Download Patients With Syndrome X Have Normal Transmural Myocardial

Patients With Syndrome X Have Normal Transmural
Myocardial Perfusion and Oxygenation
A 3-T Cardiovascular Magnetic Resonance Imaging Study
Theodoros D. Karamitsos, MD, PhD; Jayanth R. Arnold, DPhil; Tammy J. Pegg, DPhil;
Jane M. Francis, DCRR, DNM; Jacqueline Birks, MA, MSc; Michael Jerosch-Herold, PhD;
Stefan Neubauer, MD, FRCP, FMedSci; Joseph B. Selvanayagam, MBBS, DPhil, FRACP, FESC
Downloaded from http://circimaging.ahajournals.org/ by guest on November 2, 2016
Background—The pathophysiology of chest pain in patients with cardiac syndrome X remains controversial. Advances in
perfusion imaging with cardiovascular magnetic resonance (CMR) now enable absolute quantification of regional myocardial
blood flow (MBF). Furthermore, blood oxygen level-dependent (BOLD) or oxygenation-sensitive CMR provides the
unprecedented capability to assess regional myocardial oxygenation. We hypothesized that the combined assessment of
regional perfusion and oxygenation with CMR could clarify whether patients with syndrome X show evidence of myocardial
ischemia (reduced perfusion and oxygenation) during vasodilator stress compared with normal volunteers.
Methods and Results—Eighteen patients with syndrome X (chest pain, abnormal exercise treadmill test, normal coronary
angiogram without other causes of microvascular dysfunction) and 14 controls underwent CMR scanning at 3 T.
Myocardial function, scar, perfusion (2–3 short-axis slices), and oxygenation were assessed. Absolute MBF was
measured during adenosine stress (140 ␮g/kg per minute) and at rest by model-independent deconvolution. For
oxygenation, using a T2-prepared BOLD sequence, signal intensity was measured at adenosine stress and rest in the slice
matched to the midventricular slice of the perfusion scan. There were no significant differences in MBF at stress (2.35
versus 2.37 mL/min per gram; P⫽0.91), BOLD signal change (17.3% versus 17.09%; P⫽0.91), and coronary flow
reserve measurements (2.63 versus 2.53; P⫽0.60) in patients with syndrome X and controls, respectively. Oxygenation
and perfusion measurements per coronary territory were also similar between the 2 groups. More patients with syndrome
X (17/18 [94%]) developed chest pain during adenosine stress than controls (6/14 [43%]; P⫽0.004).
Conclusions—Patients with syndrome X show greater sensitivity to chest pain compared with controls but no evidence of
deoxygenation or hypoperfusion during vasodilatory stress. (Circ Cardiovasc Imaging. 2012;5:194-200.)
Key Words: ischemia 䡲 chest pain 䡲 microvascular angina 䡲 blood flow 䡲 oxygen
C
experience their typical chest pain during cardiac catheterization maneuvers (simple catheter movements or saline injection in the heart) has led several investigators to believe that
enhanced cardiac pain perception is a central component of
the pathophysiology of the syndrome.8,9
ardiac syndrome X is the presence of predominantly
effort-induced angina and ST-segment depression on
stress electrocardiography despite angiographically normal
coronary arteries.1 There has been substantial controversy
about whether myocardial ischemia is widely prevalent in
syndrome X.1 Some studies, using both invasive and noninvasive testing, have shown that both endothelium-dependent
and -independent coronary vasodilatation is reduced in some
patients with syndrome X, and up to 20% of patients have
metabolic evidence of myocardial ischemia.2– 4 In contrast,
other studies, especially those using stress echocardiography,
have shown normal global or regional contractile reserve
despite the provocation of typical symptoms.5–7 Moreover,
the observation that patients with syndrome X commonly
Clinical Perspective on p 200
Cardiovascular magnetic resonance (CMR) imaging permits assessment of both myocardial scar and myocardial
perfusion concurrently with high spatial resolution.10,11 CMR
during the first pass of an injected tracer permits assessment
of myocardial perfusion both at rest and during pharmacological stress and gives superior spatial resolution compared
with nuclear imaging methods.11 CMR perfusion results from
animal experiments have shown a strong correlation with
Received September 16, 2011; accepted January 25, 2012.
