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JACC: CARDIOVASCULAR IMAGING
© 2010 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
VOL. 3, NO. 4, 2010
ISSN 1936-878X/10/$36.00
DOI:10.1016/j.jcmg.2009.11.015
Strain-Encoded CMR for the Detection of
Inducible Ischemia During Intermediate Stress
Grigorios Korosoglou, MD,* Stephanie Lehrke, MD,* Angela Wochele, RN,*
Birgit Hoerig, RN,* Dirk Lossnitzer, MD,* Henning Steen, MD,*
Evangelos Giannitsis, MD,* Nael F. Osman, PHD,†‡ Hugo A. Katus, MD*
Heidelberg, Germany; Baltimore, Maryland; and Cairo, Egypt
O B J E C T I V E S This study sought to evaluate the diagnostic accuracy of strain-encoded cardiac
magnetic resonance (SENC) for the detection of inducible ischemia during intermediate stress.
B A C K G R O U N D High-dose dobutamine stress cardiac magnetic resonance (DS-CMR) is a well-
established modality for the noninvasive detection of coronary artery disease (CAD). However, the
assessment of cine scans relies on the visual interpretation of wall motion, which is subjective, and
modalities that can objectively and quantitatively assess the time course of myocardial strain response
during stress are lacking.
M E T H O D S Stress-induced ischemia was assessed by wall motion analysis and by SENC in 80
patients with suspected or known CAD and in 18 healthy volunteers who underwent DS-CMR in a clinical
1.5-T scanner. Quantitative coronary angiography was used as the standard reference for the presence
of CAD (ⱖ50% diameter stenosis).
R E S U L T S On a patient level, 46 of 80 patients (58%) had CAD, including 20 with single-vessel, 18
with 2-vessel, and 8 with 3-vessel disease. During peak stress, SENC correctly detected ischemia in 45
versus 38 of 46 patients with CAD (7 additional correct findings for SENC), yielding significantly higher
sensitivity than cine (98% vs. 83%, p ⬍ 0.05). No patients were correctly diagnosed by cine and missed
by SENC. During intermediate stress, SENC showed diagnostic value similar to that provided by cine
imaging only during peak dobutamine stress (sensitivity of 76% vs. 83%, specificity of 88% vs. 91%, and
accuracy of 81% vs. 86%; p ⫽ NS for all). Quantification analysis demonstrated that strain rate response
is a highly sensitive marker for the detection of inducible ischemia (area under the curve ⫽ 0.96; SE ⫽
0.01; 95% confidence interval: 0.93 to 0.99) that precedes the development of inducible wall motion
abnormalities and already significantly decreases with moderate 40% to 60% coronary lesions.
C O N C L U S I O N S Using SENC, CAD can be detected during intermediate stress with similar
accuracy to that provided by cine only during peak stress. By this approach, patient safety may be
improved during diagnostic procedures within lower time spent (Strain-Encoded Cardiac Magnetic
Resonance Imaging for Dobutamine Stress Testing; NCT00758654 (J Am Coll Cardiol Img 2010;3:
361–71) © 2010 by the American College of Cardiology Foundation
From the *University of Heidelberg, Department of Cardiology, Heidelberg, Germany; †Russell H. Morgan Department of
Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland; and ‡Nile
University, Cairo, Egypt. Dr. Osman is a founder and shareholder in Diagnosoft Inc., the software used for the analysis of the
acquired SENC images.
Manuscript received June 23, 2009; revised manuscript received November 2, 2009, accepted November 6, 2009.
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SENC Detects CAD During Intermediate Stress
H
igh-dose dobutamine stress cardiac cardiac
magnetic resonance (DS-CMR) is a wellestablished diagnostic modality for the noninvasive detection of coronary artery disease
(CAD). However, the assessment of cine images
relies on the visual interpretation of regional wall
motion, which depends on the experience of the
readers. Especially with nonexpert magnetic resonance readers, the human eye primarily tracks the
radial displacement of the myocardium with cine
images, which is less sensitive than circumferential
and longitudinal components for the detection of
myocardial dysfunction (1– 4).
See page 372
Objective approaches for the quantification of
myocardial strain during DS-CMR have been very
limited so far. Strain-encoded cardiac magnetic
resonance (SENC) has been previously proposed
for the objective color-coded evaluation of
ABBREVIATIONS
regional myocardial strain in experimental
AND ACRONYMS
and in clinical settings (5–7). The purpose
of the present study was to investigate the
CAD ⴝ coronary artery disease
ability of SENC to detect myocardial ischDS-CMR ⴝ dobutamine stress
emia during intermediate stress in a cohort
cardiac magnetic resonance
of subjects with suspected or known
LV ⴝ left ventricular
CAD. The results were compared with
S ⴝ peak systolic strain
cine images, and quantitative coronary
SENC ⴝ strain-encoded cardiac
angiography was deemed as the standard
magnetic resonance
reference for the presence of anatomically
SR ⴝ peak systolic strain rate
significant CAD.
