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European Journal of Radiology 74 (2010) e12–e17
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European Journal of Radiology
journal homepage: www.elsevier.com/locate/ejrad
Acute oedema in the evaluation of microvascular reperfusion and
myocardial salvage in reperfused myocardial infarction
with cardiac magnetic resonance imaging
Arintaya Phrommintikul a,b,1 , Hassan Abdel-Aty c,d , Jeanette Schulz-Menger c ,
Matthias G. Friedrich c,d , Andrew J. Taylor a,∗
a
Baker Heart Research Institute, Melbourne, Australia
Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
c
Franz-Volhard-Klinik, Helios-Klinikum Berlin, Kardiologie, Charité Campus Berlin-Buch, Humboldt-Universität zu Berlin, Berlin, Germany
d
Department of Cardiac Sciences, Foothills Medical Centre, University of Calgary, 1403-29th Street NW, Calgary, Alberta, Canada
b
a r t i c l e
i n f o
Article history:
Received 29 October 2008
Received in revised form 18 February 2009
Accepted 6 March 2009
Keywords:
Myocardial infarction
Myocardial salvage
Myocardial oedema
Myocardial necrosis
T2 -weight imaging
a b s t r a c t
The accurate measurement of myocardial salvage is critical to the ongoing refinement of reperfusion
strategies in acute myocardial infarction (AMI). Cardiac magnetic resonance imaging (CMR) can define
the area at risk in AMI by the presence of myocardial oedema, identified by high signal intensity on T2 weighted imaging with a short inversion time inversion-recovery (STIR) sequence. In addition, myocardial
necrosis can be identified with CMR delayed contrast enhanced imaging. In this prospective study we
examined the relationship of acute oedema and necrosis with impaired microvascular reperfusion. We
also evaluated acute oedema as a marker of the area at risk in AMI, for the purposes of documenting
myocardial salvage. CMR was performed on 15 patients with (AMI), within 24 h of successful percutaneous coronary intervention (PCI). Left ventricular (LV) systolic dysfunction was defined by a systolic
thickening <40% (severe <20%). Microvascular reperfusion was evaluated during the acute phase of contrast wash-in. CMR was repeated 3 months post-PCI to evaluate recovery of LV function and final infarct
size. Myocardial salvage was defined as the percentage of the area at risk that was not infarcted on follow
up CMR. There was a significant correlation between impaired microvascular reperfusion and the extent
of segmental oedema (R = 0.363, P < 0.01), but not myocardial necrosis (R = 0.110, P > 0.5). The extent of
myocardial salvage correlated with recovery of systolic function (R = 0.241, P < 0.05), which was strongest
in LV segments with severely reduced systolic function (R = 0.422, P < 0.01). Conclusions: In acutely reperfused AMI, oedema can be used to identify the area at risk for the purpose of calculating myocardial
salvage. The correlation between myocardial oedema and reperfusion status suggests a pathological role
of acute oedema in the impairment of microvascular reperfusion.
© 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Myocardial salvage represents the raison d’être of all reperfusion strategies for acute myocardial infarction (AMI) [1,2]. Critical
to the ongoing refinement of reperfusion strategies in AMI is the
accurate measurement of myocardial salvage [3]. Acutely, reperfusion status, at both a macrovascular and microvascular level, has
∗ Corresponding author at: Alfred Hospital and Baker Heart Research Institute,
Heart Centre, Alfred Hospital, Commercial Road, Melbourne 3004, Australia.
Tel.: +61 390763263; fax: +61 390762461.
E-mail addresses: [email protected] (A. Phrommintikul),
[email protected] (H. Abdel-Aty), [email protected]
(J. Schulz-Menger), [email protected] (M.G. Friedrich),
[email protected] (A.J. Taylor).
1
Tel.: +66 53946713; fax: +66 53945486.
0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejrad.2009.03.010
been shown to correlate with survival [4,5] and/or improvement
of cardiac function [6,7]. Whilst acute oedema has been postulated
to impair microvascular reperfusion, differentiating the effects of
acute oedema from acute necrosis has not been possible.
Recently, cardiac magnetic resonance imaging (CMR) utilising
delayed contrast enhancement (DCE) has emerged as an accurate method for documenting the geographic extent of myocardial
infarction, in both its acute and chronic phases [8–11].
