ml/m2 82 � 16 81 � 16 81 � 17 76 � 14 0.16

RVEF, % 50 � 16†‡§ 52 � 20 56 � 8 58 � 8 0.001

No. of segments with edema 4 (1–8)†‡§ 3 (1–5) 2 (1–4) 2 (1–3) 0.01

No. of segments with hyperemia 2 (1–4) 2 (2–4) 2 (2–4) 2 (1–3) 0.70

No. of segments with LGE 5 (3–7)†‡§ 2 (1–3) 2 (1–3) 0 <0.001

Values are mean � SD, n (%), or median (interquartile range). The data refer to the population of 374 patients with LGE images of sufficient image quality. *p significant vs.AS-group. †p significant vs. IL group. ‡p significant vs. other-LGE group. §p significant vs. no-LGE group.

AS ¼ anteroseptal; IL ¼ inferolateral; other abbreviations as in Tables 1 and 2.

TABLE 4 Incidence of Cardiac Events During Follow-Up

AS Group(n ¼ 135)

IL Group(n ¼ 154)

Other-LGEGroup

(n ¼ 59)

No-LGEGroup

(n ¼ 26)

Combined endpoint 21 (16)*† 4 (3) 4 (7) 0 (0)

Sudden cardiac death 4 (3)* 0 (0) 0 (0) 0 (0)

Appropriate ICD shock 2 (2) 0 (0) 0 (0) 0 (0)

Resuscitated cardiac arrest 0 (0) 0 (0) 2 (4) 0 (0)

Hospitalization for heartfailure

15 (11)* 4 (3) 2 (4) 0 (0)

3-yr event probability 0.14 (0.05–0.24) 0.04 (0–0.07) 0.04 (0–0.08) 0

5-yr event probability 0.36 (0.20–0.52) 0.03 (0–0.06) 0.08 (0–0.09) 0

Values are n (%) or hazard ratio (95% confidence interval). *Significant vs. IL group. †Significant vs. no-LGE.

ICD ¼ implantable cardioverter-defibrillator; other abbreviations as in Tables 2 and 3.

J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7 Aquaro et al.O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

1983

As reported in Table 4, there were 8 major car-diac events (4 sudden cardiac deaths; 2 resuscitatedcardiac arrests, 2 appropriate ICD firings) and 21hospitalizations for heart failure. Major cardiacevents occurred more frequently in the AS groupthan in the IL group (AS: 6; IL: 0; p < 0.01),whereas no differences were found with othergroups (2 events in the other-LGE group and nonein the no-LGE group). The AS group also had morefrequent hospitalizations for heart failure than didthe IL group (15 vs. 4; p ¼ 0.004). Fifteen patientshad recurrence of AM with clinical manifestation ofchest pain, troponin increase, and evidence of 2 ormore signal abnormalities in the CMR evaluation.The prevalence of recurrence was not significantlydifferent among the groups (5 for AS, 6 for IL, and 4for other-LGE).

Overall, the combined endpoint of major cardiacevents and hospitalization for heart failure occurredin 21 patients (16%) in the AS group, 4 (3%) in the ILgroup, and 4 (5%) in other-LGE group, whereas noevent occurred in the no-LGE group. In the Kaplan-Meier curve analysis, the AS group had worse event-free survival rates than did the other groups (CentralIllustration). No prognostic differences were found

among IL, other-LGE, and no-LGE groups. The char-acteristics of patients with and without cardiacevents are summarized in Table 5. A logistic regres-sion analysis was carried out using the combinedendpoint as the dependent variable and the AS groupand troponin peak as independent variables.Belonging to the AS group was the best predictor ofthe combined endpoint (AS group: odds ratio: 2.73;95% confidence interval: 1.20 to 5.90; p ¼ 0.01; and

CENTRAL ILLUSTRATION Prognostic Role of Different LGE Patterns in Patients With AM and Preserved EF

Aquaro, G.D. et al. J Am Coll Cardiol. 2017;70(16):1977–87.

In a population of patients with acute myocarditis (AM) and preserved ejection fraction (EF), we identified 4 main patterns of distribution of late gadolinium

enhancement (LGE) (left). The anteroseptal pattern of late gadolinium enhancement was associated with a worse prognosis than the other patterns (right).

AS ¼ anteroseptal; IL ¼ inferolateral.

Aquaro et al. J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7

1984

troponin peak: odds ratio: 1.14; 95% confidence in-terval: 1.03 to 1.63; p ¼ 0.12).

DISCUSSION

The main results of the present study are as follows:1) 3 main patterns of LGE were found in patients withAM and preserved LVEF: IL, AS, and other-LGE; 2) theAS group had higher a RVEDVi and LVEDVi, highertroponin release, and lower inflammatory markers;3) the AS group was associated with a worse prognosisaccording to Kaplan-Meier analysis; and 4) being inthe AS group was the best CMR predictor of thecombined endpoint (Central Illustration).

