Diffusion-Weighted Magnetic Resonance Imaging and
Neurobiochemical Markers After Aortic Valve Replacement
Implications for Future Neuroprotective Trials?
Erwin Stolz, MD; Tibo Gerriets, MD; Alexander Kluge, MD; Wolf-Peter Klövekorn, MD;
Manfred Kaps, MD; Georg Bachmann, MD
Downloaded from http://stroke.ahajournals.org/ by guest on September 29, 2016
Background and Purpose—Cardiac surgery carries a high risk of neurological complications; therefore, these patients
would be an appropriate target population for neuroprotective strategies. In this study, we evaluated postoperative
diffusion-weighted imaging (DWI) as a potential surrogate marker for brain embolism and its relationship to
neurobiochemical markers of brain injury.
Methods—Of a total of 45 consecutive patients undergoing aortic valve replacement, 37 completed preoperative and
postoperative MRI. At the time of the MRI studies, serum S100␤ and neuron-specific enolase concentrations were
determined. Preexisting T2 and postoperative DWI lesion volumes were quantified. All patients had a blinded
neurological examination before and after operation.
Results—New perioperative DWI lesions were present in 14 patients (38%), of whom only 3 developed focal neurological
deficits. Eighteen small lesions were found in the white matter or vascular border zones in all but 2 patients with
territorial stroke. The appearance of new DWI lesions correlated with age, pre-existing T2 lesion volume, and
postoperative S100␤ concentrations on days 2 to 4 after surgery. In a forward stepwise canonical discrimination model,
only T2 lesion volume was selected as a relevant variable.
Conclusions—The incidence of postoperative DWI lesions in aortic valve replacement is high, and a suitable marker for
neuroprotective trials would be a reduction in the number of such lesions. The volume of preexisting T2 lesions is related
to the development of perioperative DWI lesions. (Stroke. 2004;35:888-892.)
Key Words: embolism 䡲 magnetic resonance imaging 䡲 neuron-specific enolase 䡲 stroke 䡲 S100 proteins
chemical markers of neuronal injury such as S100␤ or
neuron-specific enolase (NSE) has been found to be associated with postoperative cognitive deficits after both heart
surgery10,11 and embolic stroke.12,13 The measurement of
these markers is fairly easy, but their relationships to symptomatic embolic stroke and subclinical embolism are not yet
clear. Diffusion-weighted MRI (DWI) is an emerging surrogate marker for clinical and subclinical brain embolism.
In this study, we analyzed clinical and subclinical brain
embolism by DWI and the release of neuronal destruction
markers in serum in a cohort of patients undergoing aortic
valve replacement (AVR).
P
erioperative stroke is a devastating complication of heart
surgery. The reported frequencies range between 1% and
4% in patients undergoing coronary artery bypass grafting
(CABG), with the risk nearly doubled in older age.1–5 Similar
rates were found for patients receiving heart valve replacement.6,7 Cognitive deficits after heart surgery have been
observed in 33% to 83% of patients during the first weeks
after surgery.8 Both stroke and cognitive disturbance are
thought to be related to macroembolism and microembolism
during surgery.9
Patients undergoing heart surgery could be a suitable target
population for neuroprotective trials including preemptive
neuropharmacological approaches. However, to examine
large patient cohorts, easy-to-use and reliable surrogate markers for brain embolism are needed. Neuropsychological tests
are time consuming, show a considerable variability in results
depending on the number and type of test systems used, and
are confounded by several variables such as the frequent
development of postoperative delirium.8 The release of bio-
Patients and Methods
Patients
Between January 2001 and July 2002, 45 consecutive patients
underwent elective AVR and were enrolled prospectively in this
study after giving written informed consent. Patients with combined
procedures, history of previous stroke, and carotid artery stenosis of
Received November 28, 2003; final revision received December 10, 2003; accepted December 16, 2003.
