Download Myocardial Perfusion Reserve Assessed by T2

Myocardial Perfusion Reserve Assessed by T2-Prepared
Steady-State Free Precession Blood Oxygen Level–Dependent
Magnetic Resonance Imaging in Comparison to
Fractional Flow Reserve
Thomas Walcher, MD; Robert Manzke, PhD; Vinzenz Hombach, MD; Wolfgang Rottbauer, MD;
Jochen Wöhrle, MD, FESC; Peter Bernhardt, MD, FACC
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Background—Blood oxygen level–dependent (BOLD) cardiac magnetic resonance imaging (CMR) has been shown to
be able to detect myocardial perfusion differences. However, validation of BOLD CMR against fractional flow reserve
(FFR) is lacking. The aim of our study was to analyze the potential diagnostic accuracy of BOLD CMR in comparison to
invasively measured FFR, which served as gold standard for a hemodynamic significant coronary lesion.
Methods and Results—BOLD image was performed at rest and during adenosine infusion in a 1.5-T CMR scanner. Thirtysix patients were analyzed for relative BOLD signal intensity increase according to the 16-segment model. Invasive FFR
measurements were performed in the 3 major coronary arteries during adenosine infusion in all patients. An FFR≤0.8
was regarded to indicate a significant coronary lesion. Relative BOLD signal intensity increase was significantly lower in
myocardial segments supplied by coronary arteries with an FFR≤0.8 compared with segments with an FFR>0.8 (1.1±0.2
versus 1.5±0.2; P<0.0001). Sensitivity and specificity yielded 88.2% and 89.5%, respectively.
Conclusions—CMR BOLD imaging reliably detects hemodynamic significant coronary artery disease and is, thus, an
alternative to contrast–enhanced perfusion studies. (Circ Cardiovasc Imaging. 2012;5:580-586.)
Key Words: blood oxygen level dependence ◼ cardiac magnetic resonance imaging ◼ coronary artery disease
◼ fractional flow reserve
A
blood flow.9 Furthermore, T2* BOLD CMR sequences can be
used to image changes of myocardial oxygenation induced
by dipyridamole as an indicator of myocardial ischemia.10
Recently, it has been shown that semiquantitative assessment
of relative BOLD signal increase using a T2-prepared SSFP
sequence highly correlates with the standard approach of
contrast–enhanced perfusion CMR imaging.11 Myocardial
perfusion assessed by the change in myocardial oxygenation
with BOLD CMR has been correlated to quantitative coronary
angiography.7,8 Fractional flow reserve (FFR) has been
proposed for the physiological assessment of CAD to better
characterize the clinical significance of coronary stenosis.12 It
has been showed that FFR guided intervention significantly
reduced mortality and myocardial infarction and is, thus,
prognostically important.13 We compared a T2–prepared
BOLD CMR sequence to FFR in patients with suspected CAD.
ssessment of myocardial ischemia in patients with suspected
coronary artery disease (CAD) is essential to guide further
therapeutic strategy. Contrast–enhanced first-pass perfusion cardiac magnetic resonance imaging (CMR) during vasodilatation
visualizes perfusion defects.1–5 However, high temporal and spatial resolution is required. Image artifacts as dark rim artifact can
mistakenly be interpreted as perfusion defects.6 Furthermore, the
use of exogenous contrast agents is required, which is especially
an important issue in patients with severe renal failure.
Clinical Perspective on p 586
Blood oxygen level–dependent (BOLD) CMR is based
on the fact that oxyhemoglobin is slightly diamagnetic and
deoxyhemoglobin paramagnetic resulting in the loss of T2*
and T2, depending on tissue microvasculature and resulting
blood volume. BOLD CMR, thus, uses an endogenous contrast
without additional use of an exogenous contrast. Using a
T2-prepared steady-state free precession (SSFP) BOLD
CMR sequence, detection of myocardial ischemia in patients
with CAD is possible.7,8 T2-prepared SSFP CMR has been
shown to be related to blood oxygen saturation and coronary
Methods
Forty-two consecutive patients with stable angina pectoris and suspected CAD were prospectively included. All patients were referred
for coronary angiography and had a previous positive or inconclusive
stress test by the referring physician. Exclusion criteria were clinical
Received November 30, 2011; accepted June 18, 2012.
