Keywords CAD - SPECT - beta-blockers - dipyridamole - myocardial perfusion
Introduction
Coronary artery disease (CAD) is a disorder that occurs due to atherosclerotic occlusions
of the coronary arteries and is manifested by stable or unstable angina, myocardial
infarction, or sudden cardiac death.[1 ] CAD is the leading cause of cardiovascular mortality in the world.[2 ] Therefore, appropriate diagnostic methods are necessary for diagnosis and prognostication
in CAD.
Myocardial perfusion single-photon emission computed tomography (MSPECT) is a diagnostic
method that measures blood flow in the myocardium and makes it possible to diagnose
myocardial ischemia or infractions.[3 ] MSPECT provides valuable information about the severity and extension of CAD, which
effects the patient's risk, prognosis, and better management.[4 ] This method is often examined separately in two phases: stress (pharmacological
or exercise stress) and rest phases.[5 ] Pharmacologic stress agents include vasodilators such as adenosine and dipyridamole
as well as inotropic-chronotropic agents such as dobutamine.[6 ] Dipyridamole exerts its pharmacological effects by blocking the cellular uptake
of adenosine and so increasing the blood levels of endogenous adenosine.[7 ]
In recent years, much research has been done to increase the diagnostic accuracy of
myocardial perfusion scan.[8 ]
[9 ]
[10 ] One of the most challenging factors affecting the diagnostic accuracy of dipyridamole
myocardial perfusion scan is the cessation or continuation of beta-blockers consumption
before the stress phase. Beta-blockers are one of the most important medications used
in the treatment of CAD that block beta-adrenergic receptors in the target cells[11 ] and cause to decrease cardiac output, stroke volume, and arterial blood pressure
by reducing heart rate and myocardial contractility.[12 ] Thus, discontinuation of beta-blockers in treated patients can increase the risk
of ischemic attack or complications such as sudden rise of blood pressure and heart
rate. Some studies suggest that holding of beta-blockers is not mandatory before diagnostic
scan, and, on the other hand, others have suggested that beta-blockers may reduce
the presence and severity of cardiac perfusion defects in postdipyridamole stress
images.[13 ]
[14 ]
[15 ] So, the effect of beta-blockers on the diagnostic value of MSPECT and the severity
of dipyridamole-induced perfusion defects is controversial.
Uncertainty and limited studies about the effect of beta-blockers on MSPECT results
led us to investigate the impact of beta-blockers on the dipyridamole stress /rest
gated myocardial perfusion SPECT variables.
Materials and Methods
Selection of Patients
Thirty patients with abnormal MSPECT (23 patients with ischemia and 7 patients with
ischemia + infarction) were studied. After obtaining informed written consent, patient
underwent dipyridamole stress myocardial SPECT, two times on 2 separate days. First
stress imaging was performed after holding beta-blockers for 72 hours prior to the
scan, and the second stress imaging was done on the beta-blocker consumption, 1 week
later. In both stress imaging, other antianginal and anti-ischemic medications and
statins were discontinued for 72 hours. Inclusion criteria were patients with ischemic
heart disease and presence of reversible defects in their myocardial perfusion scans
who were treated with beta-blockers for at least 3 months. Exclusion criteria were
shorter course of treatment, incorrect medicine usage, and patient's dissatisfaction
to enter the study.
Dipyridamole Stress and Single-Photon Emission Computed Tomography
Pharmacological stress was performed with infusion of 0.56 mg/kg dipyridamole over
4 minutes and radiopharmaceutical (740–925 megabecquerel of [99m Tc]Tc-Sestamibi) injected 4 minutes after the infusion of dipyridamole. During dipyridamole
infusion, heart rate, blood pressure, electrocardiogram, and patients' symptoms were
monitored continuously.
One hour after the injection of radiopharmaceutical, imaging was done by the gated
SPECT method, Siemens gamma camera and GE (dual head variable angle), E-soft software,
and low-energy high-resolution collimator in the supine position. Imaging was acquired
in 32 projections (20 seconds each projection) from right anterior oblique to left
posterior oblique using matrix: 64 * 64 and 140 keV photopeak (15% energy window)
and 1.45 magnification. In gated SPECT imaging, eight frames per cycle and 20% window
were used. Then, images were reconstructed with filtered back projection and Butterworth
filter (order: 5 and cutoff frequency: 0.55).