From the Department of Cardiovascular Medicine, Centre for Clinical Magnetic Resonance Research (T.D.K., J.R.A., T.J.P., J.M.F., S.N.), and Centre
for Statistics in Medicine (J.B.), University of Oxford, Oxford, UK; Department of Radiology, Brigham and Women’s Hospital, Boston, MA (M.J.-H.);
and Department of Cardiovascular Medicine, Flinders University, Flinders Medical Centre, Adelaide, SA, Australia (J.B.S.).
Guest Editor for this article was William Gregory Hundley, MD.
Correspondence to Theodoros D. Karamitsos, MD, PhD, Department of Cardiovascular Medicine, John Radcliffe Hospital, Headley Way, Headington,
Oxford OX3 9DU, UK. E-mail [email protected]
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
194
DOI: 10.1161/CIRCIMAGING.111.969667
Karamitsos et al
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microspheres for the assessment of blood flow,12 and we have
previously used this technique to report resting myocardial
blood flow (MBF) in patients with hibernating myocardium.13
Over the past decade, several investigators have reported on
CMR perfusion in cardiac syndrome X with conflicting results.
Panting et al,14 using semiquantitative perfusion analysis,
showed global subendocardial ischemia in patients with syndrome X; Lanza et al15 demonstrated regional perfusion defects
only in the left anterior descending coronary territory; and
Vermeltfoort et al16 found no differences between subendocardial and subepicardial perfusion. It should be noted, though, that
all 3 studies used visual or semiquantitative assessment of
myocardial perfusion. No study has yet used CMR to quantify
MBF in absolute terms in patients with syndrome X.17 Furthermore, the addition of blood oxygenation level-dependent
(BOLD) or oxygenation-sensitive CMR allows for the unprecedented capability to assess regional myocardial oxygenation,18 –20 providing a more direct measure of microvascular
dysfunction and ischemia than perfusion.
Using these novel and complementary techniques, the aim
of the present study was to quantify regional MBF and
oxygenation using CMR in patients with syndrome X and to
compare them with age-matched healthy volunteers. We
hypothesized that patients with syndrome X would demonstrate myocardial ischemia by impairment in both regional
perfusion and oxygenation as assessed by perfusion and
BOLD CMR, respectively.
Methods
Study Population
We recruited 18 patients with cardiac syndrome X and 14 controls.
The controls were healthy individuals with no history of chest pain
or other cardiovascular symptoms, had a normal 12-lead ECG and no
cardiovascular risk factors, and were not taking any medications. All
patients with cardiac syndrome X had a typical history of effortinduced angina and abnormal exercise electrocardiography, suggesting ischemia (ⱖ0.1 mV horizontal or downsloping ST-segment
depression 80 ms after the J point with chest pain during exercise).
All patients had undergone invasive x-ray coronary angiography,
showing angiographically smooth normal epicardial coronary arteries. The mean time from coronary angiography to CMR scan was
6⫾3 months. Despite the reassurance of a normal angiogram, all
patients continued to experience chest pain on exertion in the period
between the angiogram and the CMR scan. We excluded patients
with coronary spasm during the coronary angiography, diabetes
(defined by a fasting glucose level ⬎7.0 mmol/L), hypertension
(defined as blood pressure ⬎140/90 mm Hg), and left ventricular
(LV) hypertrophy (septum ⬎12 mm on CMR or echocardiography).
Other cardiac or systemic diseases were excluded based on clinical
history, physical examination, and routine laboratory tests. The study
protocol was approved by the Oxfordshire Research Ethics Committee, and all participants gave written informed consent.
CMR Scanning Protocol
CMR was performed on a 3-T system (TIM Trio; Siemens Healthcare). All participants were instructed to refrain from caffeinecontaining drinks and food in the 24 hours preceding the study.
Images were acquired with the patient supine, using anterior and
posterior phased-array surface coils. For cine CMR, from standard
pilot images, short-axis cine images covering the entire LV were
acquired using a retrospectively ECG-gated steady-state free precession sequence (echo time, 1.5 ms; repetition time, 3 ms; flip angle,
50°). For BOLD-sensitive CMR, a single midventricular slice was
acquired at mid-diastole using a T2-prepared ECG-gated steady-state
Perfusion and Oxygenation CMR in Syndrome X
195
free precession sequence (repetition time, 2.86 ms; echo time, 1.43
ms; T2 preparation time, 40 ms; matrix, 168⫻192; field of view,
340⫻340 mm; slice thickness, 8 mm; flip angle, 44°). Each BOLD
image was obtained during a single breath-hold over 6 heart beats. A
set of 4 to 6 images was acquired at rest and during peak adenosine
stress (140 ␮g/kg per minute). If necessary, shimming and center
frequency adjustments were performed before oxygenation imaging
to minimize off-resonance artifacts.