From the Department of Internal Medicine II, University of Ulm, Ulm, Germany (T.W., V.H., W.R., J.W., P.B.); and University of Applied Sciences,
Kiel, Germany (R.M.).
Correspondence to Peter Bernhardt, MD, Department of Internal Medicine II, University of Ulm, Albert-Einstein-Allee 23 89081 Ulm, Germany.
E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
580
DOI: 10.1161/CIRCIMAGING.111.971507
Walcher et al BOLD MRI Compared With FFR 581
instability, known previous myocardial infarction, and contraindications for magnetic resonance imaging or adenosine infusion. For at
least 24 hours before each CMR examination, methylxanthines were
not allowed. All patients underwent coronary angiography within 1
week after CMR imaging. Morise risk score for CAD14 was calculated
for each patient. The study was approved by the local ethics committee. All the participants gave written informed consent.
CMR Imaging Protocol
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Patients were examined in a 1.5-T whole-body scanner (Intera,
Philips Medical Systems, Best, The Netherlands) using a 32-channel phased-array receiver coil (Philips Medical Systems). Heart
rate, blood pressure, and oxygen saturation were noninvasively
monitored.
Functional imaging of the left ventricle was acquired using a
SSFP sequence (repetition time, 3.4 ms; echo time, 1.7 ms; voxel
size, 1.9×1.9 mm; flip angle α=55°; slice thickness, 8 mm; and no
interslice gap) in contiguous short axis covering the entire left ventricle. The acquisition was performed in end-expiratory breath-hold
with 40 phases per cardiac cycle. Slice thickness was 8 mm without
interslice gap.
For BOLD imaging a T2-prepared SSFP (repetition time, 2.6 ms;
echo time, 1.3 ms; flip angle α=90°; voxel size, 1.7×1.7 mm; slice
thickness, 8 mm; gap individually adjusted, T2 preparation time 40
ms with 4 refocusing pulses; and number of averages, 3) was acquired
in 3 short axes (apical, midventricular, and basal), as previously reported.11 Typical breath-hold time was 6.8 second for a heart rate of
80 bpm. To ensure reproducibility of the 3 slices, 5 short axis from
the mitral valve to the apex were planned and interslice gap was, thus,
individually adjusted; the most apical and most basal slice were than
deleted before image acquisition. After 3 minutes of adenosine infusion at a dosage of 140 µg/kg per minute, the BOLD sensitive sequence was repeated in the same orientation.
CMR Image Analysis
CMR images were analyzed in random order blinded to patients’ data
and angiographic results. Functional images were analyzed for enddiastolic and end-systolic left ventricular volumes and ejection fractions were calculated.
Image analysis of the BOLD sensitive images was performed using customized software developed by Matlab (TheMathoWorks,
Inc, Natick, MA). Epicardial and endocardial borders were drawn
manually in all short axes. The 3 acquired short axes were divided
into segments according to the 16-segment model,15 and mean voxel
intensities were calculated automatically for each myocardial segment.13 Mean signal intensity increase was calculated for each myocardial segment by subtraction of the signal intensity at rest from the
signal intensity during vasodilatation, divided by the signal intensity
at rest and multiplied by 100. Myocardial segments were assigned
to the supplying coronary artery, as previously described.16 Figure 1
provides an example of BOLD imaging, color-encoded BOLD signal
intensity increase and corresponding coronary angiogram. For further
analysis of each coronary perfusion territory, the mean value of the 2
lowest scoring segments was used for further analysis.