One week after the first round of pharmacological stress, stress testing was performed
again with dipyridamole, without discontinuation of beta-blockers (carvedilol, metoprolol,
propranolol, and atenolol) but with discontinuation of other antianginal, anti-ischemic
medications, and statins for 72 hours prior the scan. Imaging protocol, radiopharmaceutical
dose, injection-imaging time interval, and all imaging parameters were the same between
the two stress phases. The stress and rest phases images were interpreted separately
by two experienced nuclear medicine specialists in the field of nuclear cardiology
using 17-segment method. Interpreters were unaware about the beta-blocker usage status
of the patients.
Using quantitative perfusion SPECT (QPS) software, perfusion parameters such as summed
stress score (SSS), summed rest score, summed difference score (SDS), and total perfusion
deficit (TPD) were recorded. Also using severity and extension polar maps,[16 ]
[17 ] stress severity score, reversibility severity score, stress extension score, and
reversibility extension score in left anterior descending (LAD), left circumflex (LCX),
and right coronary artery (RCA) territories were analyzed.
Finally, by analyzing and comparing the obtained data, the effect of beta-blockers
on the diagnostic accuracy of myocardial perfusion scan with dipyridamole was investigated.
Statistical Analysis
Frequency descriptive methods will be discussed, including frequency distribution
tables, graphs, central indices, and appropriate scatter to describe the studied variables.
Kruskal–Wallis test was used to determine the correlation between myocardial perfusion
scan indices after discontinuation and after beta-blocker. The chi-square test was
used to determine the relationship between qualitative variables between patients.
The significance p -value was considered < 0.05, and all the statistical analyses were processed by SPSS
software (statistical package, version 24).
Results
In our study, 43.3% of subjects were male and 56.7% were female. The mean age of participants
was 59.27 ± 10.16 years old. Moreover, seven patients had ischemia with infarction
(23.4%) and 23 patients only had ischemia (76.6%). Patient's characteristics are demonstrated
in [Table 1 ].
Table 1
Patient's characteristics
Variable
Value
Age
59.27 ± 10.16 y old
Sex
Men
13 (43.3%)
Women
17 (56.7%)
CABG surgery
9 (30%)
Hyperlipidemia
12 (40%)
Diabetes mellitus
14 (46.7%)
Hypertension
24 (80%)
Abnormal findings in angiography
12 (40%)
Type of beta blocker
Metoprolol
25 (83.3%)
Carvedilol
5 (16.7%)
Scan report
Ischemia and infarction
7 (23.4%)
Ischemia
23 (76.6%)
Abbreviation: CABG, coronary artery bypass grafting.
Most indices including SSS, SDS, TPD, severity, and extension of perfusion defects
in RCA, LCX, and LAD territories were significantly different between the two studied
conditions including continuation and discontinuation of beta-blocker consumption
before SPECT scan (p < 0.05). However, the severity reversibility score in the LAD territory was the only
index that did not differ significantly between the two situations (p = 0.07). The results are shown in [Table 2 ].
Table 2
Myocardial perfusion scan indices in beta-blocker consumer group in two situations
including on consumption and after discontinuation of beta-blocker
Variable
After beta-blocker consumption
After beta-blocker discontinuation
p -Value
Summed stress score
5.62 ± 6.03
4.12 ± 8.20
0.0001
Summed difference score
4.67 ± 4.07
2.89 ± 6.23
0.0001
Summed rest score
1.97 ± 2.09
1.97 ± 2.09
–
Severity LAD stress
2.33 ± 1.56
2.24 ± 1.63
0.0001
Severity LCX stress
2.71 ± 1.42
2.65 ± 1.69
0.0001
Severity RCA stress
0.33 ± 0.52
0.42 ± 0.33
0.0001
Severity LAD reversibility
0.72 ± 0.78
0.45 ± 0.89
0.07
Severity LCX reversibility
0.64 ± 0.88
0.75 ± 0.9
0.0001
Severity RCA reversibility
0.48 ± 0.71
5.77 ± 2.16
0.001
Extension LAD stress
14.72 ± 10.17
13.62 ± 15.13
0.0001
Extension LCX stress
22.23 ± 9.80
23.53 ± 16.40
0.0001
Extension RCA stress
8.81 ± 3.03
5.68 ± 2.17
0.0001
Extension LAD reversibility
12.35 ± 6.10
10.41 ± 10.86
0.01
Extension LCX reversibility
9.54 ± 4.71
14.17 ± 10.53
0.001
Extension RCA reversibility
9.44 ± 3.03
5.77 ± 2.16
0.0001
Total perfusion deficit LAD stress
5.48 ± 4.25
4.53 ± 5.40
0.0001
Total perfusion deficit LCX stress
3.96 ± 1.96
3.85 ± 2.94
0.0001
Total perfusion deficit RCA stress
1.30 ± 0.52
1.06 ± 0.42
0.0001
Total perfusion deficit (total stress)
8.56 ± 7.48
7.38 ± 10
0.0001
Ejection fraction stress
67.20 ± 14.62
66.57 ± 14.34
0.0001
Abbreviations: LAD, left anterior descending; LCX, left circumflex; RCA, right coronary
artery.