From the Department of Neurology, Justus Liebig University, Giessen (E.S., T.G., M.K.), and Departments of Radiology (E.S., T.G., A.K., G.B.) and
Cardiac Surgery (W.-P.K.), Kerckhoff Klinik and Kerckhoff Research Foundation, Bad Nauheim, Germany.
Correspondence to Georg Bachmann, MD, Department of Radiology, Kerckhoff Klinik, Benekestrasse 2-8, 61231 Bad Nauheim, Germany. E-mail
georg.bachmann@kerckhoff.med.uni-giessen.de
© 2004 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000120306.82787.5A
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Stolz et al
Diffusion-Weighted MRI After Aortic Valve Replacement
889
Demographic, Clinical, and Imaging Data of the Patient Cohort
Variable
Total Cohort
(n⫽37)
Post-OP DWI Neg
(n⫽23)
Post-OP DWI Pos
(n⫽14)
P
NS
Women, n (%)
15 (41)
8 (35)
7 (50)
Men, n (%)
22 (59)
15 (65)
7 (50)
Age, y
66⫾10
64⫾10
71⫾9
22 (59%)
14 (61%)
8 (57%)
NS
5 (14%)
3 (13%)
2 (14%)
NS
22 (59%)
13 (57%)
9 (64%)
NS
⬍0.05
Risk factors
Hypertension
Diabetes
Hyperlipidemia
Smoking
5 (14%)
5 (22%)
0
Pre-OP T2 lesion volume
5.8⫾10.3
2.2⫾2.6
11.3⫾14.7
(median, range), cm3
(1.6, 0.1–49.7)
(1.3, 0.1–8.9)
(4.9, 0.5–49.7)
NS
⬍0.01
Operative values
Operation time, min
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175⫾61
167⫾62
187⫾54
NS
Extracorporeal circulation time, min
92⫾38
90⫾35
97⫾39
NS
Aortic cross-clamp time, min
68⫾28
67⫾27
70⫾29
NS
Deepest intra-OP temperature, °C
30⫾3
29⫾4
30⫾2
NS
14.0⫾1.2
14.1⫾1.1
13.9⫾1.2
NS
7.6⫾1.3
7.7⫾1.0
7.5⫾1.8
NS
Post-OP Hb, g/L
10.7⫾1.2
11.0⫾1.2
10.4⫾1.0
NS
Post-OP S100␤ days 2 to 4, ␮g/L
0.25⫾0.2
0.15⫾0.1
0.39⫾0.2
⬍0.05
Post-OP NSE days 2 to 4, ␮g/L
14.4⫾8.7
10.2⫾3.9
12.6⫾6.2
NS
Pre-OP Hb, g/L
Lowest intra-OP Hb, g/L
OP indicates operation; Neg, negative; and Pos, positive.
*Comparing the groups with and without new DWI lesions.
ⱖ70% on duplex ultrasound examination were excluded. The Table
summarizes the basic characteristics of the patient cohort.
All patients were operated on with standardized anesthetic and
surgical procedures. Twenty-four patients received an artificial valve
(Carbomedics, Medtronic, or St Jude Medical), and 12 received
biological valves (Baxter Perimount Bio, Mitroflow Bio, or Lapcor
Bio). A 20-␮m filter was used in the heart-lung machine reservoir,
and an air bubble trap was used in the venous circulation. Twentyeight patients received Bretschneider and 20 received Bruckberg
cardioplegia. Variables related to the operation are summarized in
the Table.
imaging sequence (TR, 4657; TE, 118 ms; matrix, 128⫻128;
gradients of b values; 0, 500, 1000 s/mm2). The apparent diffusion
coefficients were calculated for each pixel and composed on an
apparent diffusion coefficient map.
MRI scans were evaluated by 2 blinded independent observers, a
neuroradiologist and a neurologist as the second observer. The
preoperative lesion load was determined by planimetration of the
area of the T2-hyperintense lesions and multiplying the measured
area by slice by the respective slice distance (T2LV). There was no
interslice gap. Likewise, postoperative new lesions were quantified
on the DWI images with maximum contrast between lesion and
normal brain regions. For image analysis, the software of the MRI
unit was used.