Cardiac Catheterization
Cardiac catheterization was performed by the femoral approach using
5 or 6 F catheters within 7 days after CMR. FFR was measured with
a coronary pressure guidewire (Radi Medical Systems) at a maximal hyperemia induced by intravenous adenosine. Infusion rate of
adenosine at 140 µg/kg per minute was the same as during previous
CMR examination. FFR was measured in the left anterior descending
(LAD), circumflex artery (CX), and right coronary artery (RCA) after
3 minutes of intravenous adenosine infusion. FFR was calculated as
the mean distal coronary pressure measured with the pressure wire,
divided by the mean aortic pressure measured simultaneously with
the guiding catheter during maximal hyperemia.16,17 An FFR value
of ≤0.8 during adenosine infusion has been described to identify
coronary stenoses causing ischemia with high accuracy.18–20 Based on
these findings, we defined a cutoff FFR value as 0.8 in our study. FFR
measurements served as reference standard for BOLD analysis.
Statistical Analysis
Data are reported as mean±SD. For categorical variables, the Fisher exact test was used to test differences between the FFR≤0.8 and FFR>0.8
groups. For continuous variables, we used a 2 tailed t test. P values in
Figure 2 were calculated using t test. A P value <0.05 was considered
statistically significant. The diagnostic performance of BOLD CMR was
analyzed using receiver-operating characteristics (ROC) curve analyses.
BOLD values were tested for normal distribution using the D’AgostinoPearson test. Interobserver and intraobserver correlation was performed
in 10 patients using intraclass correlation coefficients. Correlation analysis was done using Pearson correlation. Logistic regression was performed to calculate χ2 values using the overall model fit.
Figure 1. Blood oxygen level–dependent
(BOLD) image examples in a midventricular short axis at rest (A) and during adenosine infusion (B) and color-encoded
16-segments BOLD signal intensity
increase (C) in a patient with left anterior
descending (LAD) stenosis (arrow) as
seen on coronary angiogram (D).
582 Circ Cardiovasc Imaging September 2012
Figure 2. Box and whisker graphs
of the average blood oxygen
level–dependent (BOLD) signal
intensity increase (ΔSI) including
SD for left anterior descending
(LAD), circumflex artery (CX), and
right coronary artery (RCA). BOLD
ΔSI was significantly reduced in all
coronary perfusion segments supplied by an artery with fractional
flow reserve (FFR) ≤0.8 (P<0.0001
for LAD, CX, and RCA).
Results
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Six patients had to be excluded from the analysis: in 3 patients
CMR imaging study was prematurely stopped due to claustrophobia and 3 patients declined to undergo FFR measurement
after the first CMR study with adenosine. Thirty-six patients
underwent CMR study and FFR measurement and represent
the study population. Baseline clinical and CMR imaging
data are given in Table 1. In all patients FFR was measured in
LAD, CX, and RCA.
CMR and FFR Results
In 17 (47.2%) patients, an FFR≤0.8 could be measured in
28 coronary arteries (25.9%). An FFR≤0.8 was detected in 9
(25%) LAD, 10 (27.8%) CX, and 8 (22.2%) RCA coronaries.
Hemodynamic data during rest and adenosine for CMR and
FFR examination are shown in Table 2. Table 3 provides comparison of clinical and CMR data in patients with FFR≤0.8
and >0.8.
Twelve (2.1%) BOLD segments had to be excluded from
analysis because of insufficient image quality during adenosine in 10 and rest in 2 segments. The D’Agostino-Pearson test
for normal distribution of BOLD values yielded P=0.3567
(accept normality).
Comparison of BOLD and FFR measurements yielded a
correlation coefficient r=0.66 (P<0.0001) for LAD, r=0.81
(P<0.0001) for CX, and r=0.73 (P<0.0001) for RCA.
