Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance

IJCA-26360; No of Pages 7 International Journal of Cardiology xxx (2017) xxx–xxx

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Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance Giovanni Donato Aquaro a,⁎, Francesco Negri b, Antonio De Luca b, Giancarlo Todiere a, Francesco Bianco c, Andrea Barison a, Giovanni Camastra d, Lorenzo Monti e, Santo Dellegrottaglie f,g, Claudio Moro h, Chiara Lanzillo i, Alessandra Scatteia j, Mauro Di Roma k, Gianluca Pontone l, Martina Perazzolo Marra m, Gianluca Di Bella n, Rocco Donato n, Chrysanthos Grigoratos o, Michele Emdin a,o, Gianfranco Sinagra b a

Fondazione Toscana G.Monasterio, Pisa, Italy Cardiovascular Department “Ospedali Riuniti” of Trieste and Post Graduated School of Cardiovascular Sciences, University of Trieste, Trieste, Italy c University of Chieti, Chieti, Italy d Cardiac Department, Vannini Hospital Rome, Roma, Italy e Radiology Department, Humanitas Research Hospital, I.R.C.C.S, Rozzano, (Milan), Italy f Division of Cardiology, Villa dei Fiori, Acerra, Napoli, Italy g Mount Sinai School of Medicine, New York, USA h U.O. Cardiologia e UTIC, ASST Monza, P.O. Desio, Italy i Cardiology Department, Policlinico Casilino, Rome, Italy j Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy k Radiological Department, European Hospital, Roma, Italy l Cardiac Department, Centro Cardiologico Monzino, Milano, Italy m Division of Cardiology, Department of Cardiac, Thoracic, and Vascular Sciences, University of Padua, Padua, Italy n Clinical and Experimental Department of Medicine, University of Messina, Messina, Italy o Scuola Superiore di Perfezionamento Sant'Anna, Pisa, Italy b

a r t i c l e

i n f o

Article history: Received 11 December 2017 Received in revised form 4 April 2018 Accepted 18 April 2018 Available online xxxx Keywords: Acute myocarditis Cardiac magnetic resonance Late gadolinium enhancement Myocardial edema Right ventricular myocarditis Prognosis

a b s t r a c t Objectives: Right ventricular (RV) myocarditis (MY) is unrecognized, and its prevalence is unknown. We evaluated the prevalence of RV involvement in acute MY and its association with cardiac events (cardiac death, cardiac arrest, ventricular assist device, transplantation, and appropriate ICD intervention). Methods: We enrolled 151 patients who underwent cardiac magnetic resonance for clinical suspicion of acute MY. The CMR protocol included T2-STIR images for edema detection, post-contrast cine-SSFP for hyperemia detection and late gadolinium enhancement (LGE) images. Results: Signs of RV MY were found in 27 patients (17.8%): RV edema at T2-STIR in all of these 27 patients; RV LGE was detected in 11 patients (7.3%). The median RV myocardial segment involved was 2 (1–3). In 13 patients, RV edema was in direct continuity with LV edema of septum and inferior wall or with anterior septum and anterior wall. In 2 patients RV myocarditis was found without any signs of LV involvement. Patients with RV MY had higher RV end-diastolic volume index (p = 0.04) and RV mass index (p = 0.03), and lower RV ejection fraction (p b 0.001) than others. At Kaplan-Meier survival curve patients with RV MY had more cardiac events than those without RV involvement (p = 0.015). RV involvement, anteroseptal LGE and RV LGE were associated with cardiac events. Conclusion: RV involvement in acute MY is more frequent than previously hypothesized. RV MY was associated with cardiac events. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Acute Myocarditis (MY) is an inflammatory disease of the myocardium characterized by a great heterogeneity of presentation and ⁎ Corresponding author at: Fondazione Toscana G. Monasterio, Via Giuseppe Moruzzi, 1, 56124 Pisa, Italy. E-mail address: [email protected]. (G.D. Aquaro).

evolution. Acute MY may begin as a recent-onset heart failure, arrhythmic events, or infarct-like symptoms [1–3]. Usually MY involves the left ventricular (LV) myocardium but previous studies, using endomyocardial biopsy (EMB) in patients with suspicion of MY, demonstrated a frequent involvement of right ventricle (RV) [4,5]. However, a great limitation of these studies was that tissue specimens were taken from only the right side of ventricular septum and not in the RV free wall. Furthermore, previous studies examined patients

https://doi.org/10.1016/j.ijcard.2018.04.087 0167-5273/© 2017 Elsevier B.V. All rights reserved.

Please cite this article as: G.D. Aquaro, et al., Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.04.087

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G.D. Aquaro et al. / International Journal of Cardiology xxx (2017) xxx–xxx

with decreased LV ejection fraction or in chronic MY. The prevalence of RV MY and its clinical impact have not been previously assessed in patients with clinical suspected acute MY and preserved ejection fraction. In hemodynamically stable patients endomyocardial biopsy (EMB) may not be indicated [4,6]. Cardiac magnetic resonance (CMR) is considered the best non-invasive imaging modality for the diagnosis of acute MY, and is generally preferred in stable patients. CMR can detect signs of RV myocardial damage such as myocardial edema and late gadolinium enhancement (LGE) [7]. However, the detection of RV MY in CMR has been described in only a few case reports [8,9]. In the current study, we performed CMR to evaluate the prevalence of RV involvement in hemodynamically stable patients with acute MY and preserved ejection fraction and to assess its clinical and prognostic implications. 2. Methods ITAMY II (ITAlian study in MYocarditis) was a multicenter investigation on the prognostic value of CMR in MY, which was an update of the previous ITAMY study [10]. From that study we analyzed CMR images of 180 consecutive hemodynamically stable patients with clinically suspected acute MY and preserved LV ejection fraction enrolled from 1 January 2008 to 31 December 2014. We excluded patients with heart failure and arrhythmic presentation because of the demonstrated low sensitivity of CMR for detecting acute MY of such patients. Based on recent position paper from the European Society of Cardiology [3], clinically suspected acute MY was defined when symptomatic patients with chest pain (pericarditis or pseudo-ischemic pain) fulfilled one or more of the diagnostic criteria (new ECG modification, elevated troponine, wall motion abnormalities with preserved LV ejection fraction at echocardiography) or when asymptomatic patients fulfilled two or more diagnostic criteria. A definite diagnosis of acute MY was then made when two or more CMR Lake Louise criteria (myocardial edema, hyperemia, and LGE) were satisfied [7]. EMB was performed when CMR was inconclusive (≤1 CMR criterion). To exclude obstructive coronary artery disease, coronary artery angiography was performed on all the patients with the exception of those younger than 30 years old with low risk of coronary artery disease. At hospital admission, all patients underwent clinical evaluation, ECG, echocardiography and laboratory testing (including leucocytes, C reactive protein, erythrocyte sedimentation rate, and troponine T). Informed consent was obtained from all patients at the time of CMR examination. From the initial enrolled population, 29 patients were excluded (18 for claustrophobia and 11 because of not optimal CMR images). The final population included 151 patients (118 males, mean age 39 ± 15 years). 2.1. CMR acquisition protocol CMR imaging was performed within 7 days from symptoms onset with 1.5-T systems (CVi, HD release, GE Healthcare, Milwaukee, USA) using dedicated cardiac software, a phased-array surface receiver coil, and vectocardiogram triggering. According to the protocols recommended by the Society for Cardiovascular Magnetic Resonance, we acquired cine steady-state free precession (cine-SSFP) images, T2-weighted imaging, and LGE at 10 min after gadolinium injection in the short-axis (9–13 images covering the entire LV), 2-chamber, and 4-chamber planes. A set of 6 radial equiangular slices centered on the LV were also acquired in both cine-SSFP, T2-STIR and LGE sequence. Short axis cineSSFP images were acquired immediately after gadolinium injection for hyperemia assessment [11]. 2.2. CMR analysis All CMR images were analyzed offline using a workstation with dedicated cardiac software with consensus between three experienced observers who were blinded to the clinical presentation in a highly experienced core-laboratory. End-diastolic volume (EDV), end-systolic volume, EF, and mass of both ventricles were measured by the analysis of short axis cine images and compared to reference values (12). In T2-weighted images, edema was considered present when the ratio of the signal intensity (SI) between the myocardium and the mean SI of the skeletal muscle was ≥2 [7,13]. LGE images were v analyzed visually. As previously reported [14], the LGE presentation in LV was classified in four patterns: the IL pattern, when the sub-epicardial layer of the inferior and lateral segments was involved with variable distribution in other segments except the anteroseptal segments; the AS pattern, when the mid-wall layer of the basal anteroseptal wall was constantly involved with various other segments except the inferior or inferolateral walls; the other-LGE pattern, when LGE was positive but did not involve the inferior/lateral basal or the anteroseptal walls; and no-LGE when LGE images were negative. Myocardial hyperemia was evaluated as previously reported [12,14] using the postcontrast SSFP cine images. The occurrence of edema, hyperemia, or LGE was evaluated in each of the 17 LV segments [15]. RV MY was evaluated by the detection of RV edema and fibrosis in T2-STIR and LGE images. These images were compared with the cine-SSFP image acquired in the same

orientations (to exclude slow flow artifact in T2-STIR images and epicardial fat in LGE images). 2.3. Clinical follow-up After the CMR examination, a follow-up was performed for the first consecutive 151 patients. A clinical questionnaire was compiled by a clinical physician during periodic ambulatory visitations in each hospital, by contacting their relatives by telephone, by a general practitioner, or by consulting the office of vital statistics at the patient's place of residence. The clinical questionnaire included the definition of the following major events: cardiac death, resuscitated cardiac arrest, ventricular assist device, transplantation, and appropriate implantable cardioverter defibrillator (ICD) shock; and minor events: heart failure hospitalization (supplemental data). A complete analysis of the ICD was performed by the referring physician in order to confirm the appropriateness of the shock. 2.4. Statistical analysis Values are presented as the mean ± SD or as the median (25th–75th) for variables with normal and non-normal distributions, respectively. Values with non-normal distributions according to the Kolmogorov-Smirnov test were logarithmically transformed for parametric analysis. Qualitative data are expressed as percentages. Categorical variables were compared by the Chi-square test or Fisher's exact test when appropriate. Continuous variables were compared by the ANOVA test or the Wilcoxon non-parametric test as appropriate. Bonferroni correction was used when necessary. The Kaplan-Meier time-toevent method was used to calculate and compare longitudinal curves between groups. Multivariate Cox regression analysis was used to explore the impact of each significant variable in univariate analysis to predict the occurrence of cardiac events evaluated as a combined endpoint (cardiac death, appropriate ICD-firing, resuscitated cardiac arrest, and hospitalization for heart failure). An inter-rater agreement K value was used to evaluate the interobserver reproducibility for the identification of RV edema and LGE. A p-value b0.05 was considered statistically significant.

3. Results The baseline characteristics of the entire population and groups are summarized in Table 1. The population was composed of young adults with low prevalence of risk factors for coronary heart disease. The most reported symptom was chest pain (85%), and 63% of patients presented fever 1–3 weeks before the onset of MY symptoms. All patients were in New York Heart Association class I. ECG abnormalities were found in 130 (86%) of the subjects (ST elevation in 52%, ST depression or negative T wave in 34%). Increased Troponine T and abnormal values of inflammation parameters (erythrocyte sedimentation rate and increased C-reactive protein) were found in all patients. 3.1. CMR results Signs of RV MY were found in 27 (17.8%) patients (23 males), with all of them presenting edema in the RV myocardium in T2-STIR images, while RV LGE was found in 11 (7.3%) of them. Examples of CMR images from a case of RV MY are shown in Fig. 1. Abnormalities of RV wall motion were found in 11 patients. The median number of RV segments with edema was 2 [1–3]. In 2 patients, RV MY was detected in the absence of apparent LV involvement. The remaining 25 patients had biventricular involvement. In 13 patients signs of RV edema were in continuity with LV involved segments (RV diaphragmatic wall and LV inferior or inferoseptal wall in 11 patients, RV anterior free wall and LV anteroseptal wall in 2 in patients); in the remaining 11 patients, RV segments involved were not adjacent to LV segments. Abnormalities of LV wall motion were found in 12 patients with RV MY and in 33 patients without it (p = 0.07). RV MY was more frequently associated with the IL pattern of LGE than the AS pattern (16 patients, 59% vs 8 patients, 30%, p = 0.03) and with other LGE distribution (3 patients, 16%, p = 0.0002). As shown in Table 2, there were no significant differences in clinical presentation, biohumoral parameters, risk factors, ECG and symptoms between patients with and without RV MY. However, patients with RV myocarditis had more frequently signs of pericardial involvement (pericardial effusion and/or signs of pericardial inflammation). Patients with RV MY had higher RV EDVi, RV ESVi and RV Mass index and lower RV EF than those without it. The number of LV myocardial

Please cite this article as: G.D. Aquaro, et al., Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.04.087

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Table 1 Characteristics of the population. Groups

Whole population

RV involved

RV not involved

n.

151

27

124

P value

Age (years) Males Weight (Kg) Height (cm) Body Surface Area (m2) Hypertension (n) Hyperlipidemia (n) Diabetes (n) Smoke (n) Obesity (n)

Mean ± SD n(%) Mean ± SD Mean ± SD Mean ± SD n(%) n(%) n(%) n(%) n(%)

39 ± 15 118 (78) 75 ± 15 174 ± 11 1.90 ± 0.24 11(7) 8(5) 3(2) 20(13) 3(2)

38 ± 14 23 (85) 76 ± 15 176 ± 12 1.92 ± 0.27 3(11) 3(11) 1(4) 6(22) 1(4)

39 ± 15 85(69) 75 ± 16 172 ± 9 1.90 ± 0.23 8(6) 5(4) 2(2) 14(11) 2(2)

0.99 0.10 0.46 0.07 0.62 0.41 0.15 0.44 0.20 0.44

Clinical presentation Chest pain (n) Fever in preceding weeks (n) Palpitation (n) Dyspnea (n) Fatigue (n)

n(%) n(%) n(%) n(%) n(%)

128(85) 95(63) 72(48) 33(22) 27(18)

26(96) 21(78) 10(37) 8(30) 5(19)

102(82) 74(60) 62(50) 25(20) 22(18)

0.07 0.08 0.29 0.31 0.99

ECG Ecg abnormalities (n) Negative T-wave (n) ST-elevation (n)

n(%) n(%) n(%)

130(86) 56(37) 79(52)

23(85) 11(41) 16(59)

107(86) 44(35) 63(51)

0.99 0.66 0.52

Biohoumoral results Leukocytes (103cells/ml) Troponine T peak ng/ml ERS mm/h CRP mg/L

Median(25th–75th) Median(25th–75th) Median(25th–75th) Median(25th–75th)

6.5(3.1–11.8) 6.2(3.1–11.8) 30 (7–40) 4 (2−11)

8.8(5.7–11.8) 14(9–19) 32 (8–42) 4 (1–9)

5.9 ± (3.1–11.7) 5.9 (3.1–11.7) 30(7–40) 4(2–11)

0.25 0.45 0.81 0.48

Therapy Beta blockers ACEi/ARB Diuretics Antiarrhythmic

n(%) n(%) n(%) n(%)

18(12) 25(17) 4(3) 1

3(11) 4(15) 0 0

15(12) 21(17) 4(3) 1(1)