Clinical Evaluation
Biochemical Markers
Anesthesia and Surgery
A comprehensive clinical examination, including a detailed neurological examination, was performed by a neurologist before and on
day 2 or 3 after operation in a blinded fashion.
MRI Scans
All MRI scans were acquired on a 1.5-T unit using a head coil
(Vision, Siemens). Baseline MRI studies of the brain were obtained
1 to 2 days before surgery. Follow-up MRI was scheduled for the
first or second postoperative day. This was achieved in only 18
patients (49%); 16 patients (43%) received the postoperative MRI on
day 3 or 4 and 3 patients (8%) had MRI on day 5 or 6 because of
hemodynamic compromise or external cardiac pacing. Three patients
of the original cohort did not complete the preoperative, and 5
patients did not have the postoperative MRI and were excluded.
The preoperative and postoperative imaging protocol included (1)
a proton- and T2-weighted turbo spin-echo sequence (repetition time
[TR], 4657 ms; echo time [TE], 15/135 ms; turbo factor, 8; slices, 20;
acquisition, 1; acquisition time, 2.01 minutes), (2) a T1-weighted
turbo spin-echo sequence (TR, 600 ms; TE, 20 ms; slices, 20;
acquisitions, 2), and (3) and a diffusion-weighted spin-echo-planar
Preoperative and postoperative S100␤ and NSE were determined
from venous blood collected on the day of the respective MRI study.
Samples were immediately centrifuged for 20 minutes at 5000 min⫺1
and stored at ⫺20°C for later analysis.
S100␤ concentrations were determined with a monoclonal 2-sided
immunoradiometric assay (Byk Sangtec 100 IRMA). NSE was
measured with an enzyme immunoassay based on the sandwich
technique with the solid-phase monoclonal antibody raised against
the ␥-subunit of NSE (Cobas Core II, Roche Diagnostics).
Statistical Analysis
Frequencies were compared with a ␹2 or, when appropriate, Fisher’s
exact test. The agreement of observers on the T2LV and postoperative DWI lesion volumes was analyzed by use of the Bland-Altman
method14 resulting in 2-SD confidence intervals (2SD-CI). With an
intraclass correlation coefficient, the agreement on the presence of
DWI lesions was tested. Nonparametric data were compared with a
Mann-Whitney U test. An association between the presence of DWI
lesions and continuous variables was examined by use of Spearman’s
rank correlation. For correlation of continuous variables, a linear
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April 2004
Figure 1. Perioperative DWI lesions. Top row, Territorial DWI
lesions; remaining scans, typical small perioperative DWI
lesions.
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regression analysis was used. We used a stepwise canonical discrimination function based on the unexplained variance to separate
patients with or without new DWI lesions by entering the variables
significantly related to new DWI lesions on univariate or bivariate
analysis into the model. A value of P⬍0.05 was considered
significant.
Results
MRI Scans
Twenty-six patients (70%) already showed pre-existing T2
lesions (the Table). Interobserver agreement on the T2LV
was acceptable with a 2SD-CI of ⫾4.3 cm3. Preexisting
lesions were found mostly in the white matter of the hemispheres predominantly in the frontal lobe representing microcirculation damage, ie, leukoaraiosis and lacunar infarcts, and
were significantly associated with older age (P⬍0.05). Statistical power was not sufficient to show an association with
cardiovascular risk factors. No DWI lesions were found
preoperatively.
