Predictors of severe stenosis at invasive coronary angiography in patients with normal myocardial perfusion imaging
Neth Heart J
Predictors of severe stenosis at invasive coronary angiography in patients with normal myocardial perfusion imaging
S. