Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery.

Abstract

This study sought to evaluate the long-term mortality in patients with viral myocarditis, and to establish the prognostic value of various clinical, functional, and cardiovascular magnetic resonance (CMR) parameters.
Long-term mortality of viral myocarditis, as well as potential risk factors for poor clinical outcome, are widely unknown.
A total of 222 consecutive patients with biopsy-proven viral myocarditis and CMR were enrolled. A total of 203 patients were available for clinical follow-up, and 77 patients underwent additional follow-up CMR. The median follow-up was 4.7 years. Primary endpoints were all-cause mortality and cardiac mortality.
We found a relevant long-term mortality in myocarditis patients (19.2% all cause, 15% cardiac, and 9.9% sudden cardiac death [SCD]). The presence of late gadolinium enhancement (LGE) yields a hazard ratio of 8.4 for all-cause mortality and 12.8 for cardiac mortality, independent of clinical symptoms. This is superior to parameters like left ventricular (LV) ejection fraction, LV end-diastolic volume, or New York Heart Association (NYHA) functional class, yielding hazard ratios between 1.0 and 3.2 for all-cause mortality and between 1.0 and 2.2 for cardiac mortality. No patient without LGE experienced SCD, even if the LV was enlarged and impaired. When focusing on the subgroup undergoing follow-up CMR, we found an initial NYHA functional class >I as the best independent predictor for incomplete recovery (p = 0.03).
Among our population with a wide range of clinical symptoms, biopsy-proven viral myocarditis is associated with a long-term mortality of up to 19.2% in 4.7 years. In addition, the presence of LGE is the best independent predictor of all-cause mortality and of cardiac mortality. Furthermore, initial presentation with heart failure may be a good predictor of incomplete long-term recovery.

Full text

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Myocarditis
Long-Term Follow-Up
of Biopsy-Proven Viral Myocarditis
Predictors of Mortality and Incomplete Recovery
Stefan Grün, MD,* Julia Schumm, MD,* Simon Greulich, MD,* Anja Wagner, MD,†
Steffen Schneider, PHD,‡ Oliver Bruder, MD,‡ Eva-Maria Kispert, RN,* Stephan Hill, MD,*
Peter Ong, MD,* Karin Klingel, MD,§ Reinhardt Kandolf, MD,§ Udo Sechtem, MD,*
Heiko Mahrholdt, MD*
Stuttgart, Essen, and Tübingen, Germany; and Stamford, Connecticut
Objectives
This study sought to evaluate the long-term mortality in patients with viral myocarditis, and to establish the
prognostic value of various clinical, functional, and cardiovascular magnetic resonance (CMR) parameters.
Background
Long-term mortality of viral myocarditis, as well as potential risk factors for poor clinical outcome, are widely unknown.
Methods
A total of 222 consecutive patients with biopsy-proven viral myocarditis and CMR were enrolled. A total of 203
patients were available for clinical follow-up, and 77 patients underwent additional follow-up CMR. The median
follow-up was 4.7 years. Primary endpoints were all-cause mortality and cardiac mortality.
Results
We found a relevant long-term mortality in myocarditis patients (19.2% all cause, 15% cardiac, and 9.9% sud-
den cardiac death [SCD]). The presence of late gadolinium enhancement (LGE) yields a hazard ratio of 8.4 for
all-cause mortality and 12.8 for cardiac mortality, independent of clinical symptoms. This is superior to parame-
ters like left ventricular (LV) ejection fraction, LV end-diastolic volume, or New York Heart Association (NYHA)
functional class, yielding hazard ratios between 1.0 and 3.2 for all-cause mortality and between 1.0 and 2.2 for
cardiac mortality. No patient without LGE experienced SCD, even if the LV was enlarged and impaired. When
focusing on the subgroup undergoing follow-up CMR, we found an initial NYHA functional class ?I as the best
independent predictor for incomplete recovery (p ? 0.03).
Conclusions
Among our population with a wide range of clinical symptoms, biopsy-proven viral myocarditis is associated with
a long-term mortality of up to 19.2% in 4.7 years. In addition, the presence of LGE is the best independent pre-
dictor of all-cause mortality and of cardiac mortality. Furthermore, initial presentation with heart failure may be
a good predictor of incomplete long-term recovery.(J Am Coll Cardiol 2012;59:1604–15) © 2012 by the
American College of Cardiology Foundation
Viral myocarditis is a common cardiac disease that is
identified in up to 9% of post-mortem examinations (1,2). It
appears to be a major cause of sudden, unexpected death (3),
and may progress to dilated cardiomyopathy (4,5).
Advanced diagnostic procedures such as cardiovascular
magnetic resonance (CMR) or immunohistologic and mo-
lecular pathologic workup of endomyocardial biopsies pro-
vided new insights into this common, but not well charac-
terized, disease (6,7). However, the clinical management
remains difficult, and the long-term mortality of viral
myocarditis, as well as potential risk factors for poor clinical
outcome, are widely unknown.
Recent publications suggested several parameters that
may be associated with poor outcome (8–10), including
clinical symptoms, type of viruses, left ventricle (LV) size
and LV function, and late gadolinium enhancement (LGE),
which has been identified as a predictor of long-term
mortality in other nonischemic heart diseases (11,12).
Consequently, the primary objective was to evaluate the
long-term mortality in patients with viral myocarditis, as
well as to establish the long-term prognostic value of various
clinical,functional,andCMRparametersinthispatientgroup.
From the *Department of Cardiology, Robert-Bosch-Medical Center, Stuttgart,
Germany; †Comprehensive Cardiology of Stamford and Greenwich, Stamford,
Connecticut; ‡Institut für Herzinfarktforschung Ruhr, Essen, Germany; and the
§Department of Molecular Pathology, University of Tübingen, Tübingen, Germany.
This study was funded in part by the Deutsche Forschungsgemeinschaft SFB-TR19,
the Federal Ministry of Education and Research (01EZ0817), and the Robert Bosch
Foundation (KKF-11-18). All authors have reported that they have no relationships
relevant to the contents of this paper to disclose.
Manuscript received October 11, 2011; revised manuscript received December 20,
2011, accepted January 2, 2012.