Postoperative DWI lesions were present in 14 patients (38%)
(the Table). Two patients developed territorial infarcts in the
left cerebellar hemisphere and left posterior lobe, respectively
(Figure 1); the remaining 12 patients had 18 total small
globular lesions in the white matter or cortical border zones
with diameters of 5 to 12 mm (Figure 1). Only 3 patients
displayed a single lesion. Ten DWI lesions were located in
the vertebrobasilar and 8 in the anterior circulation. The
agreement of 2 blinded observers on the presence of new
DWI lesions was perfect (intraclass correlation coefficient,
␬⫽1.0). DWI lesion volume ranged from 0.1 to 24.8 cm3
(median, 0.5 cm3; mean, 3.8⫾8.4 cm3) with a 2SD-CI of
⫾0.92 cm3.
The appearance of DWI lesions correlated with the preoperative T2LV (r⫽0.33, P⬍0.05) and age (r⫽0.36, P⬍0.05).
No correlation was found for DWI lesions and the operative
variables, as well as the lowest intraoperative hemoglobin
(Hb) concentration.
We found no significant correlation between the frequency
of DWI lesions and the latency between surgery and MRI
examination.
Neurological Evaluation
Postoperatively, only 3 patients had focal neurological deficits. New large territorial lesions were found in 2 patients, and
Figure 2. Preoperative and postoperative S100␤ and NSE concentrations in serum.
a small white matter lesion was seen in 1 patient. Neurological examination revealed no clinically apparent deficits in
the remaining 11 patients with postoperative DWI lesions.
Biochemical Markers
Both S100␤ and NSE increased significantly after AVR
(Figure 2) but independently from operative variables. However, concentrations significantly decreased with the interval
from AVR to measurement (r⫽0.57, P⬍0.01). We used the
difference in the postoperative and lowest intraoperative Hb
concentrations as a crude measure of the intraoperative
volume loss or transfusion volume, respectively. With increasing transfusion volume, S100␤ concentrations showed a
clear trend to decrease (r⫽⫺0.29, P⫽0.08), and NSE showed
a weak trend to increase (r⫽0.27, P⫽0.11) (Figure 3).
Relationship Between Biochemical Markers and
Imaging Results
The highest correlation between postoperative S100␤ concentrations (r⫽0.54, P⬍0.01) and the preoperative to postoperative difference (⌬S100␤; r⫽0.45, P⬍0.01) and the
presence and volume (post-OP S100␤, r⫽0.64, P⬍0.01;
⌬S100␤, r⫽0.59, P⬍0.01) of new DWI lesions was found
for the measurements on days 2 to 4. Measurements on the
first or after the fourth postoperative day did not correlate
Stolz et al
Diffusion-Weighted MRI After Aortic Valve Replacement
891
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Figure 3. Relationship between postoperative S100␤ and NSE
concentrations and the difference in Hb concentration of the
postoperative and lowest intraoperative values.
with the presence of new DWI lesions. Neither postoperative
NSE concentrations nor ⌬NSE showed any association with
new DWI lesions. Canonical discrimination function (canonical correlation, 0.40; eigenwert, 0.2; Wilk’s ␭, 0.84; P⬍0.05)
included only the T2LV (Fisher’s discrimination coefficient,
0.15) as the relevant variable. This model correctly identified
65% of cases.
Discussion
The high incidence of neurological problems would make
cardiac surgery a suitable field for neuroprotective strategies.
Clinical risk factors for perioperative stroke in CABG procedures were found to be atherosclerotic disease of the aorta and
the carotid arteries, including their surrogate markers advanced age, peripheral vasculopathy, and atherosclerotic risk
factors, together with recent myocardial infarction and postoperative atrial fibrillation, supporting the hypothesis of an
embolic origin.15 Further support for an embolic nature of
brain injury is provided by postmortem studies,9,16 with
numerous emboli logged in the microcirculation.
However, neuroprotective trials need robust and objective
markers for brain injury. Problems associated with neuropsychological testing were outlined in the introduction. S100␤
and NSE concentrations have been found to correlate closely
with the volume of territorial ischemic stroke.12,17 However,
timing of measurements is crucial. Best correlations with
infarct volume were found for the 2-to-4-day interval after
stroke.12,17 In this time interval, we found an association
between S100␤ concentrations and the presence and volume
of postoperative DWI lesion. However, on the level of single
measurements (Figure 4), we doubt the clinical usefulness of
this parameter for identifying patients with perioperative
embolic brain lesions because the lesion volume in these
patients is generally small and the power of S100␤ to separate
groups with or without postoperative DWI lesions is weak.