Immediately following stress BOLD-sensitive imaging (4 –5 minutes after commencing the adenosine infusion), a 0.04-mmol/kg
bolus of gadolinium-based contrast (gadodiamide; Omniscan; GE
Healthcare) was injected followed by 15 mL of normal saline at a
rate of 6 mL/s for first-pass perfusion imaging. During the first pass
of contrast, 2 to 3 short-axis images were acquired every cardiac
cycle using an ECG-gated T1-weighted fast gradient echo sequence
with generalized autocalibrating partially parallel acquisitions reconstruction (echo time, 0.96 ms; repetition time, 2 ms; saturation
recovery time, 95 ms; voxel size, 2.1⫻2.6⫻8 mm3; flip angle, 17o;
slice thickness, 8 mm; acceleration factor, 2; reference lines, 20;
temporal acquisition, 157 ms/slice for a typical 400⫻333-mm field
of view). The adenosine infusion was then discontinued, and after a
break of at least 20 minutes, the same sequence was repeated for
resting perfusion. Patients were instructed to hold their breath for as
long as possible in end expiration during perfusion imaging. For late
gadolinium enhancement CMR, a top-up bolus of 0.05 mmol/kg of
gadodiamide followed by a 15-mL saline flush was administered.
After a 5-minute delay, ECG-gated images were acquired in longand short-axis planes identical to those of the cine images by using
a breath-hold T1-weighted segmented inversion-recovery turbo fast
low-angle shot sequence as previously described.21 Heart rate and
blood pressure were recorded by a vital signs monitoring machine at
baseline and at 1-minute intervals during stress.
Each participant was questioned during and immediately after
termination of adenosine infusion about the occurrence of the
following adverse events: chest pain or tightness, shortness of breath,
and other minor symptoms (flushing, nausea, headache). Additionally, those participants who experienced chest pain or tightness
during the infusion of adenosine were asked to grade the severity of
pain on a scale from 1 (minimal pain) to 10 (maximum pain).
CMR Data Analysis
For each patient, LV volumes, ejection fraction, and mass were
calculated using Argus version VA60C software (Siemens AG) by
manually tracing the endocardial and epicardial contours in end-diastolic and end-systolic images as previously described.22 The
BOLD analysis has been previously published.18 Briefly, myocardial
signal intensity was measured after manually tracing the endocardial
and epicardial contours using QMass version 6.2.3 software (Medis
Medical Quantification Software). Each midventricular short-axis
BOLD image was divided into 6 segments (inferior septum, anterior
septum, anterior, anterolateral, inferolateral, and inferior) according
to the middle slice 6 segments of the American Heart Association
17-segment model.23 Mean signal intensities were calculated for
resting and stress conditions by averaging signal measurements from
images during rest and adenosine stress, respectively. BOLD signal
intensity measurements were corrected for variations in heart rate
between resting and stress as previously described.18
For analysis of myocardial perfusion, signal intensity curves were
generated by tracing endocardial and epicardial contours (QMass
version 6.2.3 software) as previously described.24 Based on the
American Heart Association segmentation model,23 the myocardium
was divided into equiangular segments (6 for basal and midventricular slices and 4 for apical slices), and a region of interest was placed
at the center of the LV cavity to measure the arterial input of
contrast. The 3 contours (epicardial, endocardial, LV blood pool)
were drawn on a single image and propagated automatically throughout the perfusion series. Each image was then checked for positioning, and if necessary, contours were manually corrected for respiratory movement.
