An Enigma for Cardiac MRI? - Hindawi Publishing Corporation

Hindawi Publishing Corporation
BioMed Research International
Volume 2015, Article ID 859073, 8 pages
http://dx.doi.org/10.1155/2015/859073
Review Article
Intramyocardial Hemorrhage: An Enigma for Cardiac MRI?
Camilla Calvieri,1 Gabriele Masselli,2 Riccardo Monti,2 Matteo Spreca,2
Gian Franco Gualdi,2 and Francesco Fedele1
1
Department of Cardiovascular, Respiratory, Nephrologic and Geriatric Sciences, La Sapienza University of Rome,
Viale del Policlinico 155, 00161 Rome, Italy
2
Department of Radiology, La Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy
Correspondence should be addressed to Camilla Calvieri; [email protected]
Received 31 January 2014; Revised 25 September 2014; Accepted 8 October 2014
Academic Editor: Jiang Du
Copyright © 2015 Camilla Calvieri et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cardiovascular magnetic resonance (CMR) is a useful noninvasive technique for determining the presence of microvascular
obstruction (MVO) and intramyocardial hemorrhage (IMH), frequently occurring in patients after reperfused myocardial
infarction (MI). MVO, or the so-called no-reflow phenomenon, is associated with adverse ventricular remodeling and a poor
prognosis during follow-up. Similarly, IMH is considered a severe damage after revascularization by percutaneous primary coronary
intervention (PPCI) or fibrinolysis, which represents a worse prognosis. However, the pathophysiology of IMH is not fully
understood and imaging modalities might help to better understand that phenomenon. While, during the past decade, several
studies examined the distribution patterns of late gadolinium enhancement with different CMR sequences, the standardized CMR
protocol for assessment of IMH is not yet well established. The aim of this review is to evaluate the available literature on this issue,
with particular regard to CMR sequences. New techniques, such as positron emission tomography/magnetic resonance imaging
(PET/MRI), could be useful tools to explore molecular mechanisms of the myocardial infarction healing process.
1. Introduction
“No Reflow” is a multifactorial phenomenon, also known
as microvascular obstruction (MVO) ranging from 5%
to 50%, occurring in patients having had a ST-elevation
myocardial infarction (STEMI) after a primary percutaneous
coronary intervention (PPCI) or thrombolysis. The MVO
phenomenon is associated with a greater myocardial injury
[1]. It has been defined as a patency restoration of an
epicardial infarct-related coronary artery without complete
microvascular reperfusion [1]. It has been described as a
multifactorial pathogenesis including distal embolization,
ischemia-reperfusion injury, and individual predisposition
of coronary microcirculation injury [2]. MVO is generally
assessed after PPCI, with myocardial reperfusion indexes
as thrombolysis in myocardial infarction (TIMI) flow grade
and myocardial blush grade (MBG) in the cath-lab and
the electrocardiographic ST-segment elevation resolution
(STR) in the coronary care unit. However, it can be better quantified by noninvasive imaging techniques, as cardiovascular magnetic resonance (CMR) [3]. Microvascular
obstruction is associated with a worse prognosis at short
and long time. In fact, it is a prognostic index of postinfarct
adverse left ventricular (LV) remodeling, LV dysfunction, and
increased mortality [4]. Microvascular obstruction is currently detected as hypoenhancement within bright regions
of late gadolinium enhancement (LGE) on delayed postcontrast sequences, which are T1-weighted inversion recovery
sequences acquired with different times after intravenous
administration of gadolinium (Figure 1). Reperfusion injury
may also cause intramyocardial hemorrhage (IMH) by erythrocytes extravasation through severely damaged endothelial walls [5]. IMH can be found in almost half of patients
with successfully revascularized acute myocardial infarction
(MI) and is associated with larger infarcts, presence of MVO,
higher left ventricular volumes, lower ejection fraction, and
the lack of improvement at follow-up. Therefore, it has been
shown that the presence of IMH is associated with adverse LV
remodeling and poor prognosis [6, 7].