WMA ⴝ wall motion abnormality
METHODS
Patient population. Consecutive patients with suspected or known CAD (n ⫽ 131) were screened for
inclusion in our study before clinically indicated
coronary angiography. Patients were excluded for
the following reasons: nonsinus rhythm (n ⫽ 5),
electrocardiography signs or a history of previous
myocardial infarction (n ⫽ 17), regional resting wall
motion abnormalities (WMAs) or ejection fraction
⬍55% (n ⫽ 8), severe arterial hypertension (⬎200/
120 mm Hg) (n ⫽ 2), moderate or severe valvular
disease (n ⫽ 2), or general contraindications to
magnetic resonance examination (n ⫽ 8). Thus 89
patients were scheduled for DS-CMR. Agematched healthy volunteers (n ⫽ 18) also underwent DS-CMR to acquire normal values for myocardial strain and strain rate response. All
volunteers underwent laboratory testing before inclusion in our study. Exclusion criteria were history,
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symptoms, electrocardiographic signs, or biochemical findings indicative of cardiovascular disease,
evidence of systemic hypertension (baseline blood
pressure ⬎140/85 mm Hg), diabetes, abnormal
glucose tolerance, hyperlipidemia (low-density lipoprotein ⬎130 mg/dl) or the presence of WMA at
baseline or during DS-CMR. All procedures complied with the Declaration of Helsinki and were
approved by our local ethics committee, and all
patients gave written informed consent.
Cardiovascular magnetic resonance examination.
Subjects were examined in a clinical 1.5-T wholebody Achieva system (Philips Medical Systems,
Best, the Netherlands) using a 5-element cardiac
phased-array receiver coil. Images were acquired at
rest and during a standardized high-dose dobutamine/atropine protocol (6). A 4, 2, and 3-chamber
and 3 short-axis views (apical, mid-ventricular, and
basal) were used. Dobutamine was infused during
3-min stages at incremental doses of 10, 20, 30, and
40 ␮g/kg of body weight per min until at least 85%
of the age-predicted heart rate was reached (220age). If at peak infusion the target heart rate was not
achieved, atropine was administrated in 0.25-mg
increments up to a maximal dose of 2.0 mg. Stress
testing was discontinued when the target heart rate
was achieved or when one of the following occurred: extensive WMA in ⱖ2 adjacent segments,
severe chest pain or dyspnea, decrease in systolic
blood pressure of ⱖ40 mm Hg, arterial hypertension of ⱖ220/120 mm Hg, or severe arrhythmias.
In the absence of ischemia, failure to attain 85%
of age-predicted maximal heart rate was considered
as a nondiagnostic result.
A steady-state free-precession sequence was used to obtain cine images with 8-mm
slice thickness. Typical parameters were sensitivity
encoding factor of 2, field of view ⫽ 350 ⫻ 350
mm2, matrix size ⫽ 160 ⫻ 160, flip angle ⫽ 60°,
repetition time/echo time ⫽ 2.8/1.4 ms, acquired
voxel size ⫽ 2.2 ⫻ 2.2 ⫻ 8 mm3, image matrix ⫽
288 ⫻ 288, and reconstructed voxel size ⫽ 1.2 ⫻
1.2 ⫻ 8 mm3. The temporal resolution was 21 to 28
ms, and the total scan duration was 7 to 12 s. Cine
images were acquired at baseline, and acquisitions
were repeated during each stage, including the peak
level of dobutamine stress.
CINE IMAGING.
SENC. The SENC pulse sequence is a modified
spatial modulation of magnetization tagging pulse
sequence, which provides the color-encoded visualization and quantification of myocardial strain.
Technical details of this sequence are described
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elsewhere (5–7). SENC images were acquired at
identical plane levels of that used for cine scans with
10-mm slice thickness. Typical parameters were
field of view ⫽ 350 ⫻ 350 mm2, matrix size ⫽ 80 ⫻
80, flip angle ⫽ 30°, repetition time/echo time ⫽
25/0.9 ms, acquired voxel size ⫽ 4.4 ⫻ 4.4 ⫻ 10
mm3, image matrix ⫽ 256 ⫻ 256, and reconstructed voxel size ⫽ 1.4 ⫻ 1.4 ⫻ 8 mm3. Strainencoded images were acquired at baseline, during
20 ␮g/kg of dobutamine infusion, during peak
dobutamine/atropine administration, and 10 min
after stress testing. Details on the temporal resolution and total scan duration are provided in Online
Table 1.
Visual interpretation of cine and SENC images. For
interpretation of wall motion, corresponding rest and
peak stress cine images were displayed using View
Forum software (Philips Medical Systems, Best, the
Netherlands). Segmental wall motion was graded
semiquantitatively using a 16-segment model according to American Heart Association guidelines (8) and
a 3-point scale (0 ⫽ normal wall motion, 1 ⫽
hypokinesia, 2 ⫽ akinesia or dyskinesia), and inducible ischemia was considered present in cases of new
WMA of ⱖ1 grade during stress (6).
Corresponding baseline and peak stress SENC
images were displayed using Diagnosoft SENC
(version 1.06, Diagnosoft, Palo Alto, California), a
software package that allows the color-encoded
interpretation of myocardial strain on SENC images. Similar to wall motion analysis, myocardial
strain was graded semiquantitatively using a 3-point
color scale (0 ⫽ normal strain corresponding to red
myocardium, 1 ⫽ reduced strain corresponding to
faded orange/yellowish myocardium, 2 ⫽ severely
reduced or absent strain corresponding to white
myocardial tissue on strain-encoded images). Inducible ischemia was considered present in case of
strain reduction of ⱖ1 grade. Both cine and SENC
images were interpreted visually by 2 independent
observers (G.K. and D.L.), who evaluated images
off-line after the termination of the stress studies.
The evaluation was performed separately, and observers were blinded to all other data.
Quantitative analysis of circumferential and longitudinal
strain with SENC images. Because the tagging mod-
ulation gradient is applied in the slice selection
direction with SENC, quantification of circumferential strain was performed on 4-, 2-, and
3-chamber view, whereas quantification of longitudinal strain was performed on short-axis images.
For each segment, the temporal course of regional
myocardial strain was registered throughout the
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SENC Detects CAD During Intermediate Stress
cardiac cycle, and quadratic interpolation was used
to estimate the following parameters: 1) peak systolic strain (S), defined as the maximum strain
during the cardiac cycle and expressed as a percentage; 2) peak systolic strain rate (SR), defined as the
maximum strain rate during systole and expressed
in 1/s; 3) strain reserve, defined as the relative
increase in peak systolic strain during DS-CMR
and calculated as follows: SReserve ⫽ Sdobutamine/
Sbaseline; and 4) strain rate reserve, defined as the
relative increase in peak systolic strain rate during
DS-CMR and calculated as follows: SRReserve⫽
SRdobutamine/SRbaseline.
Quantitative coronary angiography and comparison to
cine and SENC images. Angiography was deemed as
the standard reference for the detection of CAD
and was obtained in all patients within 3 weeks
from the DS-CMR study. The procedure was
performed according to the angiographic guidelines, and at least 2 orthogonal views of every major
coronary vessel and its side branches were acquired.
Quantification of lumen narrowing was performed
off-line using Centricity QCA (GE Medical Systems, Milwaukee, Wisconsin). Myocardial segments were assigned to coronary vessels according
to American Heart Association guidelines (8) (see
Online Appendix for details).
Statistical analysis. Analysis was performed using
commercially available software (SPSS, version 12.0
for Windows, SPSS, Chicago, Illinois), and data
are presented as mean ⫾ SD. Agreement between
the 2 observers interpreting cine and SENC was
assessed using kappa statistics (9). Intra- and interobserver variability for quantification of strain were
calculated by repeated analysis of 40 representative
images. Differences in sensitivity, specificity, and
accuracy were tested using exact 2-sided McNemar
tests (10). Differences in strain and strain rate
between normal, ischemic, and nonischemic segments at different time points and differences by
stenosis severity (0%; 1% to 0%; 21% to 40%; 41%
to 60%; 61% to 80%; and 81% to 100%) were
assessed with clustered regression and using Bonferroni correction for multiple comparisons. The
relation between SReserve and SRReserve with the
stenosis severity was assessed by second-order polynomial regression analysis. Receiver-operator characteristics were used to estimate the accuracy of
SReserve and SRReserve to predict ⱖ50% stenosis, and
pairwise comparisons of areas under the curve were
assessed (11). Differences were considered significant at p ⬍ 0.05.
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RESULTS
Results of coronary angiography. Coronary angiog-
11,858 ⫾ 2,537
raphy showed ⱖ50% stenosis in 80 of 240 coronary
vessels (33%), including 32 vessels with left anterior
descending, 27 with left circumflex, and 21 with
right coronary artery lesions. On a patient level, 46
of 80 patients (58%) had CAD, including 20 with
single-vessel, 18 with 2-vessel, and 8 with 3-vessel
disease.