We selected patients with AM, preserved LVEF,and New York Heart Association functional class I.Almost all these patients had an infarct-likepresentation with chest pain and ECG abnormalities.Infarct-like myocarditis in patients with preserved EFis probably 1 of the most appropriate indications forCMR. As demonstrated by Francone et al. (17), CMR isvery sensitive for identifying AM with infarct-likepresentation compared with endomyocardial biopsy,

but it is less accurate for the diagnosis of myocarditiswhen the initial presentation includes heart failure orarrhythmic events.

Although preserved systolic function is a goodpredictor of survival in many cases of heart disease,the presence of myocardial scar is generally associ-ated with increased risk for adverse cardiovascularevents, even in patients with preserved systolicfunction. In a large group of 857 patients withischemic and nonischemic cardiomyopathies, Cheonget al. (8) showed that the presence of scar tissueexpressed by LGE predicted a worse outcome thandid the absence of LGE, even in patients with EF>50%. The data were confirmed in a cohort of 1,068consecutive patients (9), in which LGE was furtherassociated with a high occurrence of hospitalizationfor heart failure, regardless of etiology, stage of heartfailure, or severity of EF impairment.

Grün et al. (7) studied 203 patients with a definitediagnosis of AM detected by endomyocardial biopsyand found that patients with LGE had larger ventri-cles, lower LVEF, and a worse prognosis. Particularly,these investigators observed cardiac death during

TABLE 5 Characteristics of Patients With and Without Cardiac Events

No Events(n ¼ 345)

Events(n ¼ 29) p Value

Age, yrs 34 � 14 36 � 14 0.46

Hypertension 43 (12) 3 (10) 0.40

Hyperlipidemia 14 (4) 1 (4) 0.85

Diabetes 8 (2) 1 (4) 0.52

Smoking 53 (15) 2 (7) 0.21

Family history of CAD 44 (13) 4 (14) 0.72

Obesity 18 (5) 1 (4) 0.20

ECG abnormalities 315 (91) 26 (90) 0.93

Laboratory results

Leukocytes, 103cells/ml 10.2 � 3.4 9.2 � 2.7 0.12

Troponin T, ng/ml 1.03 (0.0–6.7) 4 (0.4–9.5) <0.0001

ERS, mm/h 25 (14–45) 24 (19–79) 0.60

CRP, mg/l 3.75 (1.2–7.7) 2.7 (0.8–7.4) 0.12

CMR results

LVEDVi, ml/m2 81 � 17 85 � 25 0.24

LVEF, % 62 � 6 61 � 7 0.39

LV mass index, g/m2 72 � 15 76 � 15 0.17

WMSI 1.03 � 0.2 1.06 � 0.08 0.42

RVEDVi, ml/m2 82 � 16 83 � 18 0.74

RVEF, % 53 � 20 51 � 21 0.60

No. of segments with edema 3 (1–5) 2 (1–3) 0.30

No. of segments with hyperemia 2 (0–3) 2 (1–3) 0.89

No. of segments with LGE 3 (2–4) 3 (2–6) 0.90

AS cluster of LGE 114 (33) 21 (72) <0.0001

IL cluster of LGE 150 (43) 4 (14) 0.14

No-LGE 26 (7) 0 (0) 0.09

Other site of LGE 55 (16) 4 (10) 0.77

Values are mean � SD, n (%), or median (interquartile range).

Abbreviations as in Tables 1 to 3.

J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7 Aquaro et al.O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7 CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function

1985

follow-up in 28 of 29 of patients with positive LGEand only in 1 patient with negative LGE. However, alltheir patients with events had impaired EF.

In 2014, Schumm et al. (18) used CMR to evaluate405 patients with suspected AM. These investigatorsfound that patients with abnormalities at CMR (with afinal diagnosis of AM or other cardiac diseases) had aworse prognosis than did patients with negative CMRfindings. More recently, Sanguineti et al. (6) followed203 patients with a CMR-based diagnosis of AM for anaverage of 18.9 months. These investigators observedthat the presence and extent of myocardial edemaand the extent of LGE were not predictive of theoutcome. An impaired LVEF at the first examinationwas the only independent CMR predictor of anadverse clinical outcome (6).

In our multicenter study, we found that in AM withpreserved LVEF, LGE had different patterns of pre-sentation. The most frequent pattern found in 41% ofcases involved the subepicardial layer of the inferiorand lateral wall of the left ventricle (IL group). In 36%of patients, LGE was located in the midwall of theinterventricular septum (AS group). The AS pattern ofLGE was associated with a worse prognosis than inpatients with the IL and no-LGE or other-LGE pat-terns. Patients with the AS pattern had no significantdifferences in LVEF from other groups, despite higherLVEDVi and more myocardial segments with LGE.However, the extent of LGE was not different in pa-tients with and without cardiac events. Moreover, theAS pattern of LGE was the best independent predictorof the combined endpoint. The AS group had highertroponin release than other groups but lower levels ofinflammatory markers such as ESR and CPR. Thisresult suggests a different kind of myocarditis, withless inflammation but greater myocardial damage.