IMH can be visualized by T2-weighted CMR sequences
(Figure 2), because breakdown products of hemoglobin are
paramagnetic and can influence magnetic properties of the
2
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(a)
(b)
(c)
(d)
Figure 1: Microvascular obstruction on EGE and LGE imaging. Cardiovascular magnetic resonance has been performed 5 days after PCI
in a 54-year-old male patient with anterior ST-elevation myocardial infarction. On T1 early gadolinium enhancement (EGE) images ((a),
(b)), the persistent microvascular damage appears dark (so-called “dark zones”) (black arrows) within late gadolinium enhancement area,
representing the myocardial MVO on septal and anterior wall. White asterisk is the massive thrombus inside the ventricle apex ((a), (b)). T1
LGE short axis images of the same patient ((c), (d)) show transmural late gadolinium enhancement on the anteroseptal wall and a dark zone
within this area indicating MVO (red arrows).
tissue like the MR relaxation times (T1, T2, and T2∗ ) [7, 8].
CMR is the only imaging modality able to exactly detect in
vivo IMH.
Although IMH is present in a variable proportion of the
patients after reperfused myocardial infarction and is closely
related to infarct size, MVO and LV function, its prognostic
significance still remains unclear.
Over the past decade, the rapid advances in noninvasive
imaging techniques, such as myocardial contrast echocardiography (MCE) and in particular cardiovascular magnetic
resonance, have enabled physicians to detect and quantify
regions of MVO. In this review, we reported the available data
about CMR sequences used to assess MVO and especially
IMH.
2. No-Reflow Assessment:
Cardiac MRI Prospective
A large amount of clinical data showed that MVO, detected
by CMR, can predict early adverse LV remodeling, worse
ejection fraction, larger myocardial infarct size, and major
acute cardiac events (MACEs), independently from myocardial infarction size (IS) [9, 10].
Imaging techniques can provide a direct quantification of
MVO extension and explain the relationship between IS and
MVO in determining adverse LV remodeling. It is not yet well
established what is the most accurate tool to visualize and
quantify microvascular damage.
The evaluation of the molecular and cellular mechanisms
after MI, during the first hours of ischemia-reperfusion,
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3
(a)
(b)
(c)
(d)
Figure 2: MVO and hemorrhagic areas in patient after reperfused anterolateral STEMI. ((a), (d)) in the anterolateral wall a large transmural
hyperintense region and an hypointense core centrally located therein (white arrows) are present on the T2-short time inversion recovery
(STIR) images in short axis and four chamber views showing edema on mid-apical anterolateral wall and an hypointense hemorrhagic
area within the edema. ((b), (c)) Late gadolinium enhancement images show microvascular obstruction (black arrows), consistent with the
hypointense area of haemorrhage, on mid-apical anterolateral wall.
requires different types of sequences. In fact, microvascular
obstruction is detected with different time-dependent
sequences: first pass perfusion (FPP), early gadolinium
enhancement (EGE) (Figure 1), and late gadolinium
enhancement (LGE) (Figure 1) [11]. Previous studies
demonstrated that the presence of MVO, detected on FPP
images, has a prognostic role in STEMI patients [6] and its
prevalence is higher compared with MVO assessed on LGE
images [12]. Cochet et al. found MVO on FPP in 46% and
MVO with LGE in 28% of patients with non-ST elevation
myocardial infarction (NSTEMI). Thus, comparing KaplanMeier survival curves stratified by the presence of MVO on
FPP and LGE sequences, they reported a strong relationship
between MVO on LGE and MACEs ( < 0,001), suggesting
its higher prognostic value in predicting cardiovascular
events during follow-up [13].
Judd et al. conducted the first experimental study in
1995, in a reperfused canine infarct model, which showed
correlation of CMR findings with pathology, by thioflavinS staining [14]. The authors reported for the first time areas
of no-reflow, the so-called “dark zones” characterized by
hypoenhancement within bright regions of LGE. In humans,
Lima et al. [15] described a well-defined time-intensity
curve of different areas of enhancement occurring in human
myocardial infarcts, based on the wash-in and wash-out
kinetics of contrast agent.
Since 1998, as demonstrated by Wu et al. [9], MVO
detected by delayed postcontrast CMR sequences became a
strong predictor of adverse postinfarct LV remodeling. Then,
this correlation was confirmed by studies of Hombach et al.
[16] and Ørn et al. [17], which demonstrated that the presence
of microvascular obstruction is associated with infarct size,
transmural infarction, and increased volumes in both short
term and long term follow-up, representing an index of
severe myocardial damage and of adverse left ventricular
remodeling. Recently, Hirsch et al. [18] compared no reflow
4
on LGE images by CMR with early systolic retrograde flow on
intracoronary flow measurements, showing a strong correlation between the two techniques. Angiographic blush indexes
of myocardial reperfusion have been recently associated
with the quantification of microvascular obstruction areas
assessed by CMR [3].
Small studies demonstrated, using FFP sequences, a
linear correlation between MVO areas detected by CMR
and MBG severity assessed by PPCI [19, 20]. Several studies
compared MVO (by either FFP or LGE sequences) with IS
or transmural extent, showing conflicting results concerning
their prognostic interest, with some reports favoring MVO
and others favoring infarct size or transmurality as the best
predictor of outcomes [9, 16, 21, 22]. Regarding this, it has
recently been reported that the ratio between MVO and IS
could be an index of irreversible damage, strongly influenced
by time delays before PCI [23]. Nijveldt et al. [21] showed
that late MVO is associated with increased wall thickness,
regardless of the degree of infarct transmurality. Evidence
strongly suggests that, in the acute setting, MVO might be
more relevant than infarct size or transmural extent [22].
3. Intramyocardial Hemorrhage: An Enigma
for Cardiovascular Magnetic Resonance?
IMH reflects severe reperfusion injury in acute myocardial
infarction involving the structural and functional integrity
of the microcirculation. Intramyocardial hemorrhage is frequently found in large reperfused myocardial infarctions
and is strictly correlated to the presence of MVO (Figure 2)
[12, 24]. Animal and human studies showed IMH prevalently
within the infarct core of reperfused STEMI [24, 25]. In the
prereperfusion era, intramyocardial hemorrhage was rarely
seen on autopsy studies. Few studies in humans investigated
the relationship of IMH with LV adverse remodeling and
infarct size (Table 1). In the last decade, with the improvement
of myocardial revascularization techniques, scientific attention to intramyocardial hemorrhage progressively increased.
However, the clinical significance of IMH is still unclear,
because of nonstandardized methods to detect IMH in vivo.
Noninvasive techniques can provide further prognostic information and can evaluate the effect of preventive measures
directed towards reducing reperfusion injury in the acute
phase of MI. It is still unclear whether IMH could represent a
marker of adverse LV remodeling beyond MI size, LV ejection
fraction, and MVO.
As reported previously, IMH can be visualized by T2weighted (T2W) sequences because hemorrhage and the
breakdown products of oxygenated hemoglobin influence
magnetic properties of the surrounding tissue [12]. T2W
signal is high in the very early, hyperacute phase but then falls
because of the paramagnetic effects of deoxyhemoglobin and
intracellular methemoglobin, as demonstrated in cerebral
hemorrhage [33]. Particularly in the core of the hematoma,
where there is marked hypoxia, the signal may remain very
low for a prolonged period of time [33, 34]. Instead, T2∗ weighted CMR technique is very sensitive to the paramagnetic effects of deoxyhemoglobin and methemoglobin, but it
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requires relatively long echo times that may degrade image
quality during cardiac imaging [11]. Finally, the standardized
imaging method or protocol for assessment of IMH is still
debated.
Asanuma et al. [32] described in humans an incidence
of 38% of intramyocardial hemorrhage in patients with
reperfused AMI. They demonstrated, in patients presenting
with anterior AMI, the presence of IMH using myocardial
contrast echocardiography (MCE) and T2∗ -weighted CMR
sequences. Patients with IMH, compared to patients without
IMH, showed a lower improvement of wall motion score,
assessed by contrast echocardiography, at day 31 after coronary reflow. Ochiai et al. with the same CMR sequences
reported an incidence of 33% of IMH and a strong correlation
with infarct size, with less improvement of ejection fraction,
using thallium-201 scintigraphy [31], confirming previous
observations. Recently, the role of T2∗ -weighted sequences
for detecting IMH was validated by histology in a study [35]
which showed a strong correlation between hemorrhage sizes
assessed in vivo with T2∗ and assessed ex vivo by triphenyltetrazoliumchloride (TTC).
So far, the majority of studies, all prospective, used T2weighted sequences to identify IMH, suggesting different
points of view about its prognostic role.
Ganame et al. showed, in a multivariate analysis,
that intramyocardial hemorrhage detected on T2-weighted
images is an independent predictor of adverse LV remodeling at 4 months, regardless of infarct size [6]. Only two
small studies [4, 7] did not show prognostic significance
of hypointense cores beyond late MVO in prediction of
functional changes at follow-up. The largest prospective study
was conducted by Eitel and colleagues, which examined 346
STEMI patients. The authors demonstrated that the presence
of IMH as a hypointense core in T2 weighted images in 35% of
patients was associated with larger infarcts, greater amounts
of microvascular obstruction, less myocardial salvage, and
impaired left ventricular function. Of note, IMH, together
with late MVO, was indicated as a strong predictor of MACEs
at 6 months after MI [30]. For the first time the prognostic
clinical relevance of the hypointense infarct cores in STEMI
patients after reperfusion with PPCI has been demonstrated.