Detection of CAD by SENC versus cine imaging. During intermediate stress, SENC already detected
inducible ischemia in 35 of 46 and correctly excluded CAD in 30 of 34 patients with normal strain
response (sensitivity of 76%, specificity of 88%, and
accuracy of 81%), whereas cine imaging showed low
diagnostic value (sensitivity of 20%, specificity of
97%, and accuracy of 53%, p ⬍ 0.001 vs. SENC for
sensitivity and accuracy). The diagnostic characteristics of SENC during intermediate stages were
statistically similar to those provided by cine imaging only during peak dobutamine stress (Table 2).
During peak stress, SENC correctly detected ischemia in 45 versus 38 of 46 patients with CAD (7
additional correct findings for SENC), yielding
significantly higher sensitivity than cine (98% vs.
83%, p ⬍ 0.05). No patients were correctly diagnosed by cine and missed by SENC.
In a patient without CAD, circumferential peak
systolic strain (Figs. 1A to 1F) remained constant,
as indicated by black and green curved arrows in
Figure 1G, whereas peak systolic strain rate increased stepwise, as indicated by black and green
curved arrows in Figure 1H. Conversely, in a
patient with CAD (Figs. 2A to 2H), SENC revealed a subtle, albeit clearly detectable strain defect
in the anterior left ventricular (LV) wall (white
arrow in Fig. 2D) already during intermediate
stress, which increased during peak stress (white
arrows in Fig. 2F). With cine images, ischemia was
detected only during peak stress (white arrow in
Fig. 2E). Quantitative analysis showed that longitudinal peak systolic strain decreased stepwise during stress, as indicated by black and green curved
arrows in Figure 2I, whereas peak systolic strain rate
remained unchanged, as indicated by the dotted red
circle in Figure 2J. The presence of a 68% diameter
stenosis in the left anterior descending artery was
confirmed by angiography (Figs. 2K and 2L).
107 ⫾ 25
Quantitative assessment of circumferential and longitudinal strain response during DS-CMR. In normal
Demographic and hemodynamic parameters. Diag-
nostic DS-CMR examinations (positive for ischemia or negative but with achievement of the target
heart rate) were achieved in 80 of 89 patients. Nine
patients were excluded from analysis for the following reasons: failure to achieve target heart rate in the
absence of ischemia (n ⫽ 3), increase in systolic
blood pressure ⬎220 mm Hg (n ⫽ 1), discontinuation of the study on patient’s request (n ⫽ 2), or
repeated extrasystoles during stress, resulting in
nondiagnostic image quality both for cine and
SENC images (n ⫽ 3). In 80 patients with regular
rhythm during baseline and stress, 17 segments
were not interpretable either at baseline (n ⫽ 7;
0.5%) or during stress (n ⫽ 10; 0.8%) with SENC
images. In all 18 healthy subjects, the target heart
rate was achieved and diagnostic images were acquired. Overall, no severe adverse events were recorded. Demographics are summarized in Table 1.
Table 1. Demographic and Hemodynamic Data
Parameter
Healthy Volunteers
(n ⴝ 18)
Patients
(n ⴝ 80)
Demographics
Age (yrs)
62 ⫾ 7
62 ⫾ 5
Male sex
13/18 (72%)
58/80 (73%)
Arterial hypertension
0/18 (0%)
73/80 (91%)
Hypercholesterolemia
0/18 (0%)
57/80 (71%)
Diabetes mellitus
0/18 (0%)
13/80 (16%)
Family history of CAD
0/18 (0%)
23/80 (29%)
Smoker
0/18 (0%)
21/80 (26%)
Prior percutaneous coronary intervention
0/18 (0%)
30/80 (38%)
Prior coronary artery bypass grafting
0/18 (0%)
5/80 (6%)
Coronary risk factors
Reasons for referral to angiography
Chest pain
(NA)
64 (80%)
Exertional dyspnea
(NA)
16 (20%)
Baseline hemodynamics
Mean blood pressure (mm Hg)
92 ⫾ 6
90 ⫾ 12
Heart rate (beats/min)
67 ⫾ 10
67 ⫾ 12
8,211 ⫾ 1,215
8,287 ⫾ 2,138
Double product (mm Hg/min)
Intermediate stress hemodynamics
Mean blood pressure (mm Hg)
92 ⫾ 8
98 ⫾ 16
Heart rate (beats/min)
94 ⫾ 7
90 ⫾ 13
Double product (mm Hg/min)
11,948 ⫾ 827
Peak stress hemodynamics
Mean blood pressure (mm Hg)
Heart rate (beats/min)
Double product (mm Hg/min)
Data are presented as n(%) or mean ⫾ SD.