Journal of the American College of Cardiology
© 2012 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 59, No. 18, 2012
ISSN 0735-1097/$36.00
doi:10.1016/j.jacc.2012.01.007

Page 2

Specifically, we sought to demonstrate that the presence of
LGE predicts future cardiac death. In addition, we aimed at
describing predictors for incomplete recovery during long-term
follow-up.
Methods
Patient population. Two hundred twenty-two consecutive
patients presenting at our institution in Stuttgart for workup of
myocarditis (all comers; referrals [62.9%] and self-presenting
[37.1%]) were enrolled in the long-term follow-up between
January2002andJanuary2008iftheyfulfilledallofthefollowing
criteria: 1) biopsy-proven viral myocarditis defined as presence of
myocardial inflammation and viral genome; 2) ruling out of
relevant coronary artery disease (stenosis ?50%) by angiogra-
phy; and 3) CMR performed within 5 days of initial presen-
tation. Patients with valvular or congenital heart disease dem-
onstrated by CMR were not included. All patients gave
informed consent. Some patients were also part of previous
reports (6,9).
CMR protocol. Electrocardiography-gated CMR imaging
was performed in breath-hold using a 1.5T Magnetom
Sonata (Siemens Healthcare, Erlangen, Germany) in line
with the Society of Cardiovascular Magnetic Resonance/
European Cardiovascular Magnetic Resonance recommen-
dations (13). Both cine and LGE short-axis CMR images
were prescribed every 10 mm (slice thickness 6 mm) from
base to apex. In-plane resolution was typically 1.2 ? 1.8
mm. Cine CMR was performed using a steady-state free
precession sequence. LGE images were acquired on average
5 to 10 min after contrast administration using segmented
inversion recovery gradient echo sequence (14) constantly
adjusting inversion time (15). The contrast dose (gadodi-
amide or gadopentetate-dimeglumine) was 0.15 mmol/kg.
In addition, fat-saturated and T2-weighted images were
obtained to allow differentiation between subepicardial
LGE, epicardial fat, and pericardial effusion.
CMR analysis. Cine and contrast images were evaluated by
two experienced observers as described elsewhere (6,9). In
brief, endocardial and epicardial borders were outlined on the
short-axis cine images. Volumes and ejection fraction (EF)
were derived by summation of epicardial and endocardial
contours. The LV mass was calculated by subtracting endo-
cardial from epicardial volume at end-diastole and multiplying
by 1.05 g/cm3(16). Extent of LGE was assessed using the
Siemens Healthcare Argus analysis software package and the
results were expressed as percentage of myocardial mass.
Endomyocardial biopsy protocol. Endomyocardial biop-
sies were performed in all patients. At least five biopsies
were preferentially taken from the ventricle demonstrating
LGE. Patients demonstrating LGE exclusively in the LV
lateral wall underwent selective LV biopsies (30.9%), while
those demonstrating LGE in the septum or having no LGE
at all underwent either biventricular (54.1%) or selective
right ventricular biopsies (15%).
Histopathological analysis. En-
domyocardial biopsies were
stained with Masson’s trichrome
as well as Giemsa and examined
by light microscopy. For immu-
nohistology, tissue sections were
treated with an avidin-biotin-
immunoperoxidase method (Vec-
tastain Elite Kit, Vector, Burlin-
game, California), applying the
following monoclonal antibod-
ies: CD3 (T-cells, Novocastra
Laboratories, Newcastle, United
Kingdom), CD68 (macro-
phages, DAKO, HAMBURG,
GERMANY), and human leuko-
cyte antigen-DR (DAKO) as de-
scribed previously. The detection
of ?14 infiltrating leukocytes/
mm2(CD3? T-lymphocytes
and/or CD68? macrophages) in
the presence of myocyte damage and/or fibrosis in addition
to enhanced human leukocyte antigen class II expression in
professional antigen-presenting immune cells and endothe-
lium was used for the diagnosis of myocarditis (6,9).
Detection of viral genomes. Deoxyribonucleic acid and
ribonucleic acid were extracted with the use of proteinase-K
digestion followed by extraction with phenol/chloroform.
Nested polymerase chain reaction/reverse transcriptase–
polymerase chain reaction was performed for the detection
of enteroviruses (including coxsackieviruses group A & B
and echoviruses), parvovirus B19 (PVB19), adenoviruses,
human cytomegalovirus, Epstein-Barr virus, and human
herpes virus type 6 (HHV6). As control for successful
extraction of deoxyribonucleic acid and ribonucleic acid,
oligonucleotide sequences were chosen from the
glyceraldehyde-3-phosphate-dehydrogenase gene. Specific-
ity of all viral amplification products was confirmed by
automatic deoxyribonucleic acid sequencing (6,9).
Clinical and CMR follow-up. Clinical follow-up was
performed using a standardized questionnaire at least 3
years after initial presentation. CMR follow-up using an
imaging protocol identical to that used initially was offered
to all surviving patients without contraindications to CMR.
In case of a suspected event, all necessary medical records
were obtained and reviewed by the authors acting as
endpoint committee.
Variables, endpoints, and definitions. All variables were
collected directly from patients, and/or medical records
except CMR parameters, which were evaluated as described
previously. Variables include general characteristics and
follow-up results. Most variables are self-explanatory; all
others are defined below.
There were three primary endpoints: 1) all-cause death,
defined as death from any cause, including aborted sudden
cardiac death (SCD); 2) cardiac death, defined as death
Abbreviations
and Acronyms
CMR ? cardiovascular
magnetic resonance
EDV ? end-diastolic volume
EF ? ejection fraction
HHV ? human herpes virus
HR ? hazard ratio
ICD ? implantable
cardioverter-defibrillator
LGE ? late gadolinium
enhancement
LV ? left ventricle/left
ventricular
NYHA ? New York Heart
Association
PVB19 ? parvovirus B19
SCD ? sudden cardiac
death
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from all cardiac causes, including SCD, heart failure, and
aborted SCD; and 3) SCD, defined as unexpected arrest of
presumed cardiac origin within 1 h after onset of any
symptoms that could be interpreted as being cardiac in
origin. Aborted SCD was considered as resuscitation after
cardiac arrest defined as performance of the physical act of
cardioversion, appropriate implantable cardioverter-
defibrillator (ICD) shocks, or cardiopulmonary resuscita-
tion in a patient who remained alive 28 days later. For
appropriate ICD shocks, defibrillator discharges were
considered appropriate and included automatic defibril-
lation shocks triggered by ventricular tachycardia or
fibrillation and documented by stored intracardiac elec-
trocardiographic data.