Absolute MBF (in milliliters per minute per gram) was calculated
for each myocardial segment by model-independent deconvolution
196
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March 2012
of myocardial and arterial input signal intensity curves.25 Each
myocardial segment was ascribed a coronary artery territory according to previously described standard criteria.26 To account for
cardiac workload, we corrected resting MBF for the rate pressure
product (RPP), an index of myocardial oxygen consumption, as
follows: MBF⫽(MBF/RPP)⫻104.27 Coronary flow reserve was
calculated as the ratio of MBF during adenosine-induced hyperemia
to MBF at rest corrected for RPP.28 In addition to quantitative
analysis, perfusion images were analyzed qualitatively. If an endocardial dark band appeared at the arrival of the contrast in the LV
cavity and before contrast arrival in the myocardium, this was
considered an artifact. By definition, these artifacts were present
during both rest and stress studies. Regions with reduced contrast
uptake during stress were defined as perfusion defects only if they
persisted for more than 5 frames and were absent at rest; otherwise,
they were considered to be artifacts. For late gadolinium enhancement images, qualitative (visual) analysis was performed.
Table 1.
Baseline Characteristics
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Patients With
Syndrome X
(n⫽18)
Healthy
Controls
(n⫽14)
P
Female sex
15 (83)
11 (79)
1.00
Age, y
62⫾8
58⫾6
0.25
Weight, kg
73⫾8
71⫾9
0.44
Height, cm
167⫾7
170⫾7
0.26
BSA, m2
1.84⫾0.13
1.82⫾0.13
0.75
26⫾2
24⫾3
0.064
End-diastolic volume, mL
121⫾24
136⫾24
0.10
End-systolic volume, mL
34⫾10
45⫾10
0.008
Ejection fraction, %
72⫾5
67⫾5
0.014
Statistical Analysis
Maximum wall thickness, mm
9.1⫾1.4
8.8⫾1.0
0.18
Data analysis was performed with commercially available software
packages (SPSS, version 17.0 for Windows, STATA version 10.0,
and MedCalc version 11.5). All continuous variables were normally
distributed (Kolmogorov-Smirnov test). The ␹2 test or Fisher exact
test was used to compare discrete data, as appropriate. Linear mixed
models were used to analyze perfusion and oxygenation CMR
measurements, taking into account the correlation between measurements on the same participant. Unpaired t tests were used to compare
the hemodynamic response of controls and patients with syndrome X
during the CMR scans. Statistical tests were 2 tailed, and P⬍0.05
was considered to indicate statistical significance.
Mass, g
79⫾20
91⫾25
0.14
Results
All 14 controls and 18 patients with syndrome X completed
the study protocol. The 2 groups were similar in age and sex
distribution. With respect to LV function, patients with
syndrome X had a slightly increased ejection fraction (72%
versus 67%, P⫽0.014), most likely reflecting a mildly
increased sympathetic state. LV mass and wall thickness
measurements were similar in the 2 groups and within normal
limits. There were no statistical differences in lipid and
glucose levels between patients and controls. All patients
with syndrome X received were taking least 1 medication;
some patients were taking ⬎1 medication. Table 1 presents
participant baseline characteristics.
Hemodynamic Response to Adenosine
The duration of adenosine infusion was similar for patients
with syndrome X and controls (297 versus 278 s, P⫽0.09).
Patients and controls demonstrated a similar rise in heart rate
and RPP during adenosine stress. Specifically, the heart rate
increased by an average of 30 beats/min in controls versus 29
beats/min in patients (P⫽0.68). The mean change in RPP
between stress and rest was 3576 in controls and 4352 in
patients with syndrome X (P⫽0.26). Table 2 summarizes
participant hemodynamic parameters.
Pain Perception
Seventeen of the 18 (94%) patients with syndrome X developed chest pain during the infusion of adenosine, whereas
only 6 (43%) controls experienced chest pain (P⫽0.004). The
mean chest pain score was 5.4 for patients with syndrome X,
indicating that the pain was at least of moderate severity. By
contrast, the mean score for controls was 1.7, indicating that
the pain was only mild.
BMI, kg/m2
Left ventricular analysis
Blood tests
Total cholesterol, mmol/L
4.89⫾0.61
5.03⫾0.49
0.50
HDL, mmol/L
1.39⫾0.37
1.46⫾0.28
0.58
LDL, mmol/L
3.08⫾0.85
3.13⫾0.50
0.83
Triglycerides, mmol/L
1.13⫾0.36
0.98⫾0.49
0.34
Glucose, mmol/L
5.22⫾0.56
5.05⫾0.54
0.41
␤-blocker
5 (28)
0 (0)
Calcium channel blocker
8 (44)
0 (0)
Nitrate
8 (44)
0 (0)
ACE inhibitor
4 (22)
0 (0)
Statin
7 (39)
0 (0)
Hormone replacement
2 (11)
0 (0)
Medications
Data are presented as n (%) or mean⫾SD. One patient received no
treatment, and some patients received ⬎1 medication.