0.99 0.99 0.99 0.99

CMR results LV EDVi ml/m2 LV EDVi ml/m2 LV EF% LV Mass I g/m2 LV WMSI RV EDVi ml/m2 RV ESVi ml/m2 RV EF % RV mass g LV segments with LGE LV segments with edema IL pattern of LGE AS pattern of LGE Other LGE pattern No LGE Pericardial involvement Pericardial Effusion Signs of Pericarditis (T2w/LGE)

Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Median(25th–75th) Mean ± SD Mean ± SD Mean ± SD Median(25th–75th) Median(25th–75th) n(%) n(%) n(%) n(%) n(%) n(%) n(%)

83 ± 17 32 ± 15 62 ± 4 70 ± 18 1.11 ± 0.32 80(69–92) 32 ± 12 59 ± 12 17 ± 5 3(0–5) 3(1–5) 86(56) 34(22) 25(17) 6(4) 48(32) 23(15) 25(17)

85 ± 15 33 ± 12 61 ± 10 73 ± 20 1.15 ± 0.32 87(76–98) 35 ± 16 57 ± 8 18 ± 5 3(0–4) 3(2–5) 16(59) 8(30) 3(11) 0 16(60) 7(26) 9(33)

82 ± 20 31 ± 16 62 ± 2 69 ± 16 1.09 ± 0.24 79(69–91) 30 ± 11 63 ± 7 16 ± 4 3(1–5) 3(1–5) 70(56) 26(21) 22(5) 6(5) 32(26) 16(13) 16(13)

0.33 0.5 0.65 0.35 0.19 0.05 0.02 b0.001 0.03 0.86 0.91 0.83 0.23 0.57 0.59 0.0007 0.13 0.02

ERS, erythrocyte sedimentation rate; CRP, C-reactive protein; LV, left ventricular; EDVi, End-diastolic volume index; EF, ejection fration; RV, right ventricular; LGE, late gadolinium enhancement; IL pattern, LGE involving prevalently the sub-epicardial layer of the inferior and lateral walls of LV; AS pattern, LGE involving prevalently the mid-wall of the interventricular septum and/or anterior wall.

segments with edema and those with LGE were not significantly different between patients with and without RV MY. The presence of RV MY was associated with pericardial involvement (pericarditis or pericardial effusion, p = 0.0007). The inter-rater agreement demonstrated a good interobserver reproducibility for both RV edema (K 0.97, 95% CI 0.93–1) and LGE (K 0.93, 95% CI 0.84–1) detection. 3.2. Clinical follow-up During the median follow up of 4 years (25th–75th percentile: 3–8), ICD was implanted in 5 patients (2 patients for episodes of nonvasovagal syncope associated with non-sustained ventricular

tachycardia in 24-h ECG Holter monitoring and 3 patients for evidence of sustained ventricular tachycardia in Holter monitoring). Twenty patients presented a N 5% worsening of LV ejection fraction evaluated by echocardiography during the follow-up. The combined endpoint of cardiac events was found in 21 patients: 8 major cardiac events (3 sudden cardiac deaths; 2 resuscitated cardiac arrests, 3 case of appropriate ICD firing) and 13 hospitalizations for heart failure. The prevalence of cardiac events was higher in the group of patients with RV MY (11 events, 40%) than in those without RV involvement (10 events, 8%, p b 0.0012). Cardiac events occurred most frequently in patients with AS pattern of LGE than those with IL pattern (26% vs 8%, p = 0.01). During the follow-up, 8 patients had relapse of myocarditis (4 with RV MY and 4 without, p = 0.012).

Please cite this article as: G.D. Aquaro, et al., Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.04.087

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Fig. 1. Two cases of right ventricular acute myocarditis. In the left panels, a case of lone right ventricular myocarditis with edema and late gadolinium enhancement in the lateral free wall of right ventricle. In the right panels, a case of biventricular myocarditis.

The analysis of Kaplan-Meier survival curve (Fig. 2), showed that patients with RV MY had worse prognosis than those with only LV involvement (log rank p = 0.008).

Patients with cardiac events more frequently had signs of RV involvement such as RV edema and LGE. At univariate analysis RV involvement, RV LGE and AS pattern of LGE were associated with

Table 2 Characteristics of patients with and without cardiac events at follow-up. Parameters

No event

Cardiac events

n.

