113

Metabolic Planar Imaging Using 123I-β-Methyl-Iodophenyl Pentadecanoic Acid Identifi es Myocardial Ischemic Memory

After Intracoronary Acetylcholine Provocation Tests in Patients With Vasospastic Angina

Kihei Yoneyama,1 MD, Yoshihiro J. Akashi,

1 MD, Keisuke Kida,

1 MD,

Kohei Ashikaga,1 MD, Haruki Musha,

2 MD, Kengo Suzuki,

1 MD,

Tomoo Harada,1 MD, and Fumihiko Miyake,

1 MD

Summary

The aim of this study was to determine the diagnostic accuracy of early/delayed 123

I-β-methyl-iodophenyl pentade-

canoic acid (123

I-BMIPP) planar images to detect disrupted fatty acid metabolism in patients with vasospastic angina

(VSA). Heart-to-mediastinum (H/M) ratios and washout rates were calculated from early and late (15 minutes and 4

hours after tracer injection, respectively) planar 123

I-BMIPP images from 13 hypertensive control individuals (mean age,

69.5 years) and 37 patients with VSA (mean age, 62.8 years) 10.5 (mean) days after administering the intracoronary ace-

tylcholine provocation test. Patients with VSA had signifi cantly lower early H/M and delayed H/M ratios (early; 2.2 ± 0.3

versus 2.7 ± 0.5, P = 0.007; delayed: 1.8 ± 0.3 versus 2.4 ± 0.4, P < 0.001) and signifi cantly greater washout rates (39.8

± 11.8% versus 29.3 ± 11.7%, P = 0.011) than controls. The overall area under the curve defi ning the accuracy of diag-

nostic performance was 0.76 (95% confi dence interval (CI): 0.59-0.92) and 0.85 (95% CI, 0.73-0.98) for the early and

delayed H/M ratios and 0.74 (95% CI, 0.73-0.90) for washout rates. Planar 123

I-BMIPP imaging can diagnose coronary

artery spasm with acceptable diagnostic performance and indicates that the delayed H/M ratio has a powerful ability to

assess recent ischemia. This technique might be useful in the face of apparently normal coronary angiographic fi ndings

during the subacute and chronic phases after ischemic events. (Int Heart J 2014; 55: 113-118)

Key words: Acute coronary syndrome, Angina pectoris, Angiography, Cardiac catheterization, Cardiovascular disease,

Coronary angiography, Heart, Ischemic heart disease, Myocardial ischemia, Variant angina

F atty acid metabolism is a major pathway of energy pro-

duction in the normally perfused myocardium.

Ischemia caused by reduced coronary blood fl ow shifts

the substrate, which elevates glucose uptake (anaerobic) while

fatty acid uptake remains reduced (aerobic).1) The persistence

of altered fatty acid metabolism even after the restoration of

blood flow is termed ischemic memory.2)

123

I-β-methyl-

iodophenyl pentadecanoic acid (123

I-BMIPP) is a useful tracer

with which to identify myocardial ischemic memory because

of its high myocardial uptake and prolonged retention.3-5)

Im-

aging using 123

I-BMIPP single-photon emission computed to-

mography (SPECT) can detect vasospasm more accurately

than rest-exercise tetrofosmin scintigraphy5) and defects on

123I-BMIPP SPECT images disappear from patients with va-

sospastic angina (VSA) who respond well to therapy.4) The in-

tracoronary acetylcholine (ACH) provocation test is the stand-

ard procedure for diagnosing VSA 6,7)

despite this test being

invasive and complications such as sustained ventricular tachy-

cardia, shock and cardiac tamponade occasionally arise.8-10)

Takagi, et al have reported ventricular tachycardia/fi brillation

developed at a rate of 3.2% during the provocation test in a na-

tionwide multicenter Japanese registry in patients with VSA.11)

Thus, a noninvasive test should be established to identify va-

sospastic angina. Global myocardial fatty acid metabolism as-

sessed by 123

I-BMIPP using planar imaging is useful, and the

severity of myocardial dysfunction is accurately reflected in

the delayed heart-to-mediastinum (H/M) ratio in patients with

heart disease.12,13)

However, whether or not planar 123

I-BMIPP

imaging can accurately detect disrupted fatty acid metabolism

in patients with VSA has not been fully evaluated. The present

study attempted to determine whether or not 123

I-BMIPP-pla-

nar imaging can detect abnormal fatty acid metabolism after

ischemic attack caused by coronary artery spasm.

Methods

Study participants: We initially enrolled 49 patients with

From the 1 Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine and

2 Department of Cardiology, St. Marianna Uni-

versity Yokohama-city Seibu Hospital, Kanagawa, Japan.

Address for correspondence: Kihei Yoneyama, MD, Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1,

Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. E-mail: kyoneya1@gmail.com

Received for publication July 2, 2013. Revised and accepted September 24, 2013.

Released advance online J-STAGE March 14, 2014.

All rights are reserved to the International Heart Journal Association.

114Int Heart J

March 2014YONEYAMA, ET AL

VSA who were admitted to the St. Marianna University School

of Medicine Hospital between April 2007 and August 2009.

We defi ned VSA as chest pain at rest with or without ST seg-

ment changes and ≥ 90% luminal narrowing in the ACH prov-

ocation test. Among the study patients, 12 were excluded due

to problems with the ACH provocation test (n = 2), abnormal

Q waves in electrocardiograms (n = 2), left ventricular ejection

fraction (LVEF) < 50% (n = 2), refusal to participate (n = 5),

and untreated renal cancer (n = 1). Therefore, 37 patients with

VSA including 10 (27%) current smokers were included in the

study. The patients were basically treated with sublingual fast-

and short-acting nitrates (nitroglycerin) for ischemic attack af-

ter the test. Of these, 40.5% who were prescribed calcium an-

tagonists before enrolment could continue them during the

study period. Calcium antagonists were withdrawn at least 48

hours before the ACH provocation test to ensure its validity.

This study included 13 hypertensive volunteers as controls

who underwent exercise stress testing using a treadmill to con-

fi rm the absence of ischemic ST-T changes. Hypertension was

defi ned as a systolic blood pressure of 140 mmHg or a diastol-

ic blood pressure DBP of 90 mmHg or receiving antihyperten-

sive therapy. Individuals with structural heart diseases were ex-

cluded from the study based on echocardiographic findings.

This study was performed in accordance with the ethical prin-

ciples established in the Declaration of Helsinki. The St. Mari-

anna University School of Medicine Institutional Committee

on Human Resources (Kawasaki, Japan) approved the study

protocol. The nature and purpose of the study and the risks in-

volved were fully explained to all participants, who then pro-

vided written informed consent to participate in all procedures

associated with the study.

Provocation test for coronary vasospasm: Two experts per-

formed multidirectional coronary angiography in all patients

with VSA using a Judkins catheter. A temporary pacing lead

was inserted into the right ventricle of each patient and set at a

pacing rate of 40 beats/min. An incremental dose of ACH was

injected every 30 seconds (up to 50 and 100 μg into the right

and left coronary arteries, respectively). Coronary arteriogra-

phy was performed if the ST segment changed and/or chest

pain developed at 3 minutes after each injection. Induced coro-

nary vasospasm that did not spontaneously terminate was re-

leased by administering isosorbide dinitrate (1 - 2 mg) via the

intracoronary catheter. The provocation test proceeded to the

contralateral coronary artery even when right coronary artery

spasm was induced. We defi ned VSA as luminal diameter nar-

rowing of ≥ 90%.123I-BMIPP myocardial scintigraphic images: 123

I-BMIPP im-

ages were typically acquired two weeks after the ACH provo-

cation test (mean, 10.5 days). Planar images were acquired at

15 minutes (early) and at 4 hours (delayed) after injecting 123

I-

BMIPP (111 MBq; Nihon Medi-Physics, Tokyo) into the left

antecubital vein. Before the SPECT study, we acquired anteri-

or and lateral planar images for 90 seconds using a double-

head gamma camera (E.CAM Duet, Toshiba Medical, Tokyo)

with a low-energy and general-purpose collimator, as well as a

gamma camera with a low-energy, general-purpose collimator

and a 256 × 256 matrix. Two detectors (2 × 180°) acquired 60

views for 19 seconds in 6° increments using a 64 × 64 matrix.