BOLD signal intensity increase was significantly lower
in all perfusion territories supplied by coronary arteries with FFR≤0.8 in comparison with FFR>0.8 (1.1±0.2%
Table 1. Baseline Clinical and CMR Imaging Data
Age, y
63.1±9.9
Men, N (%)
27 (75)
Cardiovascular risk factors, N (%)
Hypertension
28 (77.8)
Hypercholesterolemia
19 (52.8)
History of smoking
17 (47.2)
Diabetes mellitus
5 (13.9)
Family history for coronary artery disease
16 (44.4)
CMR imaging
Left ventricular end-diastolic volume index, mL/m2
72.8±17.8
Left ventricular end-systolic volume index, mL/m2
27.1±14.9
Left ventricular ejection fraction, %
64.5±10.0
CMR indicatescardiac magnetic resonance imaging.
versus 1.5±0.2%; P<0.0001). This applied for the LAD
(1.1±0.3% versus 1.5±0.2%; P<0.0001), CX (1.0±0.3%
versus 1.5±0.2%; P<0.0001), and RCA (0.9±0.2% versus
1.5±0.2%; P<0.0001) territories. Box and whisker graphs
according to the coronary perfusion territories are provided
in Figure 2.
ROC curve analysis yielded a BOLD cutoff value of 1.3%
providing best values for sensitivity and specificity of 88.2%
and 89.5%, respectively (95% CI, 76.7–97.9) on a per-patient
analysis. ROC curve is provided in Figure 3. Sensitivity and
specificity of the BOLD approach were 88.9% and 92.6%
for LAD (95% CI, 71.1–95.6), 90.0% and 88.5% for CX
(95% CI, 80.7–99.0), and 100% and 89.3% for RCA (95%
CI, 86.6–99.4) perfused myocardial segments. ROC curves
including area under the curve for the per-vessel analysis are
provided in Figure 4. Using the cutoff value of 1.3% assessed
by ROC analysis, Figure 5 provides an example of a falsepositive BOLD result in a patient with hypertensive smallvessel disease and a false-negative example in a patient with
a short RCA stenosis and a resulting FFR of 0.78. Intraclass
correlation coefficient yielded 0.84 for interobserver and 0.87
for intraobserver variability.
Discussion
We compared a T2-prepared SSFP BOLD sensitive CMR
approach to FFR in patients with suspected CAD and could
show that the relative BOLD signal intensity difference at rest
and during adenosine highly correlated to invasively measured
FFR in the corresponding supplying coronary artery. Myocardial oxygenation assessed by T2-prepared CMR imaging has
Table 2. Hemodynamic Data for CMR and FFR During Rest
and Adenosine
Rest
Adenosine
Systolic blood pressure, mm Hg
142±23
132±32*
Diastolic blood pressure, mm Hg
75±14
74±14
Heart rate, bpm
65±12
83±17**
CMR
FFR
Systolic blood pressure, mm Hg
138±22
131±26*
Diastolic blood pressure, mm Hg
74±14
73±13
Heart rate, bpm
62±11
77±16**
CMR indicates cardiac magnetic resonance imaging; FFR, fractional flow reserve.
*P<0.01.
**P<0.0001.
Walcher et al BOLD MRI Compared With FFR 583
Table 3. Clinical and CMR Comparison of FFR≤0.8 vs FFR>0.8
FFR≤0.8
(N=17)
FFR>0.8
(N=19)
P
χ2
Age, y
64.5±8.2
61.9±11.3
0.4517
0.4
Men, N (%)
12 (70.6)
15 (78.9)
0.7060
6.6
Cardiovascular risk factors, N (%)
Hypertension
13 (76.5)
15 (78.9)
0.9999
0.1
Hypercholesterolemia
7 (41.2)
12 (63.2)
0.3161
0.5
History of smoking
5 (29.4)
12 (63.2)
0.0543
0.5
Diabetes mellitus
3 (17.6)
2 (10.5)
0.6504
6.0
Family history for coronary artery disease
8 (47.1)
8 (42.1)
0.9999
0.2
68.1±18.0
77.5±16.8
0.1285
1.6
Left ventricular end-systolic volume index, mL/m
26.0±17.1
28.1±12.8
0.6815
0.5
Left ventricular ejection fraction, %
64.1±11.8
65.0±8.1
0.7961
<0.01
CMR imaging
Left ventricular end-diastolic volume index, mL/m2
2
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CMR indicates cardiac magnetic resonance imaging; FFR, fractional flow reserve.