Incompleterecoverywasusedasasecondaryendpointinthe
group of patients with CMR follow-up. Incomplete recovery
was defined as EF ?60% or end-diastolic volume (EDV)
?180 ml, or clinical signs of heart failure (New York Heart
Association [NYHA] functional class ?I).
Statistical analysis. Absolute numbers and percentages
were computed to describe the patient population. Medians
(with interquartile range) or mean ? SD were computed as
appropriate. Categorical values were compared by chi-
square test or Fisher exact test as appropriate. Kaplan-Meier
curves were calculated for visualizing the cumulative survival
of patients with and without LGE. A log-rank test was
performed to compare both survival curves. A multivariable
Cox proportional hazards model was used for analyzing
independent associations with all-cause and cardiac mortal-
ity. All p values ?0.05 were considered significant. All p
values are results of 2-tailed tests. All statistical analyses
were performed using the SAS statistical package, version
9.2 (SAS Institute, Cary, North Carolina).
Results
Patient characteristics. Two hundred three of all 222
patients were available for clinical follow-up, yielding a
follow-up rate of 91.5%. The remaining 19 patients were
lost due to no contact. The following paragraphs describe
the characteristics of the 203 patients who underwent
clinical follow-up.
At inclusion, patients were 52 years old (interquartile
range: 40 to 54). Chest pain was the primary reason to seek
medical attention (n ? 74), followed by new onset of heart
failure (n ? 62), and various combinations of malaise and
palpitations (n ? 49) (Table 1). Most patients had an
abnormal electrocardiogram upon admission (n ? 188 of
203, 92.6%), with ST-segment abnormalities as the most
common finding (n ? 111 of 188, 59%), followed by bundle
branch block (n ? 20 of 188, 10.6%).
Endomyocardial biopsy revealed PVB19 as most frequent
virus (n ? 113), followed by HHV6 (n ? 49), and the
combination of PVB19 and HHV6 (n ? 35). Epstein-Barr
virus was also present, whereas other viruses were not found
(Table 1).
All patients presenting with heart failure were treated
with state-of-the-art heart failure medication according to
guidelines. If indicated, an ICD was offered, which was
accepted by 23 patients. No patient in this cohort received
additional immunosuppressive, immunomodulatory, or an-
tiviral therapy.
CMR findings. The mean LVEF was 45% and the mean
LVEDV was 167 ml (Table 1). LGE was present in 108 of
Baseline Patient Characteristics(All Patients With Clinical Follow-Up)
Table 1
(All Patients With Clinical Follow-Up)
Baseline Patient Characteristics
All patients with follow-up 203 (91.5)
Time to follow-up, days 1,685 (1,267–2,102)
Female 63 (31.0)
Age, yrs
BMI, kg/m2
BSA, m2
52 (40–54)
26.3 (24.0–29.1)
2.0 (1.8–2.1)
Primary clinical presentation
Symptoms of ACS74 (36.5)
Subacute new-onset HF 62 (30.5)
Reoccurring episodes of overt HF 18 (8.9)
Combination of palpitations, fatigue,
dyspnea on exertion
49 (24.1)
Aborted SCD0
Initial NYHA functional class
I 48 (23.6)
II 64 (31.5)
III71 (35.0)
IV 20 (9.9)
Virus type by endomyocardial biopsy
PVB19113 (55.7)
HHV649 (24.1)
PVB19/HHV635 (17.2)
EBV 2 (1.0)
PVB19/HHV6/EBV 1 (0.5)
PVB19/EBV 2 (1.0)
HHV6/EBV1 (0.5)
Blood testing
Troponin positive46 (22.7)
BNP, pg/ml 190 (39–652)
NT-proBNP, pg/ml 1,938 (220–8822)
CMR imaging parameter
LVEF, %
EF indexed, %/m2
45 (31–60)
23.7 (15.9–31.2)
LVEDV, ml167 (129–210)
LVESV, ml90 (47–144)
LGE present 108 (53.2)
LGE mass, g 5.3 (3.2–18.6)
LGE, % of LV mass4.2 (2.3–9.3)
Event
All-cause death39 (19.2)
Cardiac death29 (15.0)
SCD 18 (9.9)
Values are n (%) or median (interquartile range).
ACS ? acute coronary syndrome; BMI ? body mass index; BNP ? B-type natriuretic peptide;
BSA ? body surface area; CMR ? cardiovascular magnetic resonance; EBV ? Epstein-Barr virus;
HF ? heart failure; HHV6 ? human herpes virus type 6; LGE ? late gadolinium enhancement; LV ?
left ventricle/left ventricular; LVEDV ? left ventricular end-diastolic volume; LVEF ? left ventricular
ejection fraction; LVESV ? left ventricular end-systolic volume; NT-proBNP ? N-terminal pro–B-type
natriuretic peptide; NYHA ? New York Heart Association; PVB19 ? parvovirus B19; SCD ? sudden
cardiac death.
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203 patients. LGE was usually located in the subepicardial
or intramural areas of the LV.
Using the presence of LGE as only diagnostic criterion, the
sensitivity of LGE to detect myocarditis was 53.2%. However,
when also taking morphological and functional information
into account, we found that 170 of 203 patients had an
abnormal CMR (LVEF ?60% and/or LVEDV ?180 ml
and/or presence of LGE). Thus, the overall diagnostic perfor-
mance of CMR to detect myocarditis was 83.7% using mor-
phology, function, and LGE according to 2008 Society of
Cardiovascular Magnetic Resonance/European Cardiovascular
Magnetic Resonance recommendations (13).
Dividing our patient population in groups with and without
LGE reveals that patients with LGE had larger ventricles,
poorer LVEF, and were more likely to have elevated levels of
B-type natriuretic peptide (Table 2). However, we did not find
significant differences in clinical symptoms or type of viruses
between the two groups with and without LGE (Table 2).
Typical CMR results are displayed in Figure 1.