CAD ⫽ coronary artery disease; NA ⫽ not applicable.
92 ⫾ 12
149 ⫾ 7
141 ⫾ 9
19,522 ⫾ 2,265
19,510 ⫾ 5,438
and nonischemic segments, circumferential and
longitudinal strain remained constant (hatched and
dotted lines in Figs. 3A and 3B), whereas strain rate
increased stepwise (hatched and dotted lines in
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Table 2. Detection of Coronary Artery Disease During Intermediate and Peak Stress MR
Sensitivity
Specificity
PPV
NPV
Accuracy
Cine imaging
Intermediate stress
Peak stress
20% (9/46)
97% (33/34)
90% (9/10)
47% (33/70)
53% (42/80)
83%* (38/46)
91% (31/34)
93% (38/41)
79% (31/39)
86%* (69/80)
76%§ (35/46)
88% (30/34)
90% (35/39)
73% (30/41)
81%§ (65/80)
98%†‡ (45/46)
85% (29/34)
90% (45/50)
97% (29/30)
93%† (74/80)
Strain-encoded MR
Intermediate stress
Peak stress
Data are presented as %(n). *p ⬍ 0.05 for intermediate versus peak cine imaging. †p ⬍ 0.01 for intermediate versus peak strain-encoded MR. ‡p ⬍ 0.05 for peak
cine imaging versus peak strain-encoded MR. p ⫽ NS for intermediate strain-encoded MR versus peak cine imaging for sensitivity, specificity, and accuracy. §p ⬍
0.001 for intermediate imaging versus intermediate strain-encoded MR. (All by exact 2-sided McNemar tests.)
MR ⫽ magnetic resonance; NPV ⫽ negative predictive value; PPV ⫽ positive predictive value.
Figs. 3C and 3D). Conversely, in ischemic segments, strain decreased stepwise (solid lines in Figs.
3A and 3B), whereas strain rate remained constant
(solid lines in Figs. 3C and 3D) (p ⬍ 0.001 vs.
nonischemic and normal).
During both intermediate and peak stimulation,
significant correlations were observed between
stenosis severity and circumferential SReserve and
SRReserve (p ⬍ 0.001 for all) (Figs. 4A, 4C, 4E, and
4G). Interestingly, segments with new WMA during peak stress on cine images were located at the
bottom right corner (pink dots within the hatched
red circles in Figs. 4E and 4G), whereas a considerable amount of segments, classified as “normal” by
wall motion readings, had impaired SReserve and
SRreserve (blue dots within the dotted red squares in
Figs. 4E and 4G). SReserve decreased with ⬎80%
and ⬎60% coronary lesions, respectively, during
intermediate and peak stress, whereas SRReserve
already decreased with ⬎60% and with ⬎40%
lesions, respectively (i.e., 1 stage earlier) (Figs. 4B,
4D, 4F, and 4H). Similar findings were obtained
for longitudinal strain (Online Fig. 1).
SRReserve provided significantly higher accuracy
than strain for the detection of coronary lesions
ⱖ50% than SReserve (green and pink arrows in Fig. 5,
indicating significant increase in accuracy between
strain and strain rate with intermediate and peak
stress, respectively). Hereby, the highest accuracy
was acquired by SRReserve during peak stress.
Figure 1. SENC in a Patient Without CAD
Systolic 4-chamber and mid–short-axis SENC images are shown (A to F). Quantification of regional circumferential strain yielded constant
peak systolic strain (S) values (SReserve ⬃1, black and green curved arrows in G), whereas peak systolic strain rate (SR) increased stepwise during stress (SRReserve ⬃2, as indicated by black and green curved arrows in H). Arrowheads indicate signal voids on SENC
images due to low signal-to-noise ratio. CAD ⫽ coronary artery disease; SENC ⫽ strain-encoded cardiac magnetic resonance.
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Figure 2. SENC in a Patient With CAD
Mid–short-axis SENC and cine images are shown (A to H). With cine images, inducible ischemia is detected only during peak stress in
the mid-anterior left ventricular wall (E, white arrow). Conversely, with SENC, a subtle, albeit clearly detectable, strain defect is already
observed during intermediate stages (D, white arrow). Quantification analysis showed that peak systolic strain decreased stepwise during
inotropic stimulation (as indicated by black and green curved arrows in I), whereas peak systolic strain rate remained unchanged (J,
dotted red circle). The presence of a 68% diameter lesion in the distal left anterior descending artery was confirmed by angiography (K
and L). Arrowheads indicate signal voids on SENC images due to low signal-to-noise ratio. Abbreviations as in Figure 1.