previously been shown to be able to estimate oxygen saturation and to be exponentially related to vasodilator-induced
increases of blood flow.9,21 Therefore, this technique appears
to be able to assess myocardial ischemia.
A previously described BOLD sensitive CMR approach11
was evaluated for the detection of inducible myocardial
ischemia. We now demonstrate that BOLD analysis is suitable to detect hemodynamic significant coronary lesions
determined by an FFR≤0.8. In the myocardial segments supplied by the coronary arteries with an FFR≤0.8 BOLD signal intensity increase was significantly lower than in those
segments perfused by a coronary artery with an FFR>0.8.
This correlation was demonstrated for all coronary arteries
but also for each separate perfusion territory for the LAD,
CX, and RCA. ROC analyses yielded good sensitivity and
specificity of the BOLD analysis for detection of significant
coronary lesion. A recently published manuscript showed
dissociation between BOLD sensitive CMR and positron
emission tomography indicating differences between ischemia and myocardial oxygenation.22 However, the latter
study compared a single midventricular BOLD sensitive
CMR slice to a positron emission tomographic 3-dimensional imaging approach covering the entire myocardium.
Figure 3. Receiver-operating characteristics curve of blood oxygen
level–dependent cardiac magnetic resonance imaging for the diagnostic accuracy to detect a patient with a fractional flow reserve
≤0.8 yielded a sensitivity of 88.2% and specificity of 89.5%.
Moreover, BOLD imaging was acquired after 90 seconds,
whereas positron emission tomography after 7 minutes of
adenosine infusion at the same rate. Therefore, the results
and conclusions of that article may be misleading and cannot be applied to our study.
Diagnostic accuracies provided by BOLD CMR in the
detection of significant coronary artery stenosis seem to be
similar to those found by first-pass perfusion CMR using FFR
as a gold standard.23
We have previously shown that BOLD imaging correlates to ischemia detected by CMR perfusion imaging.11
However, perfusion analysis was evaluated visually in that
study and was compared with quantitative BOLD analysis. A
semiquantitative analysis including MPR calculation seems
to be more adequate for comparison of MPR and relative
BOLD signal intensity increase during adenosine. This has
been recently evaluated by Jahnke et al8 in 50 patients yielding similar good sensitivities and specificities for detection of coronary stenoses with a diameter reduction ≥50%.
Hence, the BOLD sensitive CMR approach, which visualizes changes in myocardial oxygenation, appears capable
for detection of relevant CAD. However, comparing this
functional approach with an anatomical evaluation of the
degree of coronary luminal narrowing by quantitative coronary angiography serving as the reference standard seems
inappropriate. Rather, it should be compared with the physiological assessment of coronary artery stenoses by invasive
measurement of the FFR. Thus, the diagnostic accuracy of
BOLD imaging was compared with FFR.
Detection of inducible myocardial ischemia is a main
clinical indication for CMR. Because BOLD imaging relies
on detection of different oxygenation in myocardial tissue
that serves as an endogenous contrast, it does not require
the application of exogenous contrast agents as surrogates
for evaluation of myocardial perfusion. Because of its
independency to accurate timing of contrast bolus arrival and
first pass, spatial resolution can be improved. Furthermore,
a 3-dimensional approach, as recently demonstrated,8
could be implemented for complete coverage of the entire
584 Circ Cardiovasc Imaging September 2012
Figure 4. Receiver-operating
characteristics curves on a
per-vessel basis showing the
diagnostic accuracy of blood
oxygen level–dependent cardiac
magnetic resonance imaging in
left anterior descending (LAD),
circumflex artery (CX), and right
coronary artery (RCA). Area
under the curve (AUC) including 95% CI and P values are
provided.