In the group of patients who only used metoprolol, all studied indices including SSS,
SDS, TPD severity, and extension scores were significantly reduced when patients continued
beta-blocker consumption before the stress phase of the study (p < 0.05) ([Table 3 ]).
Table 3
Myocardial perfusion scan indices in the metoprolol consumer group in two situations
including on consumption and after discontinuation of metoprolol
Variable
After metoprolol consumption
After metoprolol discontinuation
p -Value
Summed stress score
5.20 ± 5.13
7.88 ± 3.78
0.0001
Summed difference score
3.16 ± 3.81
5.48 ± 2.11
0.0001
Summed rest score
2.04 ± 2.24
2.04 ± 2.24
–
Severity LAD stress
1.60 ± 2.55
1.69 ± 2.45
0.0001
Severity LCX stress
1.28 ± 2.55
1.58 ± 2.56
0.0001
Severity RCA stress
0.23 ± 0.30
0.27 ± 0.33
0.001
Severity LAD reversibility
0.73 ± 0.76
0.84 ± 0.44
0.17
Severity LCX reversibility
0.048 ± 0.48
0.60 ± 0.61
0.01
Severity RCA reversibility
0.67 ± 0.49
1.03 ± 5.04
0.006
Extension LAD stress
9.28 ± 15.03
15.36 ± 14.29
0.001
Extension LCX stress
7.12 ± 15.56
14.00 ± 18.24
0.0001
Extension RCA stress
1.40 ± 3.77
1.36 ± 4.85
0.0001
Extension LAD reversibility
4.80 ± 12.07
10.64 ± 11.01
0.03
Extension LCX reversibility
3.37 ± 7.07
9.20 ± 12.06
0.001
Extension RCA reversibility
3.96 ± 1.24
5.04 ± 1.36
0.0001
Total perfusion deficit LAD stress
3.96 ± 5.74
5.36 ± 4.69
0.0001
Total perfusion deficit LCX stress
1.45 ± 2.82
2.58 ± 3.02
0.0001
Total perfusion deficit RCA stress
0.28 ± 0.60
0.27 ± 0.86
0.0001
Total perfusion deficit (total stress)
6.56 ± 7.38
9.20 ± 6.76
0.002
Abbreviations: LAD, left anterior descending; LCX, left circumflex; RCA, right coronary
artery.
Evaluating the carvedilol consumer group (five patients) demonstrated that SSS, SDS,
as well as stress severity score, stress extension score, and TPD in the stress phase
in RCA and LCX territories as well as extension reversibility score in RCA territory
were significantly increased after carvedilol consumption compared to carvedilol withdrawal
phase ([Table 4 ]).
Table 4
Myocardial perfusion scan indices in the carvedilol consumer group, in two situations
including on consumption and after discontinuation of carvedilol
Variable
After carvedilol consumption
After carvedilol discontinuation
p -Value
Summed stress score
10.20 ± 6.72
9.80 ± 5.76
0.0001
Summed difference score
8.60 ± 6.34
8.20 ± 5.31
0.0001
Summed rest score
1.60 ± 1.14
1.60 ± 1.14
–
Severity LAD stress
1.34 ± 0.49
1.32 ± 0.55
0.17
Severity LCX stress
2.16 ± 3.34
2.24 ± 3.35
0.002
Severity RCA stress
0.82 ± 1.04
0.66 ± 0.68
0.002
Severity LAD reversibility
1.06 ± 0.43
1.16 ± 0.43
0.31
Severity LCX reversibility
1.44 ± 1.80
1.50 ± 1.67
0.03
Severity RCA reversibility
0.92 ± 0.46
6.02 ± 8.01
0.1
Extension LAD stress
14.60 ± 13.61
14.00 ± 11.31
0.2
Extension LCX stress
43.14 ± 23.20
42.47 ± 28.40
0.01
Extension RCA stress
11.20 ± 19.48
6.20 ± 8.25
0.01
Extension LAD reversibility
12.60 ± 12.93
12.00 ± 7.48
0.38
Extension LCX reversibility
11.40 ± 17.09
17.20 ± 20.70
0.44
Extension RCA reversibility
12.00 ± 20.78
6.20 ± 8.01
0.01
Total perfusion deficit LAD stress
5.66 ± 4.15
5.74 ± 4.11
0.12
Total perfusion deficit LCX stress
4.50 ± 7.50
4.72 ± 6.91
0.01
Total perfusion deficit RCA stress
1.70 ± 2.82
1.18 ± 1.69
0.001
Total perfusion deficit (total stress)
14.20 ± 11.98
14.00 ± 9.82
0.07
Abbreviations: LAD, left anterior descending; LCX, left circumflex; RCA, right coronary
artery.