Observer agreement and variabilities. Agreement be-
tween observers interpreting wall motion on cine
images and myocardial strain on SENC images was
87% (kappa ⫽ 0.78) and 84% (kappa ⫽ 0.75),
respectively. SENC allowed for reproducible quantification of strain and strain rate, showing intraand interobserver variabilities of 7.4% and 10.2%
for strain and 8.7% and 11.1% for strain rate.
DISCUSSION
The results of our study demonstrate for the first
time in the current literature the ability of a strain
imaging technique to detect CAD during intermediate stages of inotropic stimulation with similar
accuracy to that provided by conventional wall
motion analysis only during peak stress. SENC can
objectively assess the time course of regional myocardial strain and strain rate response during inotropic stimulation and provide a sensitive, noninvasive estimate of coronary stenosis severity.
Previous echocardiographic studies used tissue
Doppler techniques to evaluate strain response during stress (12). However, to our knowledge no
echocardiographic or magnetic resonance imaging
studies have investigated thus far the ability of
strain imaging to detect ischemia during intermediate stages. Recently, we demonstrated that the
direct color-coded visualization of myocardial strain
with SENC allows for the objective detection of
subtle differences in regional myocardial strain (6).
In the present study, we show for the first time that
the reversible decrease of regional myocardial strain
on SENC images precedes the development of
WMAs, aiding the detection of CAD during intermediate stages of inotropic stimulation with
sensitivity and accuracy, similar to that provided by
cine imaging during peak stress. Thus the implementation of SENC in the clinical routine may help
with the early detection of strain defects with
intermediate stages, increasing patient safety during
diagnostic procedures and simultaneously reducing
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-5
Time Course of Circumferential Strain
and Strain Rate
Baseline
Intermediate
Stress
*
-10
Peak Stress
Post Stress
*
-15
-20
-25
-30
C
0
Baseline
Intermediate
Stress
Peak Stress
Post Stress
-1
-2
-3
-4
-5
‡
§
B
Peak Longitudinal Systolic Strain (%)
A
Peak Longitudinal Systolic Strain Rtae (1/s)
Peak Circumferential Systolic Strain Rtae (1/s)
Peak Circumferential Systolic Strain (%)
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-5
Time Course of Longitudinal Strain
and Strain Rate
Baseline
Intermediate
Stress
*
-10
Peak Stress
Post Stress
*
-15
-20
-25
Normal
Non-ischemic
Ischemic
-30
D
0
Baseline
Intermediate
Stress
Peak Stress
Post Stress
-1
-2
-3
‡
-4
§
-5
Figure 3. Temporal Course of Myocardial Strain and Strain Rate During Stress
In normal and nonischemic segments, strain remained constant during inotropic stimulation (A and B, hatched and dotted lines),
whereas strain rate increased stepwise (C and D, hatched and dotted lines). Conversely, in ischemic segments, strain decreased stepwise
(A and B, solid lines) (*p ⬍ 0.001 vs. ischemic segments during baseline and vs. nonischemic/normal during stress), whereas strain rate
remained constant (C and D, solid lines) (‡p ⬍ 0.001 vs. baseline and peak strain rate in normal and nonischemic segments, and §p ⬍
0.001 vs. intermediate strain rate in normal and nonischemic and vs. peak strain rate in ischemic segments).
time spent. Furthermore, newer, fast SENC techniques were recently shown to allow for quantification of myocardial strain within a single heartbeat,
obviating the need of prolonged breathholds (5).
Because cardiac abnormalities during stress procedures are of a transient nature, single heartbeat
imaging might be able to detect wall motion disorders, which conventional 10-heartbeat or more
segmented sequences might miss due to temporal
averaging.
In the present study, quantitative analysis
yielded different temporal patterns of strain and
strain rate response between ischemic and nonischemic myocardium. Thus myocardial strain rate
increased stepwise during stress (SRReserve ⬃2) in
nonischemic and remained constant in ischemic
segments. On the other hand, strain remained
constant in nonischemic segments (SReserve ⬃1)
and decreased stepwise during intermediate and
peak stress in ischemic segments. Conversely,
using magnetic resonance tagging, circumferential strain was previously shown to slightly increase (by 10% to 20%) during low-dose inotropic
stimulation in normal segments (13). This mismatch may be attributed to differences in methodology used for the acquisition of SENC images, where in contrast to conventional tagging,
the gradient is applied in the slice-selection
direction, orthogonal to the imaging plane and
not in the phase- or frequency-encoding direction (14). Furthermore, conventional SENC
techniques fail to compensate for the throughplane motion of the heart (the motion in the
slice-selection direction). For example, in longaxis images of the LV, long-axis shortening is
observed as the base moves toward the apex
during systole. This displacement can be ⬃2 cm
at baseline and increases during inotropic stimulation. However, because the imaged slice is fixed
with respect to the magnet co-ordinate system,
the images acquired at different heart phases do
not always represent the same piece of myocardium. This effect may cause tissue misregistration
when different SENC images are combined to
create cardiac strain images. Because the displacement is higher during peak stress, the absence of through-plane motion correction is expected to underestimate strain values to a higher
extent during stress, resulting in an underestimation of the calculated strain reserves. Throughplane motion tracking is, however, now available
with new implementations of the SENC pulse
sequence (15), which may allow for more accurate
estimation of strain in future studies.