Follow-up results. During follow-up 28 of 203 patients
died, and 11 patients survived SCD due to adequate ICD
discharge. Those 11 patients were also counted as events as
described previously (Table 1). The majority of events (n ? 29)
occurred for cardiac reasons, and the remaining 10 events were
related to cancer, fatal infections, or accidents. Note that no
patient with normal CMR at initial presentation (n ? 33) died.
Seventy-seven of the surviving patients without ICD
(n ? 141) agreed to undergo follow-up CMR in addition to
clinical follow-up (54.6%). The mean time between initial
and follow-up CMR was 4.7 years. During this time 24 of
the77patientsrecoveredfully(LVEF?60%andLVEDV?180
ml and no clinical signs of heart failure).
Predictors of events. For evaluation of predictors for
events we looked at: 1) all patients who experienced any
Characteristics of Patients With and Without LGE
Table 2 Characteristics of Patients With and Without LGE
LGE Present
(n ? 108)
No LGE
(n ? 95)p ValueOR (95% CI)
Age, yrs 55.0 (40.5–67.5)50.0 (38.0–59.0)0.08
Female
BMI, kg/m2
BSA, m2
26 (24.1)37 (38.9)
?0.05 0.50 (0.27–0.91)
26.8 (24.5–29.4)25.8 (23.5–28.4) 0.16
2.0 (1.8–2.2)1.9 (1.8–2.1)
?0.05
Primary clinical presentation
Symptoms of ACS37 (34.3) 37 (38.9) 0.490.82 (0.46–1.45)
Subacute new-onset heart failure37 (34.3) 25 (26.3)0.221.46 (0.80–2.67)
Reoccurring episodes of overt HF11 (10.2)7 (7.4) 0.481.43 (0.53–3.84)
Combination of palpitations,
fatigue, dyspnea on exertion
23 (21.3) 26 (27.4)0.310.72 (0.38–1.37)
Aborted SCD0 (0)0 (0)1.00
Initial NYHA functional class
I 25 (23.1) 23 (24.2) 0.860.94 (0.49–1.80)
II 32 (29.6)32 (33.7) 0.530.83 (0.46–1.50)
III40 (37) 31 (32.6)0.511.21 (0.68–2.17)
IV11 (10.2) 9 (9.5)0.87 1.08 (0.43–2.74)
Virus type by endomyocardial biopsy
PVB1961 (56.5)52 (54.7)0.80 1.07 (0.62–1.87)
HHV623 (21.3)26 (27.4)0.31 0.72 (0.38–1.37)
PVB19/HHV 620 (18.5)15 (15.8)0.61 1.21 (0.58–2.53)
EBV1 (0.9) 1 (1.1)0.930.88 (0.05–14.24)
PVB19/HHV6/EBV1 (0.9)0 (0)0.35
PVB 19/EBV2 (1.9) 0 (0)0.18
HHV6/EBV0 (0)1 (1.1) 0.29
Blood testing
Troponin positive30 (27.8)16 (16.8)0.06 1.90 (0.96–3.76)
BNP, pg/ml 336 (82–983)67 (27–457)
?0.001
NT-proBNP, pg/ml2,359 (547–18,092) 1,938 (38–4,391)0.55
CMR imaging parameter
LVEF, %
EF indexed, %/m2
37.5 (24.5–57.0)53.0 (39.0–64.0)
?0.0001
19.9 (12.7–28.4) 26.8 (19.6–33.8)
?0.0001
LV-EDV, ml 187.5 (140–263)155.0 (120–193)
?0.001
LV-ESV, ml119.5 (57.5–179.0) 73.0 (43.0–113.0)
?0.0001
LGE mass, g 5.3 (3.2–18.6)—
LGE, % of LV mass4.2 (2.3–9.3)—
Values are median (25th–75th percentile) or n (%).
CI ? confidence interval; OR ? odds ratio; other abbreviations as in Table 1.
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death (all-cause mortality); 2) the subgroup of patients who
experienced cardiac death (cardiac mortality); and 3) the
subgroup of patients experiencing SCD. Univariate analysis
(all-cause mortality, cardiac mortality, SCD) is displayed in
Table 3, 4, and 5. There is no significant correlation
between events and clinical presentation (except reoccurring
episodes of overt heart failure), type of virus, or positive
troponin at initial presentation. However, there is a trend to
poorer outcome in combined PVB19/HHV6 infection.
Besides age, which is obviously related to mortality and
morbidity, functional parameters such as LVEF, LVEDV,
and the presence of LGE reached statistical significance. In
fact, the presence of LGE yields an odds ratio for death of
24.2 in the all-cause mortality group and 36.7 in the cardiac
mortality group. The odds ratio for SCD could not be
calculated because no patient without LGE experienced
SCD. Typical examples are displayed in Figure 2.
Kaplan-Meier survival curves for all-cause mortality,
cardiac mortality, and SCD comparing patients with LGE
with patients without LGE are displayed in Figures 3A to 3C.
Note that only 1 patient without LGE experienced cardiac
death during follow-up (Fig. 3B) and that no patient
without LGE experienced SCD (Fig. 3C).
Multivariable Cox proportional hazards regression anal-
ysis including the initial presence of LGE, the initial LVEF,
the initial LVEDV, and the initial NYHA functional class
also revealed LGE as the best independent predictor of
all-cause mortality (hazard ratio [HR]: 8.4, p ? 0.004). In
this model neither initial LVEDV (HR per milliliter in-
crease in LVEDV: 1.003, p ? 0.08), nor initial NYHA
functional class (HR: 3.2, p ? 0.11), nor initial LVEF (HR
per percent increase in LVEF: 0.98, p ? 0.13) reached
significance. Looking at patients experiencing cardiac death
only, LGE was also the best independent predictor of
cardiac death (HR: 12.8, p ? 0.01). Also in this model
neither initial LVEDV (HR per milliliter increase in
LVEDV: 1.004, p ? 0.09), nor initial LVEF (HR per
percent increase in LVEF: 0.98, p ? 0.16), nor initial
NYHA functional class (HR: 2.2, p ? 0.30) reached
significance. Those results do not change if the variable
Figure 1 Typical Cardiac Magnetic Resonance Results
Cardiovascular magnetic resonance of a 25-year-old male patient presenting for workup of new heart failure (top row, Patient #169). Cine images show an enlarged left
ventricle (LV) with severely impaired left ventricular ejection fraction (LVEF). Late gadolinium enhancement (LGE) is present in many areas (white arrows) adding up to
24% of LV mass. Endomyocardial biopsy revealed human herpes virus type 6 myocarditis. The bottom row (Patient #130) displays cardiovascular magnetic resonance
findings in a 52-year-old female presenting for workup of chest pain. LVEF and LV size is normal (cine) and no LGE can be found. This patient was diagnosed with parvo-
virus B19 myocarditis. LVEDV ? left ventricular end-diastolic volume.