However, whilst DCE is believed to correspond to areas of necrosis and scar formation in the acute and chronic phases of myocardial
infarction respectively, a more definitive CMR method for acutely
defining the area at risk in AMI is the presence of myocardial
oedema, identified by high signal intensity on T2 -weighted imaging. Previously, a strong geographic correlation between myocardial
oedema and myocardium at risk has been demonstrated in an
animal model using microspheres [12,13]. Using short inversion
A. Phrommintikul et al. / European Journal of Radiology 74 (2010) e12–e17
time inversion-recovery (STIR) sequences, T2 -weighted imaging
has been shown to reliably identify areas of AMI in human subjects
[14–18]. Recently the utility of STIR imaging in the evaluation of
AMI has been highlighted [3,16,17]. as well as the potential impact
of myocardial oedema on microvascular reperfusion [19,20].
In this prospective study we examined the relationship of acute
oedema and necrosis with impaired microvascular reperfusion. We
also evaluated acute STIR imaging as a marker of the area at risk in
AMI, for the purposes of documenting myocardial salvage.
Table 1
Cardiac MRI protocol.
1.
Analysis of wall motion:
Short axis imaging
Steady state free precession pulse
sequence (TR 3.8 ms, TE 1.6 ms, 30
phases), slice thickness 15 mm.
2.
Analysis of acute oedema:
Short axis imaging
Short inversion time
inversion-recovery (STIR) sequence.
T2-weighted triple inversion-recovery
sequence (repetition time 2 × R-to-R
interval; echo time 65 ms; inversion
time 140 ms), slice thickness of 15 mm
3.
Evaluation of microvascular:
Perfusion:
Short axis image
First-pass perfusion CMR (saturation
recovery, gradient echo/echo
planar-readout sequence, TR/TE
113–134 ms/1.3–1.7 ms, flip angle 25◦ ,
slice thickness 15 mm) following a
bolus of Gadolinium-DTPA
(0.1 mmol/kg body weight).
4.
Delayed contrast enhancement:
Short axis imaging
Inversion-recovery gradient echo
technique (TR 7.1 ms; TE 3.1 ms; TI
individually determined to null the
myocardial signal, range 180–250 ms,
slice thickness 15 mm, matrix
256 × 192, number of acquisitions = 2).
Evaluate 10 min following
Gadolinium-DTPA administration.
2. Methods
2.1. Patient selection
All subjects were enrolled through the Department of Cardiology, Humboldt-University, Charité; Campus Buch, Franz Volhard
Klinik, Berlin Germany. Patients with AMI were considered for
enrolment if they had undergone successful emergency percutaneous coronary intervention (PCI) within the preceding 24 h. This
study is a subanalysis of a previously published study in which
patients were enrolled between January and December 2002 [6].
We have previously reported the impact of microvascular reperfusion status on recovery of left ventricular (LV) systolic function
in this group. Patients enrolled in this prior study who also had
CMR evaluation of myocardial oedema were included in the present
study. The definitions of AMI, as well as the inclusion/exclusion criteria for CMR have been fully described in this prior paper. Informed
consent was obtained before CMR, and the study was carried out
under the guidelines of the Franz Volhard Klinik Ethics Committee.
2.2. Coronary angiography and angioplasty procedure
All patients underwent coronary angiography on a Siemens
angiography suite (Hicor, Siemens, Germany). All patients received
standard post-infarct PCI care, which included combined oral
antiplatelet therapy with aspirin (100 mg/day) and clopidogrel
(75 mg/day following an oral bolus of 300 mg) for a minimum of
1 month after PCI. The administration of intravenous antiplatelet
agents, such as abciximab or tirofiban was at the proceduralist’s discretion. Heparin was administered as an intravenous bolus during
PCI to attain an activated clotting time >300 s. Procedural success
in AMI patients was defined by an open coronary artery with less
than 30% residual stenosis.
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2.3.1. Analysis of wall motion
Cine imaging of the LV was obtained with a steady state free
precession pulse sequence (TR 3.8 ms, TE 1.6 ms, 30 phases, slice
thickness 15 mm) on both acute and 3-month follow-up CMR scanning. Systolic function was assessed on a segmental basis and
percent myocardial thickening was calculated, defined as ratio of
the systolic thickness minus the diastolic thickness divided by the
diastolic thickness. This ratio was then converted to a percentage
by multiplying by a factor of 100. Systolic dysfunction was deemed
to be present if systolic thickening was less than 40%, and severe if
systolic thickening was less than 20%. Recovery of systolic dysfunction was defined as the difference in systolic thickening between
acute and 3-month CMR scans.
2.3.2. Analysis of acute oedema
Acute myocardial oedema was identified by bright signal
intensity on a short inversion time inversion-recovery sequence.
2.3. Cardiac MRI protocol
We performed CMR in 15 AMI subjects within 24 h of successful emergency PCI, and then 3 months following AMI, on a clinical
1.5 T CMR scanner (General Electric CV/i, Milwaukee, USA). All CMR
sequences were performed in three standard short axis slices (apical, mid and basal), kept identical for each sequence throughout
the acute CMR examination as well as on follow up CMR scanning.
From a four-chamber long axis view, five equally spaced slices were
planned, so that the two outer slices lined up exactly either with the
tip of the apex or the mitral annulus. The two outer slices were then
deleted, leaving three slices corresponding to typical basal, mid and
apical short axis views. The slice thickness and separation were
recorded to permit accurate reproducibility of views in subsequent
studies. All analyses were performed on the three standard short
axis slices, utilising a 16-segment LV model. All sequences except
perfusion were acquired during a breath-hold of 10–15 s. As the perfusion sequence ran for 60 heartbeats, patients were instructed to
hold their breath for as long as was comfortable, taking a further
breath when required and then breath-holding again (Table 1).
Table 2
Angiographic and percutaneous coronary intervention data.
Parameter
Findings pre PCI
Infarct related artery
Left anterior descending
Left circumflex
Right coronary
8 (53.3)
5 (33.3)
2 (13.3)
Lesion grade
A or B1
B2 or C
2 (13)
10 (67)
TIMI flow
0
I
II
III
9 (60)
5 (33)
1 (7)
0
Time to reperfusion (h)
Peak creatine kinase level (IU)
Multivessel CAD
8.3 ± 1.1
1903 ± 303
3 (20)
Values are n (%) or mean ± SEM. CAD – coronary artery disease.
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This sequence consisted of a black-blood, T2-weighted triple
inversion-recovery sequence (repetition time 2 × R-to-R interval;
echo time 65 ms; inversion time 140 ms). Three standard short axis
slices (basal, mid-ventricular, and apical) were obtained at a slice
thickness of 15 mm according to the landmarks described above.
The area a risk was defined in each segment with acutely impaired
systolic thickening as the percentage of the segment with signal
intensity greater than two standard deviations above a normal
remote region in the same slice.
2.3.3. Delayed contrast enhancement
We performed DCE at the time of acute scanning, as well as 3
months post AMI. In both cases this was evaluated 10 min following Gadolinium-DTPA administration to identify the infarct region
using an inversion-recovery gradient echo technique (TR 7.1 ms; TE
3.1 ms; TI individually determined to null the myocardial signal,
range 180–250 ms, slice thickness 15 mm, matrix 256 × 192, number of acquisitions = 2). The cut-off for the presence of DCE was
signal intensity greater than two standard deviations above that of
a non-infarcted remote segment in the same slice [6,8]. Final infarct
size in each segment was defined as the percentage area of the segment with signal intensity above our defined cut-off on 3-month
CMR scanning.
2.3.4. Evaluation of microvascular perfusion
Microvascular perfusion was assessed on a segmental basis
at rest by first-pass perfusion CMR (saturation recovery, gradient
echo/echo planar-readout sequence, TR/TE 113–134 ms/1.3–1.7 ms,
flip angle 25◦ , slice thickness 15 mm) following a bolus of
Gadolinium-DTPA (0.1 mmol/kg body weight; Magnevist® , Schering, Germany). Semi-quantitative perfusion analysis was performed
by calculating the time to 50% maximum myocardial enhancement
(T50%max ) during the first pass of contrast in each myocardial segment, utilising a specialized software package (MASS 6.0® , Medis,
Leiden, The Netherlands). The contrast delay in AMI segments was
then calculated by subtracting the T50%max of these segments from
that of a remote myocardial segment. Impairment of microvascular reperfusion was defined by the presence of contrast delay in
the AMI segment relative to the remote segment. The criteria for
the selection of the remote segment were the complete absence
of infarction (as assessed by delayed hyper-enhancement) as well
as uniform wash-in over all three slices in that myocardial segment.
2.3.5. Calculation of myocardial salvage
Myocardial salvage was calculated using the area at risk according to acute STIR in each segment with acutely impaired systolic
dysfunction, defined as the percentage of the area at risk that was
not infarcted on follow up CMR. In some instances, the final area of
infarction was actually greater than the initial “at-risk” area, yielding a negative value for myocardial salvage. The correlation between
myocardial salvage and recovery of LV systolic function was then
evaluated.
2.4. Statistics
All data are expressed as mean ± SE except where otherwise
stated. Comparisons between groups were made using paired or
unpaired Student’s t-tests. The Pearson Product Moment was calculated to assess correlation. Statistical power of the correlation
between myocardial salvage and recovery of LV function was >0.8,
given an alpha value of 0.05 and an estimated correlation coefficient of 0.3 and a sample size of 90 AMI segments. A computerised
statistical program (SPSS for Windows© , Release 14.0 SPSS Inc) was
used for all analyses.
3. Results
Fifteen subjects with AMI (14 males) were enrolled in our study.
The mean age was 54 ± 2 years. The infarct locations were anterior (8), anterolateral (1), lateral (3), inferior (2) and inferolateral
(1). Infarct PCI was performed in all cases, with procedural success
being achieved in all. The TIMI 3 and 2 flows were achieved in 14 and
1 patients, respectively (Table 2). A total of 89 segments within the
corresponding AMI location with impaired systolic function were
identified. Of these, 41 had severe impairment of systolic function.
Acute CMR scanning was carried out in all patients without complication. After 3 months post AMI all patients returned for repeat
CMR scanning.
3.1. Acute CMR scanning for oedema and necrosis
Of 89 segments, 84 segments were evaluable by STIR and 87
segments were evaluable by DCE. The mean extent of myocardial oedema was 12.55 ± 0.85% of the left ventricular short axis
slice. The mean extent of myocardial oedema in AMI segments was
59.4 ± 3.4% of the segment area. The mean extent of acute DCE was
11.27 ± 1.00% of the left ventricular short axis slice and 56.9 ± 4.3% of
Fig. 1. Mid-ventricular short-axis MR images detected acute myocardial edema using a short inversion time inversion-recovery sequence (black-blood, T2-weighted triple
inversion-recovery sequence (repetition time 2 × R-to-R interval; echo time 65 ms; inversion time 140 ms, slice thickness 15 mm, spacing 8 mm) and acute myocardial necrosis
using acute DCE following Gadolinium-DTPA administration using an inversion-recovery gradient echo technique (TR 7.1 ms; TE 3.1 ms; TI individually determined to null
the myocardial signal, range 180–250 ms, slice thickness 15 mm, matrix 256 × 192, number of acquisitions = 2. The images demonstrate the discordance between acute STIR
and acute DCE, with myocardium at risk in the anteroseptal region (arrows) defined by acute myocardial edema using acute STIR but negative for acute DCE.
A. Phrommintikul et al. / European Journal of Radiology 74 (2010) e12–e17
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Fig. 2. There was a significant correlation between microvascular perfusion delay and extent of myocardial oedema.
the segmental area for each AMI segment. There were 10 segments
with an area at risk defined by STIR without evidence of necrosis
defined by DCE (Fig. 1).
3.2. Relationship of acute oedema to microvascular reperfusion
Of a total of 89 AMI segments with acute systolic dysfunction,
55 (62%) had impaired microvascular reperfusion. The extent of
myocardial oedema documented by acute STIR correlated with
the degree of impairment of microvascular reperfusion (R = 0.363,
P < 0.01, Fig. 2). Considering the degree of impaired myocardial
reperfusion in quartiles, there was a significant difference in the
extent of myocardial oedema amongst groups (P < 0.001). There was
no correlation between the extent of acute DCE and the degree of
impairment of microvascular reperfusion (R = 0.135, P = NS).
3.3. Follow up CMR scanning
Three months post AMI, acute changes seen on STIR imaging had
resolved in all cases. There was a significant reduction in the mean
segmental extent of DCE on follow up CMR scanning compared
with acute scanning (40.5 ± 4.1% on chronic scanning vs. 56.9 ± 4.3%
on acute scanning, P < 0.001). Of 89 infarct segments with acutely
impaired systolic function, 76 (85%) demonstrated improved function, with 57 (64%) returning to normal. The mean improvement in
LV systolic function at a segmental level was 30.7 ± 3.8%. There was
a significant negative correlation on 3-month scanning between
the final infarct size by DCE and systolic contraction (R = −0.39,
P < 0.001).
3.4. Myocardial salvage and its relationship to recovery of LV
function
There was a significant correlation between the extent of
myocardial salvage and recovery of systolic function when acute
oedema was used to define the area at risk (R = 0.241, P < 0.05,
Fig. 3A). This correlation was strongest in LV segments with severely
reduced systolic function (R = 0.422, P < 0.01, (Fig. 3B)
4. Discussion
Our data provide further evidence for the utility of acute
myocardial oedema, defined by high signal intensity on T2 weighted imaging, in identifying the area of myocardium at risk in
acutely reperfused myocardial infarction. Furthermore, the extent
of myocardial oedema correlated with impairment of microvascular
reperfusion, suggesting a pathological role of myocardial oedema
in the impairment of reperfusion.