Energy discrimination was centered at 160 keV with a 20%

window. Transaxial images were reconstructed after filtered

back projection using a Butterworth fi lter (order 8; cut-off fre-

quency 0.27 cycles/pixel) combined with a ramp fi lter. Hori-

zontal long-axis, vertical long-axis, and short-axis slices were

generated after reorienting the axes.

Blood sampling and echocardiography: Blood samples were

collected before breakfast. Brain natriuretic peptide (BNP) was

measured using a fl uorescent enzyme immunoassay and total

cholesterol, triglycerides, high-density lipoprotein cholesterol,

low-density lipoprotein cholesterol, and HbA1c were meas-

ured using standard assays. Left ventricular volume and LVEF

were calculated by Simpson’s rule using echocardiography

(Aplio®, Toshiba, Tokyo) with a 3.5 MHz transducer.

Data analysis: Regions of interest (ROI) were drawn over the

entire heart and upper mediastinum in the anterior planar im-

ages. The H/M ratio and washout rate (WR) of 123

I-BMIPP

were calculated based on ROI counts as:

H/M = mean pixel count of cardiac ROI/mean pixel count

of mediastinal ROI and

WR (%) = [(mean early − mean delayed cardiac pixel

count)/mean early cardiac pixel count] × 100.

We calculated WR without background and/or time de-

cay correction.12-14)

Regional tracer uptake was assessed using

a 5-point scoring system (0, normal; 1, slightly reduced; 2,

mildly reduced; 3, severely reduced; 4, no uptake) on the early

and delayed SPECT images.15)

The left ventricular myocar-

dium was divided into 17 segments corresponding to the vas-

cular territories of the 3 major coronary arteries. The total de-

fect score (TDS) was calculated as the sum of all defect scores.

Two experienced nuclear cardiologists independently inter-

preted the images. We concluded that abnormal uptake corre-

sponded to coronary territories after finalizing all measure-

ments from regional uptake and conventional coronary

angiograms.

Statistical analysis: Data are expressed as the mean ± standard

deviation. Continuous values and categorical variables between

the two groups were compared using the t test and the χ2 test,

respectively. The overall performance of receiver operating

characteristic (ROC) analysis was determined by measuring

the area under the curve (AUC). Standardized values were de-

fi ned by dividing the differences between the observed values

and the sample means by the corresponding standard devia-

tion.16)

Smoothing curves were computed by LOWESS regres-

sion in STATA statistical software (Version 11. College Sta-

tion, TX, USA). The estimated nonparametric curves were

plotted with connect. The level of statistical signifi cance was

set at P < 0.05. All data were analyzed using STATA statistical

software Version 11.

Results

The baseline clinical characteristics in the control and

VSA groups (Table I) were similar except for the rate of hy-

pertension. Blood chemistry, blood pressure, and LVEF did not

differ signifi cantly between the two groups (all P > 0.1). None

of the patients had coronary stents or a > 50% obstructive le-

sion in any vessel. Among the patients with VSA, 24 and 13

had single (65%) and multivessel (35%) spasm, respectively.

The TDS did not differ signifi cantly between the early stand-

ard and delayed images (TDS, 8.3 ± 1.0 versus 8.9 ± 1.1, P =

0.334). Abnormalities in the early (n = 24, 65%) and delayed (n

= 27, 73%) SPECT images corresponded to the coronary ar-

115Vol 55

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I-BMIPP IN VASOSPASTIC ANGINA

tery territories.Early and delayed ratios of H/M and WR assessed by planar imaging: Figure 1 shows the early and delayed H/M ratios

and WR in the control and VSA groups. The early and delayed

H/M ratios signifi cantly differed between the control and VSA

groups (early: 2.7 ± 0.5 versus 2.2 ± 0.3, P = 0.007; delayed:

2.4 ± 0.4 versus 1.8 ± 0.3, P < 0.001). The WR was signifi -

cantly greater in the VSA group (39.8 ± 11.8%) than in the

control group (29.3 ± 11.7%, P = 0.011). Figure 2 shows the

relationship between SPECT with H/M ratios and WR in pa-

tients with VSA using a local linear smoothing curve. The

TDS did not linearly correlate with early or delayed H/M ratios

(A) or with WR (B). The H/M ratios decreased and WR in-

creased at higher TDS values. However, the H/M ratios were

lower and WR were greater at very low TDS values. The early

TDS greater than 7 consisted of 79% single spasms while TDS

greater than 10 consisted of 84.6% single spasms.