Other studies investigated the presence of IMH with T2weighted and T2∗ sequences suggesting a better definition of
IMH with combined use of these two techniques.
Mather et al. [29] described an association between the
presence of IMH, as a hypointense signal within the area at
risk (AAR) on both T2W and T2∗ images, and prolonged
QRS duration, a marker of arrhythmic risk. Both were
markers of adverse remodeling.
Recently, Kali et al. [28] compared the two types of
sequences in humans and in dogs suggesting a superiority
of T2∗ for characterization of acute reperfusion myocardial
hemorrhage. Moreover, using T2∗ sequences, an iron deposit
has been observed, measured by mass spectrometry within
the areas of hemorrhagic infarction. This probably represents
a prolonged inflammatory burden during the chronic phase
of MI [27].
Previous studies [27–30, 35] identified intramyocardial
hemorrhage as a hypointense signal or “negative contrast,”
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Table 1
Study
Type of study
Kidambi A et al. [26]
Prospective
(2013)
Kali et al. [27]
Prospective
(2013)
Kali et al. [28]
Prospective
(2013)
∘
IMH (%) Time after MI
MVO
(mean %)
56
IMH
assessment
T2-weighted
and T2∗
Follow-up
90 days
39
35
2 days
15
73
3 days
T2∗
6 months
/
14
3 days
T2 STIR and
T2∗
Unclear
T2 W
6 months
End point
Infarct contractility
Scar tissue
Hemorrhage
Infarct size
myocardial salvage
index MVO
LVEF, LVES QRS
myocardial salvage
infarct size
MACE: death,
reinfarction
congestive heart
failure
Porto et al. [20]
(2007)
Prospective
52
23
4–7 days
Mather et al. [29]
(2011)
Prospective
48
25
2 days
63
T2 W and
T2∗
3 months
Eitel et al. [30]
(2011)
Prospective
346
35
3 days
43
T2-weighted
6 months
Prospective
90
43
5 ± 2 days
54
T2-weighted 103 ± 11 days LV remodeling
Prospective
45
44
5.1 ± 2.1 days
60
T2-weighted
4 months
Ejection fraction
Prospective
98
25
1 week
64
T2-weighted
4 months
LV Adverse
remodeling
1 month
LVEF infarct size
31 days
Wall motion score
Bekkers et al. [4]
(2010)
Beek et al. [7]
(2010)
Ganame et al. [6]
(2009)
Ochiai et al. [31]
(1999)
Prospective
39
33
5.7 days
66
Asanuma et al. [32]
(1997)
Prospective
24
38
6 days
33
within a region of hyperintensity, by exploiting the T2 and
T2∗ shortening effects caused by the elevated myocardial
densities of paramagnetic hemoglobin degradation products
(deoxyhemoglobin, methemoglobin) or blood degradation
products (ferritin and hemosiderin).
Pedersen et al. demonstrated for the first time a higher
diagnostic sensitivity and specificity of T1-weighted inversion recovery sequences (T1WIR), compared to T2 short
tau inversion recovery sequences (T2-STIR) and to T2∗ weighted sequences. They were able to detect the presence
of hemorrhage in porcine myocardium exposed to ischemiareperfusion injury [36]. Moreover, a superior agreement of
T1WIR sequences with pathology has been reported. Of note,
this study showed that the combination of T1W and T2STIR allows a better differentiation between MVO with and
without IMH, by exploiting the T1 shortening effect of methemoglobin [36]. In fact, T1WIR sequences, depicting IMH
as an area of hyperintense signal and normal myocardium
as hypointense signal intensity, provide a superior image
contrast.
Recently, Kandler et al., using T2∗ mapping, found MVO
on LGE images in 66% and IMH in 50% of patients after
reperfused STEMI, which occurred in the majority of cases
concomitantly with MVO [37] in the center of large MVO
areas. These findings confirmed the strong interplay between
occurrence of IMH and MVO [4] and the prevalence of
T2∗ -weighted
gradientecho
T2∗ -weighted
gradientecho
IMH described in other studies [7]. Moreover, they compared
patients with MVO and presence of IMH with ones without
IMH, reporting a significantly lower EF, larger LV volumes
(both systolic and diastolic), and larger infarct sizes in
patients with IMH. In addition, concerning predictors of
IMH presence, they revealed at multivariate analysis that
MVO on LGE images and a “hypointense core” on T2
weighted images stated a high risk for the occurrence of IMH.