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“initial presentation as heart failure” is introduced in the
regression models (HR: 0.77, p ? 0.45). For SCD the
analysis could not be performed because no patient without
LGE experienced SCD.
When focusing on the 77 patients that underwent CMR
follow-up, univariate analysis revealed an initial NYHA
functional class ?I as the best predictor of incomplete
recovery, followed by initial LVEF (Table 6). This finding
was also confirmed by multivariable regression revealing
initial NYHA functional class ?I as the best independent
predictor of incomplete recovery (p ? 0.03). In this
model neither initial LVEF (p ? 0.16), nor initial LVEDV
(p ? 0.61), nor LGE (p ? 0.70) reached significance.
Figure 4 compares typical initial to follow-up CMR results.
Discussion
This study is unique in that we could demonstrate that the
presence of LGE is the best independent predictor of death
in patients with viral myocarditis. In comparison with
previous studies (8,10,17,18), we only included patients
with biopsy-proven viral myocarditis, who all underwent
CMR imaging within 5 days after initial presentation. Our
data indicate that there is a relevant long-term mortality in
myocarditis patients (Table 1). In addition the presence of
LGE may be useful for noninvasive risk stratification of
myocarditis patients, yielding a Cox proportional hazards
HR of 8.4 for all-cause mortality and 12.8 for cardiac
mortality, independent of clinical symptoms. This is supe-
Univariate Analysis: All-Cause Mortality
Table 3Univariate Analysis: All-Cause Mortality
No Event
(n ? 164)
All-Cause Death
(n ? 39)p ValueOR (95% CI)
Age, yrs50.0 (38.5–63.0) 61.0 (44.0–69.0)
?0.05
Female
BMI, kg/m2
BSA, m2
51 (31.1)12 (30.8)0.970.98 (0.46–2.10)
26.3 (24.1–29.1) 26.0 (23.6–28.7) 0.86
2.0 (1.8–2.1)2.0 (1.8–2.2)0.26
Primary clinical presentation
Symptoms of ACS62 (37.8) 12 (30.8) 0.410.73 (0.35–1.55)
Subacute new-onset HF49 (29.9)13 (33.3) 0.671.17 (0.56–2.47)
Reoccurring episodes of
overt HF
10 (6.1)8 (20.5)
?0.013.97 (1.45–10.87)
Combination of palpitations,
fatigue, dyspnea on
exertion
43 (26.2)6 (15.4) 0.160.51 (0.20–1.31)
Aborted SCD 0 (0)0 (0)
Initial NYHA functional class
I46 (28.0) 2 (5.1)
?0.010.14 (0.03–0.60)
II52 (31.7)12 (30.8)0.910.96 (0.45–2.04)
III51 (31.1)20 (51.3)
?0.052.33 (1.15–4.74)
IV15 (9.1)5 (12.8) 0.491.46 (0.50–4–30)
Virus type by endomyocardial
biopsy
PVB1995 (57.9)18 (48.2)0.180.62 (0.31–1.26)
HHV641 (25.0)8 (20.5) 0.560.77 (0.33–1.82)
PVB19/HHV626 (15.9) 9 (23.1)0.281.59 (0.68–3.74)
EBV1 (0.6)1 (2.6)0.27 4.29 (0.26–70.13)
PVB19/HHV6/EBV0 (0)1 (2.6)
?0.05
PVB19/EBV0 (0)2 (5.1)
?0.01
HHV6/EBV1 (0.6)0 (0)0.62
Blood testing
Troponin positive 34 (20.7) 12 (30.8)0.18 1.70 (0.78–3.70)
BNP, pg/ml152 (35–511) 674 (140–1,432)
?0.01
NT-proBNP, pg/ml1,132 (69–3,055) 3,697 (1,444–18,092) 0.12
CMR imaging parameter
LVEF, %
EF indexed, %/m2
52.5 (34.0–63.5)34.0 (20.0–42.0)
?0.0001
26.0 (17.8–32.9)16.3 (9.6–21.0)
?0.0001
LVEDV, ml 160.0 (123.5–198.0)207.0 (181.0–312.0)
?0.0001
LVESV, ml77.5 (44.0–125.5)149.0 (119.0–214.0)
?0.0001
LGE present71 (43.3)37 (94.8)
?0.000124.23 (5.65–103.9)
LGE mass, g4.5 (2.2–7.8) 18.9 (5.2–30.9)
?0.0001
LGE, % of LV mass 3.2 (1.9–5.5)9.7 (4.6–20.4)
?0.0001
Values are median (25th–75th percentile) or n (%).
Abbreviations as in Tables 1 and 2.
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rior to functional or clinical parameters such as LVEF,
LVEDV, or NYHA functional class, yielding HRs between
1.0 and 3.2 for all-cause mortality and between 1.0 and
2.2 for cardiac mortality. Importantly, in our population
no patient without LGE experienced SCD, even if the
LV was enlarged and the LVEF was severely impaired
(LVEDV ?180 ml and LVEF ?35% and no LGE; n ?
14) (Fig. 3C).
Patient characteristics. Most patients presented for workup
of chest pain or heart failure, which is in line with previous
results (6,9,19). Also types of viruses found are similar to our
(6,9,19)andotherpreviousreports(10,20).Inadditiontochest
pain and heart failure patients presented with a broad variety of
symptoms, ranging from mild to severe. Nevertheless, in
comparison with previous studies (6,9) the current patients are
less symptomatic on average. This is also reflected by the fact
that in the current population just 22.7% of patients had
elevated troponin at presentation.
CMR findings. We found a broad range of normal or
dilated ventricles with either normal or impaired function.