Diagnosis of VSA based on planar images: Table II and Figure

3 show the diagnostic performance of 123

I-BMIPP planar imag-

ing. The overall AUC defi ning the accuracy of diagnostic per-

formance was 0.76 (95% confi dence interval (CI): 0.59-0.92)

and 0.85 (95% CI, 0.73-0.98) for the early and delayed H/M

ratios and 0.74 (95% CI, 0.73-0.90) for washout rates. The

AUC for the delayed H/M ratios in the subacute (≤ 14 days)

and chronic phases (15 – 30 days) were 0.91 (95% CI, 0.73-

0.99) and 0.84 (95% CI, 0.68-0.99), respectively. Figure 4

shows the associations among the fi ndings obtained from pla-

nar 123

I-BMIPP images with LVEF and log BNP and Figure 5

shows two examples of 123

I-BMIPP images.

Discussion

We found that patients with VSA had lower H/M ratios

and greater WR than hypertensive controls. Planar cardiac 123

I-

BMIPP imaging accurately identifi es global ischemic memory

caused by recent coronary artery spasm after the intracoronary

acetylcholine provocation test. An area under the ROC curve

of 0.85 is consistent with acceptable diagnostic performance

and indicates that the delayed H/M ratio has a powerful ability

to assess recent ischemia.123I-BMIPP SPECT imaging abnormalities: Abnormal

123I-

BMIPP SPECT uptake corresponded to the coronary territories

in about 70% of patients. Watanabe, et al 17) demonstrated 71%

and 95% sensitivity and specifi city of 123

I-BMIPP imaging for

detecting vasospasm at two weeks before catheterization. Our

results using SPECT were relatively lower than these values.

Among their study population, 38% had reduced wall motion

Table I. Baseline Characteristics of Participants

Control (n = 13) VSA (n = 37) P

Age (years) 69.5 ± 9.3 62.8 ± 10.9 0.055

Male, n (%) 5 (38.5) 19 (51.4) 0.424

Body mass index, kg/m2

24.2 ± 1.5 23.1 ± 2.3 0.402

Hypertension, n (%) 13 (100) 18 (48.6) 0.001

Hypercholesterolemia, n (%) 3 (23.1) 17 (45.9) 0.148

Diabetes mellitus, n (%) 1 (7.7) 5 (13.5) 0.578

Total cholesterol, mg/dL 195.8 ± 21.4 197.8 ± 33.8 0.842

Triglyceride, mg/dL 116.8 ± 65.6 129.6 ± 58.8 0.527

HDL-cholesterol, mg/dL 61.1 ± 13.6 53.1 ± 13.5 0.087

LDL-cholesterol, mg/dL 108.0 ± 16.9 121.6 ± 33.2 0.182

HbA1c, % 4.9 ± 0.5 5.2 ± 0.4 0.157

Systolic BP, mmHg 128.9 ± 10.4 122.7 ± 19.6 0.280

Diastolic BP, mmHg 75.1 ± 6.4 73.4 ± 11.8 0.527

BNP, pg/dL 36.3 ± 32.4 42.6 ± 43.6 0.637

Log BNP, pg/dL 3.2 ± 0.8 3.7 ± 0.6 0.102

LVEF, % 70.4 ± 8.0 63.5 ± 11.8 0.076

Values are means ± SD. BNP indicates brain natriuretic peptide; BP, blood pressure; HDL, high-density lipo-

protein; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; and VSA, vasospastic angina.