132

21

P-value

Age (years) Males Weight (Kg) Height (cm) Body Surface Area (m2)

Mean ± SD n(%) Mean ± SD Mean ± SD Mean ± SD

38 ± 15 94(71) 78 ± 15 173 ± 9 1.89 ± 0.2

41 ± 16 15(78) 82 ± 15 177 ± 9 1.99 ± 0.3

0.34 0.48 0.07 0.09 0.09

Biohoumoral results Troponine T peak ng/ml ERS mm/h CRP mg/L

Median(25th–75th) Median(25th–75th) Median(25th–75th)

18(5–22) 35(32–39) 3.9(0.8–9.8)

12(10–15) 25(20–49) 4.1(0.7–10.1)

0.8 0.7 0.49

Therapy Beta blockers ACEi/ARB Diuretics

n(%) n(%) n(%)

3(2) 3(2) 1(1)

3(14) 2(9) 2(9)

0.23 0.8 0.3

CMR results LV EDVi ml/m2 LV ESVi ml/m2 LV EF% LV Mass I g/m2 LV WMSI RV EDVi ml/m2 RV ESVi ml/m2 RV EF % RV mass I g/m2 LV segments with LGE, n. LV segments with edema, n. IL pattern of LGE AS pattern of LGE Other LGE pattern No LGE RV involvement RV segments with edema, n. RV LGE RV segments with LGE, n

Mean ± SD Mean ± SD Median(25th–75th) Median(25th–75th) Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Median(25th–75th) Median(25th–75th) n(%) n(%) n(%) n(%) n(%) Median(25th–75th) n(%) n(%)

80 ± 15 29 ± 9 65(59–69) 72(60–80) 1.09 ± 0.22 80 ± 17 30 ± 10 63 ± 7 16 ± 4 2(1–4) 3(2–5) 79(60) 26(20) 23(17) 4(3) 18(14) 0(0–1) 7(5.3) 0

85 ± 19 34 ± 14 63(53–66) 68(63–77) 1.17 ± 0.39 81 ± 12 32 ± 16 60 ± 8 15 ± 5 2(0–4) 4(2–5) 7(33) 9(43) 3(14) 0(0) 9(43) 0(0–3) 4(19) 0(0–1)

0.18 0.06 0.15 0.7 0.2 0.94 0.4 0.15 0.68 0.9 0.43 0.06 0.008 0.9 0.6 0.0003 0.85 0.013 0.7

ERS, erythrocyte sedimentation rate; CRP, C-reactive protein; LV, left ventricular; EDVi, End-diastolic volume index; EF, ejection fration; RV, right ventricular; LGE, late gadolinium enhancement; IL pattern, LGE involving prevalently the sub-epicardial layer of the inferior and lateral walls of LV; AS pattern, LGE involving prevalently the mid-wall of the interventricular septum and/or anterior wall.

Please cite this article as: G.D. Aquaro, et al., Role of right ventricular involvement in acute myocarditis, assessed by cardiac magnetic resonance, Int J Cardiol (2017), https://doi.org/10.1016/j.ijcard.2018.04.087

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Fig. 2. Kaplan-Meier curve analysis. As evident in this image, patients with RV involvement had worse survival free from cardiac events than others.