BSA indicates body surface area; BMI, body mass index; HDL, high-density
lipoprotein; LDL, low-density lipoprotein; ACE, angiotensin-converting enzyme.
Qualitative Perfusion and Late Gadolinium
Enhancement Analysis
Only 1 patient with syndrome X (7 frames) and 1 control (6
frames) had regional or circumferential areas of hypoenhancement lasting ⬎5 frames on visual analysis of stress perfusion
images, but similar areas of hypoenhancement were seen on
their resting scans and, therefore, considered to be artifacts.
Overall, 10 (55%) patients with syndrome X and 4 (29%)
controls showed areas of short-lived regional or circumferential
hypoenhancement (P⫽0.54), which were considered to be
artifacts. None of the patients and controls had evidence of late
gadolinium enhancement in any myocardial segment.
Absolute Myocardial Perfusion and
Oxygenation Measurements
The variance of MBF measurements at stress was not equal
between the 2 groups (variance ratio, 1.68; P⬍0.001 with F
test). This was taken into account on the comparison of mean
MBF, which revealed no significant differences in mean
resting MBF or hyperemic MBF postadenosine stress between controls and patients with syndrome X (Table 3).
Similarly, there were no differences in coronary flow reserve
values between the 2 groups (P⫽0.60). The variance of
Karamitsos et al
Table 2.
Perfusion and Oxygenation CMR in Syndrome X
197
Hemodynamic Data at Rest and During Adenosine Infusion for the Study Population
Patients With Syndrome X
Rest
Heart rate, beats/min
70⫾13*
Systolic blood pressure, mm Hg
130⫾14
Diastolic blood pressure, mm Hg
75⫾9
Rate pressure product, beats/min⫻mm Hg
9110⫾1896*
Stress
99⫾17
136⫾18
75⫾11
13 462⫾3161
Healthy Controls
Rest
66⫾10†
123⫾11
77⫾8
Stress
95⫾14
122⫾15
71⫾10
8009⫾1350†
11 586⫾2204
Data are presented as mean⫾SD.
*P⬍0.05 for comparison between hemodynamic parameters at rest and stress (patients with syndrome X).
†P⬍0.05 for comparison between hemodynamic parameters at rest and stress (healthy controls).
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BOLD-sensitive signal intensity measurements was similar
for patients and controls (variance ratio, 1.10; P⫽0.65 with
F test). There were no differences in global oxygenation
measurements between controls and patients (P⫽0.91).
Figure 1 shows a representative example (midventricular shortaxis slice) of perfusion and oxygenation in 1 patient with
syndrome X.
Analysis per Coronary Artery Territory
To explore whether patients with syndrome X demonstrate
perfusion abnormalities in specific coronary artery territories,
as some previous studies suggested for the left anterior descending coronary artery, we analyzed MBF and BOLD signal
intensity change measurements on a per-coronary artery basis.
These demonstrated that resting MBF, stress MBF, and coronary
Table 3. Perfusion and Oxygenation Measurements in
Patients With Syndrome X and Healthy Controls
Patients With
Syndrome X
(n⫽18)
Healthy
Controls
(n⫽14)
P
Global analysis
Rest (corrected) MBF, mL/min per g
0.93⫾0.040
0.96⫾0.035 0.55
Stress MBF, mL/min per g
2.35⫾0.10
2.37⫾0.11
0.91
2.63⫾0.12
2.53⫾0.13
0.60
17.30⫾1.22
17.09⫾1.38
0.91
CFR
BOLD SI change, %
Analysis per coronary artery
Left anterior descending coronary artery
Rest (corrected) MBF, mL/min per g
0.96⫾0.036
Stress MBF, mL/min per g
2.40⫾0.10
2.42⫾0.12
0.84
CFR
2.57⫾0.12
2.54⫾0.14
0.86
16.69⫾1.35
17.37⫾1.54
0.74
BOLD SI change, %
0.98⫾0.041 0.73
Left circumflex coronary artery
Rest (corrected) MBF, mL/min per g
0.93⫾0.039
Stress MBF, mL/min per g
2.31⫾0.11
2.34⫾0.12
0.73
CFR
2.61⫾0.13
2.52⫾0.15
0.66
18.88⫾2.04
18.22⫾2.32
0.81
BOLD SI change, %
0.95⫾0.044 0.73
Right coronary artery
Rest (corrected) MBF, mL/min per g
0.87⫾0.037
0.93⫾0.042 0.29
Stress MBF, mL/min per g
2.31⫾0.10
2.30⫾0.12
0.94
2.73⫾0.13
2.53⫾0.14
0.30
17.44⫾1.48
16.10⫾1.68
0.55
CFR
BOLD SI change, %
Data are presented as mean⫾SE.