Figure 1. Early and delayed heart-to-mediastinum ratios and washout

rates in controls and patients with vasospastic angina (VSA). Patients with

VSA had signifi cantly lower early (A) and delayed (B) heart-to-mediasti-

num (H/M) ratios and (C) greater washout rates (WR) than hypertensive

controls.

Figure 2. Associations of H/M ratios and WR with SPECT in VSA pa-

tients. Total defect scores are nonlinearly related with H/M ratios (A) and

WR (B), respectively (local linear smoothing curves). Some patients with

lower TDS had lower H/M ratios and greater WR.

116Int Heart J

March 2014YONEYAMA, ET AL

with territorial regions that are more likely to correspond with

the coronary territories. Our patients with VSA in the absence

of wall motion abnormalities might have had relatively mild

ischemic attacks. Others have described excellent patient-level

agreement (90%) between 123

I-BMIPP and thallium SPECT

data up to 30 hours after stress-induced ischemic episodes,2)

and regional 123

I-BMIPP SPECT abnormalities in 59% of pa-

tients two days after the most recent episode of chest pain.18)

One experimental study has found that 123

I-BMIPP uptake in

ischemic territories recovers during the chronic phase (30

days).19)

Accordingly, time-dependent metabolic changes con-

siderably affect the findings obtained from SPECT images.

Compared with atherosclerosis, coronary spasm can assume

several forms and unique phenomena such as multiple spasms,

repeated chest pain, and silent ischemia.6,7,9,20-24)

Reduced up-

take persists in a specific region, resulting in overlapping or

abnormal 123

I-BMIPP uptake in other regions due to repeated

spasms. Conventional angiography cannot detect microvascu-

lar alterations because of system limitations. If 123

I-BMIPP can

detect microvascular disturbances, then the theory of conven-

tional blood supply to the coronary territories might not be ap-

Table II. Diagnostic performance of 123

I-BMIPP

AUC (95%CI) Cut off value Sensitivity (%) Specifi city (%)

Overall

Early H/M ratio 0.76 (0.59-0.92)* 2.3 59.5 76.9

Delayed H/M ratio 0.85 (0.73-0.98)* 2.0 73.0 84.6

Washout rate (%) 0.74 (0.73-0.90)* 36.7 70.3 69.6

Subacute phase (≤ 14 days)

Early H/M ratio 0.78 (0.61-0.96)* 2.3 64.3 77.9

Delayed H/M ratio 0.91 (0.73-0.99)* 2.0 85.7 84.6

Washout rate (%) 0.81 (0.64-0.99)* 38.7 78.6 84.6

Chronic phase (15 - 30 days)

Early H/M ratio 0.75 (0.56-0.94) 2.3 57.1 61.5

Delayed H/M ratio 0.84 (0.68-0.99)* 2.0 71.4 84.6

Washout rate (%) 0.78 (0.59-0.97)* 38.0 78.6 76.9

*P < 0.05 for difference between AUC and null hypothesis of true area = 0.5. AUC indicates area under the curve; CI, confi dence

interval; H/M, heat to mediastinum ratio; and VSA, vasospastic angina.

Figure 3. Diagnosis of VSA based on planar cardiac images of 123

I-BMI-

PP. Receiver operating characteristics (ROC) in all participants (A) during

subacute (B) and chronic (C) phases.

Figure 4. Associations of LVEF and Log BNP with findings obtained

from 123

I-BMIPP (local linear smoothing curves). Early H/M ratios corre-

late positively with delayed H/M ratios and negatively with washout rates

(A). A lower left ventricular ejection fraction and higher washout rate tend

to be associated with lower delayed H/M (B). Increased washout rate is

associated with decreased LVEF but did not linearly increase log brain

natriuretic peptide (BNP) (C). Early and decreased H/M ratios were not

linearly associated with increased log BNP (D).