LGE was present in 108 of 203 patients, and was usually
located in the subepicardial or intramural areas of the LV,
which is in line with previous findings (6,9,21).
The sensitivity for LGE to detect myocarditis was 53.2%
in the current study, which is lower than that in our previous
reports (6,9), but well in line with the mean sensitivity of
LGE of 59% described in a recent meta-analysis (22). The
most likely explanation for different sensitivities reported is
Univariate Analysis: Cardiac Mortality
Table 4Univariate Analysis: Cardiac Mortality
No Event
(n ? 164)
Cardiac Death
(n ? 29)p Value OR (95% CI)
Age, yrs 50.0 (38.5–63.0)61.0 (47.0–67.0)
?0.05
Female
BMI, kg/m2
BSA, m2
51 (31.1) 6 (20.7)0.260.58 (0.22–1.51)
26.3 (24.1–29.1)26.9 (24.1–29.6)0.59
2.0 (1.8–2.1)2.1 (1.9–2.2)
?0.05
Primary clinical presentation
Symptoms of ACS62 (37.8) 11 (37.9)0.991.01 (0.45–2.27)
Subacute new-onset HF49 (29.9) 9 (31) 0.901.06 (0.45–2.48)
Reoccurring episodes of
overt HF
10 (6.1)5 (17.2)
?0.053.21 (1.01–10.20)
Combination of palpitations,
fatigue, dyspnea on
exertion
43 (26.2) 4 (13.8)0.150.45 (0.15–1.37)
Aborted SCD 0 (0) 0 (0)
Initial NYHA functional class
I46 (28.0)2 (6.9)
?0.050.19 (0.04–0.83)
II52 (31.7)9 (31.0)0.940.97 (0.41–2.27)
III51 (31.1)13 (44.8)0.15 1.80 (0.81–4.02)
IV15 (9.1)5 (17.2) 0.192.07 (0.69–6.22)
Virus type by endomyocardial
biopsy
PVB1995 (57.9)14 (48.3)0.33 0.68 (0.31–1.50)
HHV641 (25.0)5 (17.2)0.370.63 (0.22–1.74)
PVB19/HHV6 26 (15.9)7 (24.1)0.271.69 (0.65–4.36)
EBV1 (0.6) 1 (3.4)0.165.82 (0.35–95.8)
PVB19/HHV6/EBV 0 (0)1 (3.4)
?0.05
PVB19/EBV0 (0)1 (3.4)
?0.05
HHV6/EBV1 (0.6) 0 (0.0)0.67
Blood testing
Troponin positive 34 (20.7) 10 (34.5)0.10 2.01 (0.86–4–73)
BNP, pg/ml 152 (35–511)674 (107–1,432)
?0.01
NT-proBNP, pg/ml1,132 (69–3,055) 3,003 (1,146–15,563)0.18
CMR imaging parameter
LVEF, %
EF indexed, %/m2
52.5 (34.0–63.5)31.0 (19.0–42.0)
?0.0001
26.0 (17.8–32.9)14.5 (8.4–21.0)
?0.0001
LVEDV, ml 160 (123.5–198.0)207.0 (190.0–312.0)
?0.0001
LVESV, ml 77.5 (44.0–125.5) 162.0 (125.0–224.0)
?0.0001
LGE present71 (43.3)28 (96.6)
?0.000136.68 (4.87–276.1)
LGE mass, g 4.5 (2.2–7.8)20.7 (5.2–35.4)
?0.0001
LGE, % of LV mass 3.2 (1.9–5.5)15.0 (5.1–22.0)
?0.0001
Values are median (25th–75th percentile) or n (%).
Abbreviations as in Tables 1 and 2.
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different patient populations with a broad range of disease
severity. The overall sensitivity of CMR to detect myocar-
ditis using morphology, function, and LGE as described
previously was 83.7%.
Furthermore, our data demonstrate that patients with
scar indicated by LGE have larger ventricles and poorer
LVEF compared with those without scar (Table 2). This
finding is illustrated in Figure 1, and nicely matches the
results from Assomull et al. (11), who reported the same
relationship in dilated cardiomyopathy. As scarring may
lead to LV dilatation and impaired LVEF, this finding
conceptually makes sense.
Follow-up results and predictors of events. In our popu-
lation with symptoms ranging from mild to severe all-cause
mortality was 19.2%, cardiac mortality was 15%, and SCD
occurred in 9.9% of patients during follow-up. Thus, our event
rate is lower than in the Mason et al. myocarditis trial (23),
most likely due to different inclusion criteria and disease
severity, but is almost as high as in the nonischemic cardio-
myopathy group of the SCD-HeFT (Sudden Cardiac Death
in Heart Failure) trial (24), although LV function was much
better in our patients, underscoring the importance of risk
stratification and optimal clinical management in myocarditis.