CFR indicates coronary flow reserve; BOLD, blood oxygen level dependent;
SI, signal intensity; MBF, myocardial blood flow.
flow reserve measurements showed no differences between
controls and patients with syndrome X on any of the 3 major
coronary artery territories. Similarly, oxygenation measurements
per coronary artery were similar in controls and patients. This
analysis is shown in Table 3 and Figure 2.
Discussion
Using quantitative perfusion and oxygenation-sensitive CMR
imaging, the present study shows that although patients with
syndrome X demonstrate a higher variance of perfusion
measurements, this is not translated into deoxygenation and
myocardial ischemia during vasodilatory stress. Furthermore,
visual assessment of CMR perfusion images revealed no
convincing regional or circumferential perfusion defects. The
study findings may have important implications for understanding the pathophysiology of chest pain in patients with
cardiac syndrome X and for understanding the relationship
between MBF and oxygenation in this condition.
To the best of our knowledge, this study is the first to use
a validated quantitative CMR technique to concurrently
examine myocardial perfusion and oxygenation in patients
with syndrome X; the only study to date to report quantitative
MBF in syndrome X using CMR (either at 1.5 or 3 T); and the
first CMR perfusion study of any description in this condition
at the higher field of 3 T, which is considered superior to 1.5
T for perfusion assessment.29,30 A major strength of the
present study is that we quantitatively assessed not only
regional myocardial perfusion, but also oxygenation in patients with syndrome X using the BOLD technique at 3 T. As
we recently showed in patients with coronary artery disease,
oxygenation-sensitive CMR at 3 T can identify not only
deoxygenated myocardial segments subtended by stenosed
vessels, but also segments with microvascular dysfunction
and intermediate signal intensity changes to adenosine stress
compared to controls.18 In the present study, we found that
the stress oxygenation response seen in the patients was
entirely within the normal range of the age-matched controls
and that there was no impairment in myocardial oxygenation
during vasodilatory stress either in the ischemic range or in
the microvascular dysfunction range. This finding gives
weight to our perfusion findings that substantial myocardial
ischemia, microvascular dysfunction, or both is not occurring
in these patients, at least during vasodilatory stress.
Previous CMR studies using semiquantitative perfusion
assessment at 1.5 T have given conflicting results. Panting
and colleagues14 found that although transmural myocardial
perfusion reserve index was similar between patients with
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March 2012
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Figure 1. Example of perfusion and oxygenation in a patient with syndrome X. A,
Blood oxygen level-dependent-sensitive
image at rest. B, Blood oxygen leveldependent-sensitive image at stress. After
correction for heart rate differences
between stress and rest, the signal intensity change ranged from 12% to 19% for
all myocardial segments. C, Corresponding late gadolinium enhancement image
showing no evidence of scarring or fibrosis. D, Still image of the stress perfusion
scan showing circumferential subendocardial hypoenhancement. This could be
mistakenly regarded as evidence of subendocardial ischemia. E, Still image of the
same scan just 5 frames later without evidence of hypoenhancement, indicating
that this was an artifact. Regional hyperemic blood flow measurements were normal and ranged from 2.4 to 3.4 mL/min
per gram. F, Still image of the rest perfusion scan.
syndrome X and controls, in patients, the subendocardial
myocardial perfusion index did not increase with adenosine.