Figure 5. Examples of SPECT and planar images from patients with an-

terior descending coronary artery (LAD) spasm. A: Anterior defect (ar-

rows) in short axis (SA) and vertical long axes (VLA) representing re-

gional myocardial ischemic memory corresponding to LAD territory

clearly demonstrated by delayed, rather than early SPECT images. Rela-

tively lower early H/M ratio (2.1), delayed H/M ratio (1.7), and higher

washout rate (48%) suggest global myocardial fatty acid metabolism. B: Anterior defect (arrows) in delayed SPECT image of SA. Early and de-

layed H/M ratios and washout rate are 1.6, 1.4 and 49% respectively, in

planar image. Lower H/M ratios and higher washout rates determined

from planar images were useful indicators of myocardial ischemic memo-

ry caused by LAD spasm.

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I-BMIPP IN VASOSPASTIC ANGINA

plicable.25)

These may affect negative correspondence with the

coronary territories. Notably, some of our patients with VSA

had lower H/M ratios and a greater WR despite a lower TDS,

indicating that fatty acid metabolism might recover on SPECT

images whereas the H/M ratios and WR values obtained from

planar imaging would still indicate disrupted fatty acid metab-

olism. Thus, global fatty acid metabolism might be considered

when assessing ischemic memory in patients with VSA. The

discrepancy may be explained by adequate accuracy of SPECT

imaging in multivessel disease. We speculated that the preva-

lence of single/multi spasms might confound the relation of

TDS with the H/M ratio and WR. However, we could not fi nd

any data to explain the discrepancy from our data with the

small sample in the present study. We believe that what ap-

pears to be a reduced H/M ratio or increased WR can be more

simply explained by the planar 123

I-BMIPP imaging in VSA.

Diagnosis of VSA using 123I-BMIPP planar imaging: We found

signifi cant differences in the early and delayed H/M ratios be-

tween the control and VSA groups, and the overall AUC was

0.85 for the delayed H/M ratio. The accumulation rate of 123

I-

BMIPP in the myocardium at 4 hours after tracer injection is

about 5%, which is higher than that of 201

Thallium.26)

Koba-

yashi, et al reported that rapid washout due to back-diffusion

(positive washout) in myocytes with impaired fatty acid me-

tabolism results in a mismatch between reduced uptake on 123

I-

BMIPP images and coronary perfusion on 201

Thallium imag-

es.27)

Delayed H/M ratios are considered useful for assessing

the disordered myocardium in several heart diseases 12,13)

and

might accurately refl ect impaired fatty acid metabolism. Some

investigators have noted that an increased WR of 123

I-BMIPP

identifi es cardiac disease.12-14,28,29)

The severities of the H/M ra-

tios and WR were associated with LVEF but BNP, respectively

the present study. Delayed H/M ratios and WR of 123

I-BMIPP

correlate with LVEF and BNP in patients with chronic heart

failure.12)

Accordingly, our findings support the notion that

dysfunctional global fatty acid metabolism assessed using pla-

nar imaging is closely associated with global left ventricular

function. The BNP level in the present study was typically be-

low 50 pg/dL, which is relatively lower than in critical heart

disease. We speculate that the traditional risk factors of age,

gender, hypertension, and diabetes may confound the relation

of BNP level with impaired fatty acid metabolism in VSA.

Study limitations: The difference in the rates of hypertension

between the controls and patients with VSA was substantial.

The uptake of 123

I-BMIPP was signifi cantly lower in patients

with VSA than in hypertensive controls, although myocardial

fatty acid metabolism in the hypertensive heart is considered

abnormal.30,31)

The H/M ratios and washout rate may have been

affected by the extension, severity, duration of spasm, and

medication. The discrepancy between the SPECT and planar

imaging must be considered, however, no data to explain the

discrepancy in the present study is also a limitation. Thus, fur-

ther assessment is needed to evaluate the potential of the dis-

crepancy in the VSA.

Conclusion: 123I-BMIPP Planar imaging can also diagnose

coronary artery spasm with acceptable diagnostic performance

and indicates that the delayed H/M ratio has a powerful ability

to assess recent ischemia. This technique might be useful in

the face of apparently normal coronary angiographic fi ndings

during the subacute and chronic phases after ischemic events.

Acknowledgments

We thank Mr. Masaru Sato, Mr. Junichi Natori, Mr. Yoshiaki Mae-

hara, Mr. Yoshio Horikoshi, and Mrs. Keiko Kohno for their expert techni-

cal assistance and data collection.

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