Interestingly, there was no such correlation between the extent
of acute necrosis and impairment of microvascular reperfusion,
implying that impaired microvascular reperfusion is at least in part
a dynamic process not simply related to necrosis, which may therefore be reversible. When acute oedema was utilised to delineate the
area at risk for the calculation of myocardial salvage, a significant
correlation between myocardial salvage and recovery of systolic
function was obtained, that was more pronounced when the analysis was limited to myocardial segments with initially severely
reduced systolic function.
Previously, both STIR and DCE imaging have been utilised as part
of CMR scanning at the time of acute infarction [17,21,22]. Temporal changes in DCE have been demonstrated post-infarction, with
the area of DCE being largest early in the course of myocardial
infarction, with subsequent reduction in size over ensuing months
[21,22]. However whilst DCE in the chronic phase of infarction
closely approximates myocardial scar [8], DCE in the acute phase
of infarction is thought to identify areas of myocardial necrosis and
not the area at risk [8,10]. In contrast, a number of studies have confirmed the reliability of STIR imaging to identify AMI in the acute
setting [14–17], with an animal model of infarction documenting a
close correlation between the area of acute oedema and the area at
risk defined by microspheres [12].
The evaluation of myocardial salvage post AMI is a powerful tool
for assessing reperfusion strategies. As it is defined as the proportion of the initial area at risk that is salvaged, it represents a method
of standardising groups that may not be equal in infarct size on
presentation. To date, the most utilised method for the calculation
of myocardial salvage post AMI has been single photon emission
computed tomography (SPECT) [3]. Whilst of proven utility in a
number of larger trials, SPECT imaging requires multiple injections
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Fig. 3. There was a significant correlation between myocardial salvage using acute STIR to define myocardium at risk and recovery of myocardial systolic function (A), which
was strongest in segments with acutely severe systolic dysfunction (B).
of radioactive contrast, and provides little extra data apart from
that of viability. The application of CMR imaging in the assessment
of myocardial salvage is attractive, as besides accurately identifying the area at risk with STIR imaging, functional imaging as well
as final infarct size can be determined with a high degree of spatial
accuracy. Recently Friedrich et al. have demonstrated the utility of
STIR imaging in quantifying the extent of both reversible and irreversible myocardial injury. The extent of myocardial injury defined
by STIR imaging was greater than that of irreversible myocardial
injury defined by DCE [23]. In addition, more specialised sequences
such as first-pass perfusion imaging can be easily performed to
investigate the interplay between factors such as acute oedema and
microvascular reperfusion. In our study, we identified a significant
correlation between the extent of myocardial oedema and impairment of microvascular reperfusion. Previously, myocardial oedema
has been muted as a potential factor inhibiting microvascular reperfusion [19,20], setting up a “vicious cycle” wherein acute infarction
precipitates oedema, which may then further exacerbate ischaemia.
The small number of patients enrolled in this study did not
provide sufficient numbers to evaluate the relationship of myocardial salvage to clinical endpoints. Prior studies utilising SPECT
imaging have related final infarct size to improved survival [24].
Similarly, the peri-infarct zone identified with CMR has recently
been shown to be a powerful predictor of post-MI mortality [25].
However to date the effect of myocardial salvage assessed by either
imaging modality on mortality has not been documented. Another
A. Phrommintikul et al. / European Journal of Radiology 74 (2010) e12–e17
limitation of our data is that repeat coronary angiography was not
performed at the time of follow-up CMR scanning; therefore we
are unable to confirm the presence of a persisting open artery. In
a number of cases, the final infarct size actually extended beyond
the initial at-risk area, possibly due to subsequent closure of the
IRA, which may have limited the strength of correlation between
myocardial salvage and recovery of LV function. Whilst the final
infarct size in our study strongly related to recovery of LV systolic
function, the identification of the area at risk also has important
potential applications. At a clinical level the area of myocardium
at risk may be important when considering therapeutic strategies
on an individual risk/benefit level, whilst at a research level the
interplay between the area at risk, factors such as reperfusion
status and clinical outcome can be examined.
The accurate identification of the area at risk in AMI is crucial to
the evaluation of future reperfusion therapies and their impact on
myocardial salvage. Our data provide further support for the use of
acute oedema, defined by high signal intensity on T2 -weighted CMR
imaging, in the identification of the at-risk area in AMI as well as a
potential role for acute oedema in the impairment of microvascular
reperfusion.
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
5. Conclusions
[14]
In acutely reperfused AMI, oedema may be used to identify
the area at risk for the purpose of calculating myocardial salvage.
The correlation between myocardial oedema and reperfusion status suggests a pathological role of acute oedema in the impairment
of microvascular reperfusion.
Conflict of interest
[15]
[16]
[17]
There is no conflict of interest.
[18]
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