Therefore, Panting et al concluded that patients with syndrome X have subendocardial hypoperfusion. In contrast,
Vermeltfoort and colleagues,16 using the same technique of
semiquantitative perfusion assessment, found that patients
with syndrome X show similar response to adenosine in both
the subendocardium and subepicardium. Finally, Lanza and
colleagues,15 using dobutamine stress perfusion CMR with
semiquantitative analysis and coronary Doppler during adenosine, found myocardial hypoperfusion with significantly
reduced coronary flow reserve in only the left anterior
descending coronary artery territory. One reason for the
discrepant findings is the different inclusion and exclusion
criteria, which resulted in different study populations. For
example, Lanza et al included patients with hypertension,
hypercholesterolemia, and active smoking history, all of
which are well-known causes of microvascular dysfunction.
However, the classic definition of syndrome X excludes
patients with cardiac or systemic diseases that adversely
affect microcirculation.1 Additionally, the classic definition
of syndrome X calls for an abnormal exercise test with at least
0.1-mV horizontal or downsloping ST-segment depression at
80 ms after the J point. Recently, a modified definition of
syndrome X that includes evidence of ischemia in any
diagnostic testing (exercise stress test, single-photon emission
CT, CMR, PET, or Doppler ultrasound) has been proposed.31
On the basis of this definition, the majority (80%) of patients
with syndrome X in the study by Vermeltfoort et al had
reversible perfusion defects in single-photon emission CT
and not an abnormal exercise ECG.
In the present study, we used strict inclusion and exclusion
criteria based on the classical definition of syndrome X,
including only patients with effort-induced chest pain and
Figure 2. Stress perfusion and oxygenation measurements per coronary artery. Error bars are ⫾SE. BOLD indicates blood oxygen
level-dependent; MBF, myocardial blood flow.
Karamitsos et al
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abnormal exercise ECG in the absence of any cardiac or
systemic diseases that can potentially cause microvascular
dysfunction. Importantly, almost all the patients continued to
have anginal symptoms even after the reassurance of a
normal angiogram. Another possible reason for the discrepant
results between our study and previous CMR studies is the
different stress agent used. For example, Lanza and colleagues15 used dobutamine and not adenosine stress to assess
myocardial perfusion. It is well-known that dobutamine stress
is associated with increased heart rate response (compared to
adenosine) and greater cardiac motion, which exacerbates
artifacts in regions perpendicular to the phase-encoding
direction (eg, septum). This is one likely explanation of why
Lanza et al found a high incidence of perfusion defects in the
left anterior descending coronary artery territory. In contrast,
Vermeltfoort et al16 used adenosine stress as we did and did
not find evidence of hypoperfusion.
The present results agree with previous PET studies that
quantitatively assessed myocardial perfusion and found no
evidence of hypoperfusion during vasodilator stress in patients with syndrome X compared with controls.9,32 Although
the CMR perfusion sequence we used resulted in greatly
improved spatial resolution (2.6 versus ⬇8.4 mm with PET),
transmural hypoperfusion was not evidenced. Previous PET
studies reported a wide dispersion of MBF values after
dipyridamole stress in patients with syndrome X.32 Interestingly, although we also found a dispersion of stress perfusion
measurements in patients with syndrome X, there was no
corresponding variation of deoxygenation at stress, indicating
that true myocardial ischemia was not present. Another rather
universal finding in studies of patients with syndrome X and
vasodilator stress is that the perception of pain is enhanced in
patients compared with healthy controls,9,14 a finding that we
also confirm in the present cohort. Several studies reproduced
typical chest pain in patients with syndrome X with stimulus
to the right side of the heart, including right atrial saline
infusion and right ventricular pacing.8,33 In these studies,
chest pain may have resulted from mechanical distortion of
mechanoreceptors to catheter stimulation. Rosen and colleagues34 showed that altered ventral neural handling of afferent
signals may contribute to the abnormal pain perception in these
patients. Autonomic nervous system imbalance with increased
adrenergic activity and impaired parasympathetic tone could
explain both increased pain sensitivity and endothelial dysfunction.34,35 More recently, Valeriani et al36 investigated abnormalities in electric cerebral signals to pain stimuli and found
decreased habituation to repetitive noxious stimuli in patients
with cardiac syndrome X. In the present study, the majority of
patients with syndrome X reported chest pain of moderate extent
during adenosine stress. In contrast, the frequency and extent of
chest pain was much reduced in controls.