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Circumferential Strain and Strain Rate During Intermediate Inotropic Stimulation
A
1.75
y = 0.9 + 0.2x - 0.6x2
r2 = 0.22
p < 0.001
Strain Reserve
1.50
B
p < 0.01
1.2
1.0
0.8
1.00
0.6
0.75
0.4
0.2
0.25
0.0
0%
20%
40%
C
2.75
Strain Rate Reserve
1.4
1.25
0.50
60%
80%
y =1.8 + 0.1x - 0.9x2
r2 = 0.30
p < 0.001
2.25
0%
100%
2.5
1- 20%
21- 40% 41- 60% 61- 80% 81-100%
D
p < 0.001
p < 0.001
2.0
1.75
1.5
1.25
1.0
0.75
0.5
0.25
0.0
0%
20%
40%
60%
80%
0%
100%
Stenosis Severity (%)
1- 20%
21- 40% 41- 60% 61- 80% 81-100%
Stenosis Severity (%)
Circumferential Strain and Strain Rate During Peak Inotropic Stimulation
1.75
E
y = 1.0 + 0.2x - 0.7x2
r2 = 0.37
p < 0.001
Strain Reserve
1.50
1.4
F
p<0.001
p<0.001
1.2
p<0.01
1.0
1.25
0.8
1.00
0.6
0.75
0.4
0.50
0.2
0.25
0.0
0%
20%
40%
G
4.0
60%
80%
0%
100%
y = 2.4 - 0.9x - 0.9x2
r2 = 0.56
p < 0.001
3.5
Strain Rate Reserve
368
3.0
3.5
1- 20%
p<0.001
p<0.001
H
p<0.001
3.0
p<0.001
p<0.05
2.5
2.5
21- 40% 41- 60% 61- 80% 81-100%
2.0
2.0
1.5
1.5
1.0
1.0
without WMA
with new WMA
0.5
0.5
0.0
0.0
0%
20%
40%
60%
80%
100%
Stenosis Severity (%)
0%
1- 20%
21- 40% 41- 60% 61- 80% 81-100%
Stenosis Severity (%)
Figure 4. Relation of Circumferential Strain and Strain Rate With Stenosis Severity
During both intermediate and peak stress, significant correlations were observed between stenosis severity and circumferential strain
reserve (SReserve) and strain rate reserve (SRReserve) (p ⬍ 0.001 for all) (A, C, E, and G). Circumferential SReserve decreased with ⬎80% and
⬎60% coronary lesions, respectively, during intermediate and peak stress, whereas SRReserve already decreased with ⬎60% and with
⬎40% diameter lesions (i.e., 1 stage earlier) (B, D, F, and H).
Emphasizing pathophysiologic aspects between myocardial strain response and lumen narrowing, the decrease of strain rate in our study
was shown to precede that of myocardial strain in
the ischemic cascade. Thus, SRReserve already
decreased with intermediate (40% to 60%) coronary lesions during peak stress, representing a
highly sensitive surrogate marker for regional
ischemia. In a similar setting and using myocardial perfusion imaging, Cullen et al. (16) previously demonstrated that regions with 40% to 60%
stenosis yield lower myocardial perfusion reserve
compared with those with ⬍40% stenosis,
whereas even regions supplied by ⬍40% coronary
Korosoglou et al.