Discussion
MSPECT introduced as a valuable diagnostic and prognostic method for patients with
CAD and stress intervention by vasodilator agents is a main component of the study
to identify recognizable myocardial defects.[18 ]
[19 ]
[20 ]
[21 ]
Given the controversial findings about the impact of cardiac medications especially
beta-blockers on the diagnostic value of MSPECT, we investigate the effect of beta-blocker
agents on diagnostic indices of dipyridamole myocardial perfusion scan.
The results of our study revealed that most MSPECT indices such as SSS, SDS, TPD,
severity, and extension of perfusion defects in RCA, LCX, and LAD territories (based
on QPS software polar maps) were significantly reduced after consuming metoprolol
compared to the condition in which this medication was discontinued before stress
study ([Fig. 1 ]). It has been proven that coronary vasodilation following dipyridamole injection
is a mechanism for detecting possible myocardial ischemia.[22 ]
[23 ] Since beta-adrenergic receptors bind to similar stimulatory G proteins; thus, inhibitors
of those receptors may reduce the activation of responsible G proteins.[24 ] This inhibitory intervention ultimately leads to a decline in cyclic adenosine monophosphate
cell concentration and a decreased response to dipyridamole infusion.[25 ] We proposed that the effect of beta-blockers by receptor inhibition reduces the
sensitivity to dipyridamole and decreases vascular response; however, the determination
of the exact mechanism needs more evaluation.
Fig. 1 Stress phases of myocardial perfusion SPECT: (A ) with no consumption of beta-blocker which shows decreased perfusion in the anterior
and anterolateral segments, and (B ) with consumption of beta-blocker which shows uniform tracer uptake.
In addition, the only index that did not differ significantly in two conditions of
discontinuation and continuation of beta-blockers consumption was the severity reversibility
polar map in LAD territory which may be due to the small number of patients who had
defects in LAD territory.
Nevertheless, in carvedilol consumers, the results were inconsistent, and we observed
that SSS, SDS as well as stress severity score, stress extension score, and TPD in
the stress phase in RCA and LCX territories as well as extension reversibility score
in RCA territory significantly were higher in the carvedilol consumption phase than
in the discontinuation phase. The most important reason is very small sample in the
carvedilol group. Carvedilol is not only a beta-adrenoceptor antagonist but also it
blocks alpha 1-adrenergic receptors. Probably, this combined action has different
effects associated with traditional beta-blockers.[26 ]
[27 ] So, this property may have different effects on the dipyridamole stress and even
contribute to the underlying pathway of dipyridamole stress testing. However, considering
the very small sample in the carvedilol group and the different involvement of coronary
territories between the two studied groups of patients, we cannot comment with certainty
on the effect of carvedilol on myocardial perfusion scan. Therefore, to accurately
and transparently evaluate the effect of carvedilol, future studies with larger sample
sizes and particular carvedilol consumption are needed.
In accordance with our findings, Hoffmeister et al revealed that discontinuation of
beta-blockers could increase myocardial blood flow in positron emission tomography
(PET) imaging using adenosine.[28 ] The study of Taillefer et al on 21 patients with proven CAD showed that the use
of beta-blocker agents may cause underestimation of the severity of CAD in dipyridamole
stress myocardial perfusion scan. In this study, patients were divided into three
groups which received placebo, up to 10 mg and up to 20 mg of metoprolol. Taillifer
et al showed that SSS and SDS, as well as the size and reversibility of perfusion
defects, were significantly reduced in metoprolol receivers compared with placebo
(p < 0.05). In this study, the effects of beta-blockers were studied acutely, while
our study was performed in patients who used beta-blockers for a long time.[29 ]
Hoffmeister et al examined the effect of beta-blockers on cardiac nuclear imaging
in 20 patients with CAD and on long-term treatment with beta-blocker medications,
who underwent 13N-ammonia PET with adenosine stress, and then, parametric PET polar
maps were converted to virtual SPECT polar maps. The beta-blockers used in this study
were metoprolol [25%], nebivolol [20%], carvedilol [5%], and bisoprolol [50%]. In
contrast to our findings, they reported no significant difference between the mean
score when taking beta-blockers and stopping beta-blockers.[30 ] In another study by Yoon et al on patients who had coronary angiography in the past
90 days, there was no significant difference between the result of nuclear imaging
between the group of patients using beta-blockers and the group that did not use beta-blocker.