Limitations
The present study has some limitations. First, we measured
only transmural perfusion and not subendocardial versus
subepicardial MBF. Therefore, subendocardial hypoperfusion
may have been missed. However, the resolution of the
technique in conjunction with the relatively low-normal
myocardial wall thickness in the predominantly female pa-
Perfusion and Oxygenation CMR in Syndrome X
199
tients precluded performing separate analyses for subendocardial versus other myocardial layers. Recently, highresolution CMR perfusion techniques have been developed at
3 T with ⬇1-mm in-plane resolution that will likely enable
reliable assessment of subendocardial versus subepicardial
perfusion.37 However, even if subtle differences in subendocardial perfusion existed in our cohort, these did not result in
myocardial deoxygenation, and therefore, true tissue ischemia was not present. Second, the sample size was small;
however, as previously described, we applied strict inclusion
and exclusion criteria and made every possible effort to
recruit only patients with true syndrome X. None of the
patients had cardiac or systemic diseases associated with
microvascular dysfunction. Finally, the majority of the patients were women; therefore, the findings may not apply to
male patients with syndrome X, who are rather rare.
Conclusions
Using CMR imaging with absolute quantification of MBF
and oxygenation measurements with the BOLD technique,
patients with syndrome X have no evidence of transmural
hypoperfusion or deoxygenation during vasodilatory stress
but show greater sensitivity to chest pain compared with
healthy controls. Further confirmation of our findings in
larger-scale studies is needed.
Acknowledgments
We thank Ruairidh Howells and Dr Matthew Robson for their help
with the technical development of the BOLD sequence.
Sources of Funding
This work was supported by a British Heart Foundation project grant
(PG/08/101/26126). The authors also acknowledge support from the
National Institute for Health Research Oxford Biomedical Research
Centre Programme. Dr Neubauer acknowledges support from the
Oxford British Heart Foundation Centre for Research Excellence.
Disclosures
None.
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CLINICAL PERSPECTIVE
The pathophysiology of chest pain in patients with syndrome X (chest pain, abnormal exercise treadmill test, normal
coronary angiogram) remains controversial. Previous studies using nuclear techniques or cardiovascular magnetic
resonance to assess myocardial perfusion have shown conflicting results. Other studies suggest that abnormal pain
perception is a central component of the pathophysiology of this enigmatic syndrome. We used cardiovascular magnetic
resonance to quantitatively assess regional myocardial blood flow and oxygenation during vasodilatory stress (adenosine)
in patients with syndrome X and healthy controls. The findings indicate that patients with syndrome X have no evidence
of transmural hypoperfusion or deoxygenation but a greater incidence of chest pain during vasodilatory stress compared
with controls. Studies using high-resolution perfusion cardiovascular magnetic resonance (⬍1-mm in-plane resolution) are
needed to further investigate subendocardial and subepicardial perfusion in these patients.
Patients With Syndrome X Have Normal Transmural Myocardial Perfusion and
Oxygenation: A 3-T Cardiovascular Magnetic Resonance Imaging Study
Theodoros D. Karamitsos, Jayanth R. Arnold, Tammy J. Pegg, Jane M. Francis, Jacqueline
Birks, Michael Jerosch-Herold, Stefan Neubauer and Joseph B. Selvanayagam
Downloaded from http://circimaging.ahajournals.org/ by guest on November 2, 2016
Circ Cardiovasc Imaging. 2012;5:194-200; originally published online February 8, 2012;
doi: 10.1161/CIRCIMAGING.111.969667
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue,
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Correction
In the article by Karamitsos et al, “Patients With Syndrome X Have Normal Transmural Myocardial Perfusion and Oxygenation: A 3-T Cardiovascular Magnetic Resonance Imaging Study,”
which appeared in the March 2012 issue of the journal (Circ Cardiovasc Imaging. 2012;5:194–
200), there is an error in Figure 2. The y axis of the graph on the left should be labeled “Stress
MBF (mL/min per g)”
This error has been corrected in the current online version of the article, which is available at:
http://circimaging.ahajournals.org/content/5/2/194.full.
 (Circ Cardiovasc Imaging. 2012;5:e56.)
© 2012 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
e56
DOI: 10.1161/HCI.0b013e318263d7b0