cardiac events. In multivariable Cox regression analysis for the prediction of cardiac events, RV involvement (HR 4.5, 95% CI 1.7–11.8, p 0.0022) and the AS pattern of LGE (HR 2.7, 95% CI 1.03–7.1, p 0.042) were independent predictors of cardiac events. 4. Discussion To the best of our knowledge this is the first study to evaluate the prevalence and clinical implications of RV MY at CMR among hemodynamically stable patients with acute MY and preserved LV ejection fraction. In this population, we found a prevalence of RV involvement of 17.8%. Patients with RV MY had higher RV EDVi, higher mass index and lower RV ejection than those without it. Moreover, RV MY, the AS pattern of LGE and RV LGE were associated with cardiac events. Studies have previously demonstrated RV involvement in MY using EMB. Yilmaz and colleagues performed EMB in 481 patients with clinically suspected MY and impaired LV function [4]. They found biventricular involvement in approximately 70% of patients and a lone RV MY in 8%. However, among the 355 patients with a histological diagnosis of MY (≥14 infiltrating leukocytes/mm2), only 10 had myocites necrosis and/or damage demonstrating acute MY. Stiemaier et al. performed EMB in 127 patients with suspicion of myocarditis and LV dysfunction (median LV ejection fraction 32%) and found MY in 89 patients but signs of acute inflammation were present in only 5 patients [5]. However, in both the studies of Stiemaier and Yilmaz, RV involvemente was evaluated by specimen taken from the right side of interventricular septum and not in the RV free wall. RV free wall biopsy is more challenging and risky than for LV myocardium. As interventicular septum is generally considered part of LV, the actual prevalence of RV MY was unknown. In the current study, the prevalence of RV MY detected non-invasively by CMR was 17.8%. We performed CMR in haemodynamically stable patients with acute MY and preserved LV ejection fraction. Patients with MY and decreased ejection fraction might probably have a more extensive disease and higher likelihood of RV involvement than those with preserved ejection fraction. In our study CMR was performed within 7 days from the onset of symptoms, whereas in the studies by Yilmaz and Stiermaier EMB showed signs of chronic MY in the majority of patients, suggesting a long-staying myocardial inflammatory. These differences are quite relevant because our population is prevalently composed of patients with acute MY with infarct-like or chest-pain presentation. A previous study demonstrated that CMR has higher accuracy for detecting signs of AM, but low sensitivity for detecting chronic MY [16]. CMR is very accurate for identifying MY with infarct-like presentation, but it has low sensitivity in MY with arrhythmic and heart failure presentation [17,[18]]. CMR can detects of

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signs of myocardial edema, hyperemia and LGE. Myocardial edema and hyperemia are temporary phenomena that are strictly related to active myocardial inflammation, while LGE is considered a sign of myocardial fibrosis and of irreversible damage [7]. We found that patients with RV MY had larger RV volumes, greater LV mass index and lower RV EF than those without it, which demonstrates the initial mechanical effect of RV inflammation. The majority of RV MY cases in our population have subepicardial involvement (edema and/or LGE) of the inferior and inferolateral wall of LV. Furthermore, as evident in Table 2, patients with RV MY had greater prevalence of signs of pericarditis than those without it. Left lateral free wall and the inferior wall might be involved because of the direct contact with the pericardium. Similarly, RV involvement may be consequences of adjacent pericardial inflammation. This may explain the association with RV MY and the inferolateral pattern of presentation of LV LGE. Another important finding of this study is that RV MY was associated with cardiac events. In a setting of LV dysfunction and extensive signs of MY, the involvement of RV might be more frequent but probably of lesser clinical and prognostic net weight than in cases of normally functioning LV. The other independent predictor of cardiac events was the AS pattern of LGE,. This finding is accordant with recent evidences demonstrating that the AS pattern of LGE was associated with worse prognosis in patients with acute MY with preserved ejection fraction [14]. In a recent study, Sanguineti et al. followed 203 patients with a CMRbased diagnosis of acute MY for an average of 18.9 months. They observed that the presence and extent of LV myocardial edema and LGE were not predictive of the outcome. An impaired LV EF at the first examination was the only independent CMR predictor of adverse clinical outcome [19]. Grün and colleagues demonstrated the prognostic role of LGE in 203 patients with EMB-confirmed MY, but all events occurred in patients with LV dysfunction [20]. The prognostic impact of RV MY in haemodynamically stable patients with acute MY and preserved systolic function has not been previously evaluated. After the acute phase of RV MY, the active inflammation may evolve into a chronic scar that could eventually present areas of fat metaplasia and regional impairment of wall motion. When the involvement is extensive, the RV may dilate with progressive impairment of systolic function. Thus, in the chronic phase, the morphological and tissue evolution of a RV MY could be indistinguishable from arrhythmogenic RV cardiomyopathy (ARVC). Based on data from major studies evaluating the prevalence of desmosomal gene mutations, a success rate of only 50% is estimated for genotyping among patients with definite diagnosis of ARVC/D by the TF criteria [21–24]. In previous studies, the prevalence of inflammatory infiltrates in ARVC was between 60 and 77% of cases [25]. RV MY may mimic ARVC, as demonstrated by Chimenti who found signs of MY at EMB among 21 out of 30 patients with clinical and imaging suspicion of ARVC, while histological features of ARVC were detected in only 9 patients [26]. Bowles and colleagues [27] demonstrated that cardiotropic viruses such as enterovirus and adenovirus were more frequently identified with polymerase chain reaction in myocardial samples of ARVC patients than in control subjects. An association between ARVC and other viruses was demonstrated, despite the identification of viral genome is not sufficient to demonstrate a direct etiological mechanism of viruses in this cardiomyopathy [28]. A specific mutation associated with ARVC may also increase the viral tropism for myocardium and viral MY or humoral autoimmunity can accelerate and worsen myocardial damage [29], which is predisposed to occur according to specific gene mutation. Diong and Knowlton reported that dystrophin-deficient mice with increased disruption of sarcolemma are more susceptible to myocardial enterovirus infection and more prone to virus-induced cardiomyopathy [30]. Future studies are needed to evaluate whether or not RV MY detected at CMR in patients with acute MY and preserved LV EF could develop into an ARVC phenotype. Cardiac sarcoidosis may cause myocardial granulomatous inflammation of both the ventricles, and in the chronic phase, RV involvement may mimic an ARVC/D phenotype. We found that patients with RV