Corresponding to clinical observations of others,18 our results
showed no relationship between NSE concentrations and
perioperative DWI lesions. The measurement of neurobiochemical markers is influenced by several confounding factors such as hemodilution or hemolysis, as demonstrated in
Figure 4. A 3-dimensional trajectory plot of DWI lesion volume
and postoperative S100␤ concentration measurements on days
2 to 4. In the time latency of days 2 to 4 between operation and
MRI, which was the only time period with correlation of DWI
lesion volume and S100␤ concentrations, the only data point
clearly above values obtained from patients without DWI lesions
corresponds to a patient with a large territorial stroke.
this study and by others,18 release from ganglionic cells in the
operation field or other extracerebral sources, suction autotransfusion, or renal failure.19 –21 In the case of NSE, Johnsson
and coworkers18 observed a close association between hemolysis during extracorporeal perfusion and NSE because NSE
is not strictly neuron specific but can be set free from
hemolized erythrocytes. During operation, erythrocyte concentrates that show a certain amount of hemolysis usually are
given. This may explain our observed trend of increasing
NSE levels with increasing intraoperative to postoperative Hb
difference. However, this sheds considerable doubt on the
usefulness of these markers for neuroprotective trials.
Several studies used postoperative MRI to identify embolic
brain lesions.22 Most of them applied conventional spin-echo
sequences, flair techniques, or contrast-enhanced studies that
proved not to be appropriate for detecting acute postoperative
lesions.
DWI is a new development with a high sensitivity for acute
ischemic brain lesions combined with a high spatial resolution. The advantage of choosing an AVR cohort is that the
operative procedure is fairly standardized. We found new
perioperative DWI lesions in 38% of the patients, 3 of whom
had focal neurological deficits. This rate complies with the
few studies using postoperative DWI after CABG.23–26 Most
of these lesions were small and located in the border zones of
brain circulation or within regions affected by leukoaraiosis.
Except for the 2 patients with territorial stroke, the DWI
lesion volume was small, so reducing the number of DWI
lesions would be a suitable surrogate marker for neuroprotective trials.
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April 2004
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Despite the low frequency of neurologically symptomatic
patients, asymptomatic DWI lesions are likely to originate
from the same sources as macroemboli, so DWI lesions might
represent mostly the lower end of brain embolism in terms of
size. This may be of importance, for example, for evaluating
new surgical techniques. We cannot comment on a relationship between small DWI lesions and cognitive deficits; this
topic requires further study.
In agreement with others,23 we found an association
between new DWI lesions and the preexisting T2LV caused
by microcirculation damage. So far, the only studies evaluating postoperative brain perfusion25,26 by MRI were not able
to show any focal perfusion lesions, so, considering the
location of most of the asymptomatic DWI lesions, a decreased microemboli washout as proposed by Caplan and
Hennerici27 caused by preexisting microcirculation damage
may play a role. The implication is that, in neuroprotective
trials, the reduction of the rate of embolism should be
stratified for the preexisting microcirculation damage. For
quantifying both new embolic lesions and preexisting brain
damage, MRI is the most useful technique.
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Diffusion-Weighted Magnetic Resonance Imaging and Neurobiochemical Markers After
Aortic Valve Replacement: Implications for Future Neuroprotective Trials?
Erwin Stolz, Tibo Gerriets, Alexander Kluge, Wolf-Peter Klövekorn, Manfred Kaps and Georg
Bachmann
Downloaded from http://stroke.ahajournals.org/ by guest on September 29, 2016
Stroke. 2004;35:888-892; originally published online February 19, 2004;
doi: 10.1161/01.STR.0000120306.82787.5A
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