Of note, this study demonstrated that defects in T2∗ were also
present in T2 imaging but not vice versa, suggesting that T2∗
sequences are more accurate for IMH detection than T2 ones,
probably for the signal intensity changes in the earlier stage
of infarction. However, the optimal CMR sequences to assess
IMH are still being debated.
4. Emerging Techniques: From Morphology to
Function in Myocardial Infarction
Positron emission tomography/magnetic resonance imaging
(PET/MRI) offers the potential for a powerful “one-stop
shop” combination of structural, functional, and molecular
imaging technology that may be superior to that of MRI
imaging alone. PET has been considered a gold standard
for clinical evaluation of myocardial viability [27, 36] in
chronic ischemic heart disease, because the metabolic tracer
6
[18F]-deoxyglucose (FDG) can distinguish ischemically compromised but viable “hibernating myocardium” [38]. The
healing of myocardial infarction is a complex inflammatory
process, resolved over time, which involves different cell types
like monocytes and macrophages [39].
Simultaneous PET/MRI is an emerging technique combining two powerful imaging modalities [40]. In fact,
PET/MRI is very attractive because it combines the high
spatial resolution of contrast of magnetic resonance imaging
in absence of ionizing radiation, with the high sensitivity of
positron emission tomography (PET).
In fact, using 18F-fluorodeoxyglucose (18F-FDG) PET/
MRI system, Lee et al. [41] examined myocardial inflammation postinfarction in mice with coronary ligation. They
demonstrated a high 18F-FDG uptake on day 5 after
myocardial infarction and that the number of monocytes/macrophages in the noninfarcted myocardium was
lower than in the ischemic tissue.
Of note, also Fluorine 19 (19F) MRI has attracted much
interest because of its capacity of cell tracking in vivo,
useful to understand the molecular mechanism underlying
reperfused myocardium [42].
Flogel et al. validated this emerging technique, in a murine model of acute cardiac and cerebral ischemia [43].
They used PFCs, nanoemulsion of perfluorocarbons, as a
“positive” contrast agent, to detect inflammation in the
border zones of infarction. Moreover, they confirmed with
histology a colocalization of rhodamine-labeled PFCs with
circulating monocytes/macrophages.
Recently, 9F/1H MRI has been used to visualize spatiotemporal recruitment of monocytes in reperfused MI
in animals [42]. More interestingly, Ye et al. correlated
monocyte infiltration with the presence of IMH and MVO,
indicating a greater monocyte infiltration in MI areas with
severe ischemia-reperfusion injury, assessed with IMH [40].
In fact, monocyte/macrophage infiltration was significantly
impaired in MVO areas defined by MRI, compared to animals
with IMH but no MVO [42]. This situation was associated
with a worse LV functional outcome compared to MI isolated
with IMH. Post-MI functional outcome is determined not
only by MI size but also by the rate and quality of infarct healing. Myocardial infarction healing process causes changes in
architecture and tissue properties; the principal cell effectors
are monocytes which remove cell debris from granulation
tissue and promote angiogenesis. In this regard, 19F/1H MRI
can be clinically translatable into an innovative noninvasive
approach to identify target patients. Moreover, this technique
could be used to monitor medical therapies to optimize MI
healing process.
In the future, this new technique may be more useful
than cardiac MRI alone to detect labeled cells in reperfused
MI areas, because the iron oxide nanoparticles recognition
with cardiac MRI can be disturbed by magnetic susceptibility
(T2∗ ) effects on gradient echo magnetic resonance (MR)
images. Therefore, it would be also useful to better detect
IMH in vivo. Future research to evaluate the most appropriate
clinical application of PET/MRI considering diagnostic performance, technical feasibility, practicality, and cost/benefit
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ratio compared to established diagnostic techniques will
therefore be required before PET/MRI routine use.
5. Conclusions
IMH is a frequent finding in reperfused STEMI and it is often
associated with reduced ventricular function and myocardial
damage. In fact, it is a prognostic index of MACEs during
follow-up, so it could be useful for a better risk stratification
of patients with STEMI. IMH can be evaluated only by
CMR, but there is still a debate about the optimal CMR
sequences to detect it. Further research and maybe other
imaging techniques, such as PET/MRI, could be necessary to
resolve this open issue.
Conflict of Interests
The authors declare that there is no conflict of interests
regarding the publication of this paper.
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