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MY had higher RV mass, which might suggest a differential diagnosis with cardiac sarcoidosis, that presents focal wall thickening due to the presence of granumolas in acute phase. However, no patient in our population had a diagnosis of extra-cardiac sarcoidosis at enrollment or during the clinical follow-up period.

[4]

4.1. Limitations Some study limitations should be mentioned. First, we did not perform EMB in all the patients, and the diagnosis was made using the summation of clinical and CMR findings. Previous evidence demonstrated that CMR criteria are highly specific to the diagnosis of MY [7]. CMR is also very sensitive for diagnosing MY with infarct-like presentation, which is the presentation of almost all the patients of our population (33). Second, we did not perform T1 and T2 mapping in our population. T1 mapping might permit the detection and quantification of microscopic fibrosis, even in the absence of a positive LGE, while T2 mapping would allow us to quantitatively detect myocardial edema. Either T1 or T2 mapping could allow for the detection of RV involvement in a greater percentage of patients. However, the RV wall thickness is extremely thin and probably limits the accuracy of T1 and T2 measurement for this ventricle, and currently there are no studies evaluating native T1 and T2 in cardiac disease involving RV with the exception of congenital heart disease. In this study, image analysis was performed by investigators with great experience in CMR and K values of inter-rater agreement demonstrated good reproducibility of the detection of both RV edema and LGE. However, in real life detection of RV edema in T2-STIR images and RV LGE may be very challenging and more difficult than for LV due to the lower wall thickness and flow artifacts. Finally, for the small number of cardiac events recorded during the follow-up, the multivariable evaluation permitted only to evaluate 2 predictors of cardiac events.

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[6]

[7]

[8] [9] [10]

[11]

[12]

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5. Conclusion [14]

In haemodynamically stable patients with acute MY and preserved ejection fraction, RV involvement is detected at CMR in 17.8% of cases. Furthermore RV involvement is associated with higher RV volumes and lower ejection fraction. In these patients, RV MY is an independent predictor of worse prognosis. Disclosures Dr. Pontone has received institutional grants and fees from GE Healthcare, Medtronic, Bracco, Bayer, and Heartflow. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.04.087.

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