SENC Detects CAD During Intermediate Stress
JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 4, 2010
APRIL 2010:361–71
A
Prediction of Coronary Stenosis
by Circumferential Strain
B
100
80
80
60
60
Sensitivity
100
40
Prediction of Coronary Stenosis
by Longitudinal Strain
40
AUC=0.74
AUC=0.81
AUC=0.81
AUC=0.96
20
AUC=0.65
AUC=0.79
AUC=0.82
AUC=0.97
20
0
0
0
20
40
60
80
100
0
20
100-Specificity
p = 0.08 for intermediate SReserve versus SRReserve
p < 0.001 for peak SReserve versus SRReserve
p < 0.001 for peak versus intermediate SReserve
p < 0.001 for peak versus intermediate SRReserve
intermediate SReserve
intermediate SRReserve
40
60
80
100
100-Specificity
p < 0.001 for intermediate SReserve versus SRReserve
p < 0.001 for peak SReserve versus SRReserve
p < 0.001 for peak versus intermediate SReserve
p < 0.001 for peak versus intermediate SRReserve
Peak Strain SReserve
Peak Strain SRReserve
Figure 5. Accuracy of Strain and Strain Rate to Detect CAD
Strain rate reserve (SRReserve) provided significantly higher accuracy than strain reserve for the detection of CAD (green and pink arrows
indicate significant increase in accuracy between strain and strain rate, during both intermediate and peak stress). Therefore, the highest
accuracies could be acquired by circumferential and longitudinal SRReserve during peak stress. Abbreviation as in Figure 1.
ence of “signal voids” in the reconstructed images
(yellow arrowheads in Figs. 1 and 2). However,
our initial observation is that the strain measurements are more robust against noise, even in
regions darker than the rest of the myocardium.
Thus, even in regions with such signal voids, the
estimation of regional myocardial strain is feasible. Generally, increased noise with SENC images is expected to decrease the range but not the
Angina
ECG Changes
Temporal Sequence of
Ischemic Events
lesions have decreased myocardial perfusion reserve as compared with normal volunteers. Because the versatility of magnetic resonance allows
for assessment of perfusion, wall motion, and
myocardial systolic and diastolic strain within a
single diagnostic stress test, and all without X-ray
exposure for the patient, the accuracy of each of
these separate markers for the detection of ischemia remains to be compared in future studies
(Fig. 6).
Our study has some limitations. Patients with
previous infarction were excluded in order to
avoid potential problems in the detection of
inducible ischemia resulting from hibernating or
stunned myocardium. This limits the extrapolation of our findings to such patients. Although
the total scanning time was similar for cine and
SENC sequences, cine images generally had
higher spatial and lower temporal resolution
compared with SENC, which is a limitation.
This may have accounted for the slightly lower
specificity of SENC to detect inducible ischemia
compared with cine imaging. In this regard,
recent studies have used higher spatial resolution
for cine imaging (17), which may further aid the
detection of ischemia during stress. Furthermore,
SENC is based on the stimulated echo acquisition mode technique, which inherently has a low
signal-to-noise ratio. This makes SENC more
susceptible to noise, which may cause the pres-
WMA on Cine Images
Reduced Systolic SReserve
Reduced Systolic SRReserve
Reduced Perfusion Reserve
Diastolic Dysfunction
Metabolic Alterations
Increasing Coronary Artery Stenosis Severity
Figure 6. Ischemic Sequence During Inotropic Stimulation
A potential temporal sequence of ischemic events during dobutamine stress cardiac
magnetic resonance is illustrated with increasing coronary artery stenosis severity.
This sequence includes the occurrence of metabolic alterations in the myocardium,
followed by diastolic dysfunction, perfusion abnormalities, alteration of myocardial
strain and strain rate, inducible wall motion abnormalities, and, at last, by the clinical
manifestation of angina pectoris in the course of the ischemic cascade.
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APRIL 2010:361–71
absolute values of estimated strain (which would
in the vivo setting give the wrong the impression
of inducible ischemia). Furthermore, observer
agreement was slightly lower for SENC compared with cine imaging. This may be attributed
to the extensive experience of the readers with
wall motion readings during stress, so that SENC
may have more potential for improving observer
variability in less trained readers, where differences in color might be easier to interpret than
the assessment of wall motion on cine images. In
addition, relatively high variability in strain and
strain rate was observed in segments without
coronary stenosis. This may be attributed to:
1) regional heterogeneity in baseline (18) and
recruitable myocardial strain (19) between different LV segments due to variations in transmural
fiber orientation and local differences in ventricular morphology (20); and 2) to technical limitations with the current implementation of the
SENC sequence in terms of temporal and particularly spatial resolution. In this regard, technically improved SENC sequences may reduce such
variability and allow for more accurate quantification of regional strain in future studies. Because
the color-encoded visualization of myocardial
strain is not feasible with the View Forum (Philips Medical Systems) software, currently no clinical decisions can be made during stress testing
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Key Words: myocardial strain
reserve y strain-encoded cardiac
magnetic resonance y
intermediate stress y inducible
ischemia.
‹APPENDIX
For an expanded Methods section, supplementary table, and supplementary figure, please
see the online version of this article.
371