The mean SSS was 10.4 in the beta-blockers receiver group and 11.1 in the group that
did not receive beta-blockers.[31 ]
[Table 5 ] showed summarized results of previous studies about the effect of beta-blocker on
myocardial perfusion imaging.
Table 5
Results of previous studies about the effect of beta-blocker on myocardial perfusion
imaging
Author
Beta-blocker
Paper title
Conclusion or recommendation
Hoffmeister et al[28 ]
No specific
The effect of a beta blocker withdrawal on quantitative adenosine MBF and MPI results.
Most patients: myocardial perfusion imaging results and management decisions are independent
of beta-blocker consumption.
Taillefer et al[29 ]
Metoprolol
Effect of acute beta-blockade on dipyridamole Tc-99m Sestamibi myocardial perfusion
imaging
Underestimation of the coronary artery disease with consumption of beta-blocker in
dipyridamole stress MPI.
Yoon et al[31 ]
No specific
The effect of beta-blockers on the diagnostic accuracy of vasodilator pharmacologic
SPECT myocardial perfusion imaging
Beta-blockers: No clinically significant effect on the detection of coronary artery
disease.
Fallahi et al[15 ]
No specific
Withholding or continuing beta-blocker treatment before dipyridamole myocardial perfusion
imaging for the diagnosis of coronary artery disease
Beta-blocker withholding for diagnostic dipyridamole MPI is not necessary.
Lakkireddy et al[32 ]
No specific
Does beta-blocker therapy affect the diagnostic accuracy of adenosine single-photon-emission
computed tomographic myocardial perfusion imaging?
Beta-blocker: No effect on the extent, severity, and reversibility of perfusion defects.
Shehata et al[33 ]
Propranolol
Impact of acute propranolol administration on dobutamine-induced myocardial ischemia
as evaluated by myocardial perfusion imaging and echocardiography
Recommended withdrawal of beta-blocker before dobutamine stress.
Abbreviations: MBF, myocardial blood flow; MPI, myocardial perfusion imaging; SPECT,
single-photon emission computed tomography.
Dr. Fallahi et al also conducted a randomized clinical trial on 120 patients with
proven CAD on coronary angiography with history of treatment with beta-blockers for
more than 3 months and investigated the effect of beta-blockers on dipyridamole stress
MSPECT. The mean myocardial perfusion scores were not significantly different between
the patient in the first group who discontinued beta-blockers before the imaging and
the patients in the second group who were not withheld beta-blockers.[15 ] We suppose that these inconsistencies with our findings may be due to different
study designs, the type of beta-blocker, the type of pharmacological stress, studied
population, and sample size.
However, the present study was the first within-patient survey to investigate the
effect of beta-blockers on myocardial perfusion scans with dipyridamole in Iranian
patients who were on long-term treatment with beta-blocker medications. Although this
study encountered some limitations such as low sample size, reluctance of patients
to participate in the study due to fear of exposure to radiation, and different beta-blockers
used by studied patients, there were some valuable strengths. For instance, we compared
each patient's MSPECT indices in two conditions of with or without beta-blockers consumption
to remove many confounding variables. Also, we selected patients with ischemia to
enroll in this study; furthermore, perfusion parameters were evaluated with QPS software,
which caused to eliminate operator-dependent errors, and these are the advantages
of this study method.
Finally, the results of the present study confirmed that beta-blockers, especially
metoprolol, have a significant adverse effect on the diagnostic value of MSPECT scans
with dipyridamole stress in terms of underestimating the severity of perfusion defects
and decreased diagnostic accuracy of the MSPECT study. So, it is recommended to discontinue
beta-blockers before performing an MSPECT procedure with dipyridamole to improve the
diagnostic accuracy of the study.
Study limitations: The sample size in our study is relatively small. One of the reasons
is ethics for performing two times of stress phase for a person. By the way, we suggest
carrying out further multicenter studies with a larger target population and equal
medication to obtain more detailed and generalizable results and assess patients with
other cardiac medications, especially from alpha- and beta-blocker agents.
Conclusion
The results of the present study showed that the use of beta-blockers can reduce the
imaging accuracy of myocardial perfusion SPECT using dipyridamole. According to these
results, discontinuation of beta-blockers, especially metoprolol, 3 days before the
scan seems to improve diagnostic accuracy of the dipyridamole MSPECT. On the other
hand, other beta-blockers with effect on the other receptors may have different effects.