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myocardium. The use of exogenous contrast agents could
possibly induce nephrogenic systemic fibrosis,24 which could
be avoided by the use of an imaging technique without the
need of contrast agents representing another potential benefit
of BOLD imaging. Because BOLD CMR yields similar
diagnostic accuracies compared with contrast–enhanced
perfusion CMR, it represents a potential alternative,
especially, in patients with significant renal dysfunction.
Limitations
The investigated patient population was relatively small.
Hence, cutoff values and diagnostic accuracy could alter in
a larger cohort. However, BOLD imaging and FFR measurements in all 3 coronary arteries during adenosine infusion
were performed in all patients and showed good diagnostic
accuracies. Another possible limitation of our study is the fact
that we did not perform signal intensity correction for heart
rate. We included a selected patient population with stable
angina and previous pathological or inconclusive stress test.
To what extend our results could be postulated for a larger
unselected patient cohort remains unclear. Further, larger
studies are warranted to show the potential prognostic value
of BOLD CMR. The BOLD effect is partly dependent on
the blood flow. These effects might have influenced our data,
because we have not monitored coronary blood flow during
adenosine and rest, and could present a potential limitation
for the presented study. Although drug-induced vasodilation
is associated with a dose-dependent increase in blood flow,9 it
is difficult to differentiate to what extent the observed BOLD
effect is because of blood flow. An example of a false-positive
CMR result possibly because of impaired coronary blood
flow in a patient with small-vessel disease is presented in
Figure 5. Because we did not include late gadolinium
enhancement imaging in our study, we cannot conclude about
its potential incremental value.
Conclusions
BOLD CMR offers an alternative to contrast–enhanced firstpass perfusion for the detection of hemodynamic significant
CAD.
Figure 5. An example of a false-positive cardiac
magnetic resonance imaging (CMR) with pathological blood oxygen level–dependent (BOLD) signal
intensity increase in the left anterior descending
(LAD) territory without corresponding stenosis in the
LAD (fractional flow reserve [FFR] 0.87).
Walcher et al BOLD MRI Compared With FFR 585
Figure 6. Right coronary artery (RCA) stenosis
with reduced fractional flow reserve (FFR) (0.80)
in a patient without reduced blood oxygen level–
dependent (BOLD) signal intensity increase in
the RCA perfused segments as an example for a
false-negative cardiac magnetic resonance imaging
(CMR) result.
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Sources of Funding
This study was, in part, supported by a grant of the University of Ulm
(L.SBN.0050).
None.
Disclosures
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CLINICAL PERSPECTIVE
T2-prepared steady-state free precession blood oxygen level–dependent cardiac magnetic resonance imaging is based on
different magnetic properties of oxyhemoglobin and deoxyhemoglobin. This results in a relative decrease of T2* and T2
relaxation time in ischemic and thus lower oxygenated myocardium. In our study, we demonstrate that this effect correlates
to invasively measured fractional flow reserve in the respective coronary artery. Our described approach warrants consideration as an alternative to contrast–enhanced perfusion studies, especially in patients with severe renal failure in which the
use of exogenous contrast agents should be avoided.
Myocardial Perfusion Reserve Assessed by T2-Prepared Steady-State Free Precession
Blood Oxygen Level−Dependent Magnetic Resonance Imaging in Comparison to
Fractional Flow Reserve
Thomas Walcher, Robert Manzke, Vinzenz Hombach, Wolfgang Rottbauer, Jochen Wöhrle and
Peter Bernhardt
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Circ Cardiovasc Imaging. 2012;5:580-586; originally published online August 1, 2012;
doi: 10.1161/CIRCIMAGING.111.971507
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