In the group of 39 patients experiencing death during
follow-up, most individuals died from cardiac events (n ? 29),
emphasizing that cardiac events are the main cause of mortality
among various symptomatic myocarditis patients. In the clin-
ical routine, however, risk stratification based on clinical and
Univariate Analysis: SCD
Table 5Univariate Analysis: SCD
No Event
(n ? 164)
SCD
(n ? 18) p ValueOR (95% CI)
Age, yrs50.0 (38.5–63.0) 60.5 (47.0–65.0) 0.11
Female
BMI, kg/m2
BSA, m2
51 (31.1)3 (16.7)0.20 0.44 (0.12–1.60)
26.3 (24.1–29.1)27.3 (25.4–33.1) 0.25
2.0 (1.8–2.1)2.1 (1.9–2.2)
?0.05
Primary clinical presentation
Symptoms of ACS62 (37.8)6 (33.3)0.710.82 (0.29–2.30)
Subacute new-onset HF49 (29.9)6 (33.3) 0.761.17 (0.42–3.31)
Reoccurring episodes of
overt HF
10 (6.1) 3 (16.7)0.103.08 (0.76–12.43)
Combination of palpitations,
fatigue, dyspnea on
exertion
43 (26.2) 3 (16.7) 0.380.56 (0.16–2.04)
Aborted SCD0 (0) 0 (0)
Initial NYHA functional class
I46 (28.0) 1 (5.6)
?0.050.15 (0.02–1.17)
II52 (31.7) 3 (16.7) 0.190.43 (0.12–1.55)
III51 (31.1)11 (61.1)
?0.053.48 (1.28–9.50)
IV15 (9.1) 3 (16.7)0.31 1.99 (0.52–7.65)
Virus type by endomyocardial
biopsy
PVB1995 (57.9)9 (50.0)0.52 0.73 (0.27–1.92)
HHV6 41 (25.0)3 (16.7)0.430.60 (0.17–2.18)
PVB19/HHV6 26 (15.9)4 (22.2)0.491.52 (0.46–4.97)
EBV1 (0.6)1 (5.6)0.06 9.59 (0.57–160.3)
PVB19/HHV6/EBV0 (0)0 (0)
PVB19/EBV0 (0) 1 (5.6)
?0.01
HHV6/EBV1 (0.6) 0 (0) 0.74
Blood testing
Troponin positive 34 (20.7) 6 (33.3) 0.221.91 (0.67–5.46)
BNP, pg/ml 152 (35–511)890 (165–1,432)
?0.01
NT-proBNP, pg/ml1,132 (69–3,055)1,742 (1,146–3,003) 0.49
CMR imaging parameter
LVEF, %
EF indexed, %/m2
52.5 (34–63.5)30.0 (19.0–42.0)
?0.0001
26.0 (17.8–32.9)13.7 (8.4–19.7)
?0.0001
LVEDV, ml 160.0 (123.5–198.0)232.0 (196.0–331.0)
?0.001
LVESV, ml 77.5 (44.0–125.5)166.5 (119.0–266.0)
?0.001
LGE present71 (43.3) 18 (100.0)
?0.0001
LGE mass, g4.5 (2.2–7.8)7.7 (3.8–24.9)
?0.05
LGE, % of LV mass 3.2 (1.9–5.5) 6.2 (2.8–19.9)
?0.05
Values are median (25th–75th percentile) or n (%).
Abbreviations as in Tables 1 and 2.
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functional parameters remains difficult despite the value of
LVEF, LVEDV, and NYHA functional class (8,10,17). For
example, in the current study 11 patients in NYHA functional
classes I and II experienced cardiac death, 4 of them SCD
(Table 5). In addition, several patients died despite only mildly
impaired LV function (n ? 5, LVEF ?45%) or a normal-
sized LV (n ? 13, LVEDV ?180 ml). Other factors, such as
the type of virus detected in the myocardium, suggested to be
of prognostic value in previous studies (8,9) could not yet be
confirmed, despite a trend toward a poorer outcome in patients
with combined PVB19/HHV6 myocarditis, which is in line
with previous findings (9,20).
Our findings fit to the fact that LGE has also been shown
to be a good predictor of adverse events in other nonisch-
emic heart diseases, such as dilated (11) or hypertrophic
cardiomyopathy (12). These results may help to explain why
no patient without LGE experienced SCD (0 of 18)
(Table 2), and only 1 patient without LGE experienced
cardiac death (1 of 29) (Table 2), even when the LVEF was
severely impaired and/or the LV was severely dilated. This
concept is highlighted by Figure 2.
Even with our encouraging data, however, it is important
to keep in mind that there is not a 1-to-1 relationship
between the presence of LGE and cardiac death. Thus, to
further improve possible CMR risk stratification, we also
thought about a possible incremental value of additional
CMR-related parameters, such as the pattern of LGE (9),
scar volume and surface area (12), or decrease of LGE over
time (6). However, we were not able to discriminate their
individual predictive potential due to the limited number of
cases and events available in the present study. This topic
shall be revisited when the data of the European Cardio-
vascular Magnetic Resonance Registry or the Magnetic
Resonance in Myocarditis Registry becomes available.
When focusing on the subgroup of patients who also
underwent follow-up CMR (n ? 77), analysis revealed an
initial NYHA functional class ?I as the best independent
predictor for incomplete recovery (p ? 0.03), matching results
from other studies (8,10,17), whereas surprisingly LGE does
not seem to play a relevant role in this setting. This concept is
highlighted by Figure 4. However, one needs to keep in mind
that this subgroup of patients undergoing follow-up CMR
obviously lacks all patients that died during follow-up (n ? 39)
and all patients who received an ICD (n ? 23), causing a
selection bias possibly affecting reliability and resulting in an
underestimation of the role of LGE.
Clinical implications. Although our data demonstrate an
association between LGE and death in myocarditis patients,
prospectively designed international trials are required to
definitively establish LGE as causally related to death risk,
especially because myocarditis populations in other coun-
tries may show lower incidences of PVB19. However, with
Figure 2LV Function, Presence of LGE, and Sudden Cardiac Death
The top row demonstrates cardiovascular magnetic resonance findings of a 73-year-old male with parvovirus B19 myocarditis (Patient #136). This patient has a dilated,
mildly impaired LV with mostly septal LGE (27% of LV mass, white arrows). He clinically recovered from myocarditis, but experienced sudden cardiac death about 3.5
years after initial presentation, despite only mildly impaired LVEF. The middle row shows cardiovascular magnetic resonance images of a 65-year-old male patient with
combined parvovirus B19/human herpes virus type 6 myocarditis (Patient #121). The LV is enlarged and LVEF is severely impaired, and LGE is present at multiple loca-
tions (white arrows, 21% of LV mass). This patient never completely recovered and experienced cardiac death from heart failure about 2 years after initial presentation.
Cardiovascular magnetic resonance results of a 54-year-old male diagnosed with human herpes virus type 6 myocarditis (Patient #88) can be viewed in the bottom row.
The LV is also dilated and LVEF is severely impaired, but no LGE is present. This patient was still alive at follow-up. Abbreviations as in Figure 1.
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regard to our data and the results from other groups some
speculations could be made that may influence clinical man-
agement. 1) Myocarditis patients with normal CMR (LVEF
?60% and LVEDV ?180 ml and no LGE) seem to have a
good prognosis. Thus, patients with clinically suspected myo-
carditis and normal CMR are also likely to have a good
prognosis, which may give afflicted patients and worrying
physicians some peace of mind. 2) Myocarditis patients with-
out LGE did not experience SCD in our study, even if the LV
was dilated and the LVEF severely impaired. Consequently, if
LGE and not LV function or size is closer to the substrate for
SCD, we may speculate about treating all myocarditis patients
demonstrating LGE with beta-blockers, independent of LV
function and size, to prevent potentially lethal arrhythmias.