These findings were concordant with those of aprevious postmortem study by Shirani et al. (19) andwith a report by Mahrholdt et al. (11), who foundsimilar distributions of LGE patterns in a nonselectedpopulation of 86 patients with AM. Mahrholdt et al.(11) found that the IL pattern of LGE was mostlyassociated with the detection of the parvovirus B19genome, whereas the AS pattern was associated withthe human herpesvirus 6 genome and with the com-bined presence of both the parvovirus B19 andherpesvirus 6 genomes. Moreover, in that study, thepresence of LGE in the ventricular septum was thestrongest CMR predictor of chronic ventriculardysfunction, as well as ventricular dilatation atfollow-up. In accord with the results of Mahrholdtet al. (11), we found that the AS pattern was mostprevalently associated with worsening of LVEF atfollow-up than other LGE presentations.

The difference in LGE pattern could be explainedby the different tropism of viruses. In fact, humanherpesvirus 6 infects not only T cells but also cells ofthe nervous system and the cardiac conduction sys-tem, and it can establish a latent state after primaryinfection (20). After a primary infection in earlychildhood, AM may be a reactivation of the disease,with myocardial infection and damage occurring inthe septum because of the presence of virus in thecardiac conduction system (21). Repeated viral reac-tivation may be the cause of the most frequent pro-gression to LV dysfunction found in patients with theseptal pattern of LGE than in those without it.Moreover, reactivation of viral infection in the cardiacconduction system may be the trigger for arrhythmicevents in patients with the AS pattern. In contrast,parvovirus B19 is associated with polyserositis andpericarditis after initial viremia (22). Thus the leftlateral free wall and the inferior wall may be involvedbecause of the direct contact with the pericardium.

We did not perform endomyocardial biopsy in allthe patients in the study because our population was

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

CMR enabled confirmation of AM in hemodynamically

stable patients with clinically suspected AM and

preserved EF. In these patients the 2 most frequent

patterns of LGE were the subepicardial IL and the AS

midwall pattern. Patients presenting with LGE in the

midwall of the AS myocardial segments had a worse

prognosis than did patients with other patterns of

distribution.

TRANSLATIONAL OUTLOOK: Further research

should be conducted to determine whether the

different patterns of presentation of LGE in AM are

associated with different viral causes.

Aquaro et al. J A C C V O L . 7 0 , N O . 1 6 , 2 0 1 7

CMR and Prognosis in Acute Myocarditis With Preserved Systolic Function O C T O B E R 1 7 , 2 0 1 7 : 1 9 7 7 – 8 7

1986

composed of hemodynamically stable patients withpreserved LVEF, and the invasive procedure was notindicated. Thus we cannot evaluate the presence ofdifferent viral genomes in our patients, and we didnot know whether these or other viruses wereinvolved in the mechanism of damage of our patients.However, our results strengthen the role of AS LGE inmyocarditis by the finding of a prognostic role of thispattern during long-term follow-up of patients withpreserved LVEF. Future studies are needed to eval-uate whether the different patterns of LGE anddifferent prognoses could be caused by different viraltropisms or other factors.

STUDY LIMITATIONS. First, as mentioned, we did notperform endomyocardial biopsy in all the patients,and the diagnosis was made by the summation ofclinical and CMR findings. As shown in the 2009white paper in the Journal, CMR criteria are highlyspecific for the diagnosis of myocarditis but lesssensitive (5). Our population is almost completelycomposed of patients with infarct-like myocarditis, asdemonstrated by the high prevalence of chestpain (95%), new ECG abnormalities (96%), elevationsin CRP and/or ERS (99%), and troponin increases(100%). As a previous study demonstrated, in patientswith infarct-like presentations, CMR is also verysensitive for detection of AM (17). In contrast, CMRhas a low sensitivity in patients with heart failurepresentations and a very low sensitivity in those witharrhythmic presentations, and for this reason wedecided to exclude patients with these presentations.Furthermore, when compared with endomyocardialbiopsy, CMR was demonstrated to be very accuratefor the detection signs of myocardial damage in AM,whereas it was less sensitive for the diagnosis ofchronic myocarditis (23). In our population of pa-tients with clinically suspected AM and an infarct-likepresentation, CMR may be considered both specificand sensitive to confirm the diagnosis of AM.

Second, we did not perform T1 and T2 mapping inour population. T1 mapping could permit the detec-tion and quantification of microscopic fibrosis, even

in the absence of positive LGE, whereas T2 mappingwould allow us to detect myocardial edema quanti-tatively. However, at the time of patients’ enrollmentin the study, these 2 techniques were not available inall CMR scanners, and nowadays, the pulse sequenceof T1 and T2 mapping may provide different resultsfor different CMR vendors. Therefore, in the contextof a multicenter study, we preferred not to includethese 2 new yet promising techniques.

CONCLUSIONS

In this multicenter study, patients with AM andpreserved LVEF had different patterns of LGE. TheAS pattern of LGE was associated with a worseprognosis and with presentations different fromthose the IL pattern, the no-LGE pattern, and otherpatterns.

ADDRESS FOR CORRESPONDENCE: Dr. GiovanniDonato Aquaro, Fondazione Toscana G. Monasterio,Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy. E-mail:aquaro@ftgm.it.

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KEY WORDS acute myocarditis, cardiacmagnetic resonance, late gadoliniumenhancement, prognosis