This speculation satisfactorily fits to the results of Kindermann
et al. (10), describing the lack of beta-blocker therapy as a
predictor for poor clinical outcome. 3) We found initial heart
failure (NYHA functional class ?I) as the best predictor for
Figure 3 Kaplan-Meier Survival Curves for All-Cause, Cardiac, and Sudden Cardiac Death
Kaplan-Meier survival curves with regard to all-cause mortality (A), cardiac mortality (B), and sudden cardiac death (C). The number of patients at risk is shown at the
bottom of the figure. Note that in the group without any scar not a single patient experienced sudden cardiac death during follow-up. CMR ? cardiovascular magnetic
resonance; other abbreviation as in Figure 1.
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incomplete recovery. Despite the limitations discussed
previously, one should carefully optimize heart failure
therapy in all myocarditis patients presenting with even
the mildest signs of heart failure to improve the chance of
complete recovery.
Conclusions
Among our population with a wide range of clinical symp-
toms, biopsy-proven viral myocarditis is associated with a
long-term mortality of up to 19.2% in 4.7 years. In addition,
the presence of scar indicated by LGE is the best indepen-
dent predictor of all-cause mortality and cardiac mortality.
Furthermore, initial presentation with heart failure (NYHA
functional class ?I) may be a good predictor of incomplete
long-term recovery. These data support the necessity for
future large longitudinal follow-up studies to definitely
establish LGE as an independent predictor of cardiac death
in viral myocarditis, as well as to evaluate the incremental
prognostic value of additional parameters.
Reprint requests and correspondence: Dr. Heiko Mahrholdt,
Robert-Bosch-Medical Center, Auerbachstrasse 110, 70376 Stutt-
gart, Germany. E-mail: Heiko.Mahrholdt@rbk.de.
Univariate Analysis: Predictors for Incomplete Recovery
Table 6Univariate Analysis: Predictors for Incomplete Recovery
Full Recovery*
(n ? 24)
Incomplete Recovery†
(n ? 53) p ValueOR (95% CI)
Age, yrs40.0 (33.0–50.5.0)52.0 (43.0–64.0)
?0.01
Female
BMI, kg/m2
BSA, m2
6 (25) 20 (37.7)0.270.55 (0.19–1.62)
26.0 (24.0–28.4)26.8 (24.0–30.6) 0.57
2.1 (2.0–2.1) 1.9 (1.8–2.1)0.08
Primary clinical presentation
Symptoms of ACS10 (41.7)23 (43.4)0.890.93 (0.35–2.47)
Subacute new-onset HF3 (12.5) 16 (30.2)0.10 0.33 (0.09–1.27)
Reoccurring episodes of
overt HF
2 (8.3) 2 (3.8)0.40 2.32 (0.31–17.52)
Combination of palpitations,
fatigue, dyspnea on
exertion
9 (37.5)12 (22.6)0.18 2.05 (0.72–5.84)
Aborted SCD0 (0)0 (0)
Initial NYHA functional class
I15 (62.5) 15 (28.3)0.584.22 (1.52–11.71)
II 7 (29.2)13 (24.5) 0.67 1.27 (0.43–3.73)
III1 (4.2) 21 (39.6)
?0.01 0.07 (0.01–0.53)
IV 1 (4.2)4 (7.5)
?0.010.53 (0.06–5.04)
Virus type by endomyocardial
biopsy
PVB1912 (50)29 (54.7)0.70 0.83 (0.32–2.17)
HHV66 (25)16 (30.2)0.640.77 (0.26–2.30)
PVB19/HHV66 (25)7 (13.2) 0.202.19 (0.65–7.41)
EBV0 (0)0 (0)
PVB19/HHV6/EBV 0 (0)0 (0)
PVB19/EBV0 (0)0 (0)
HHV6/EBV0 (0)1 (1.9)0.50
Blood testing
Troponin positive6 (25.0)11 (20.8) 0.681.27 (0.41–3.97)
BNP, pg/ml62 (23–139)225 (59–487)
?0.01
NT-proBNP, pg/ml86.5 (37–1,037)874 (220–1,132)0.38
CMR imaging parameter
(baseline)
LVEF, %
EF indexed, %/m2
62.5 (52–68.5)53 (33–60)
?0.05
31.6 (24.3–34.0)25.7 (17.9–33.7)0.12
LVEDV, ml147.5 (125.5–169.0)147.0 (117–194.0) 0.79
LVESV, ml49.0 (42.5–84.5)69.0 (41.0–125.0) 0.20
LGE present10 (41.7) 28 (52.8) 0.360.64 (0.24–1.69)
LGE mass, g 4.3 (1.2–8.8)3.7 (2.3–7.0) 0.91
LGE, % of LV mass3.2 (1.4–7.4)2.8 (1.9–5.3) 0.75
Values are median (25th–75th percentile) or n (%). Only patients with follow-up CMR (n ? 77) included. *Full recovery is defined as LVEF ?60% and LVEDV
?180 ml and no signs of heart failure. †Incomplete recovery is defined as LVEF ?60% or LVEDV ?180 ml or NYHA functional class ?I at follow-up.
Abbreviations as in Tables 1 and 2.
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Key Words: cardiovascular magnetic resonance y mortality y
myocarditis y prognosis.
Figure 4 Initial Heart Failure is Related to Incomplete Recovery
The top row displays typical cardiovascular magnetic resonance results of a 64-year-old female at initial presentation and at follow-up 4 years later. The patient pre-
sented for workup of New York Heart Association functional class IV heart failure and was diagnosed with parvovirus B19–related myocarditis (Patient #56). The patient
improved over time (compare left vs. right cine images) but never recovered fully. The bottom row shows cardiovascular magnetic resonance images of another patient
diagnosed with parvovirus B19–related myocarditis (Patient #98, male, 49 years old). This patient presented for workup of chest pain and was clinically New York Heart
Association functional class I despite the initially dilated LV with severely impaired LVEF (left columns). This patient recovered fully during follow-up (right columns,
5 years later). FU ? follow-up; other abbreviations as in Figure 1.
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Grün et al.
Long-Term Follow-Up After Myocarditis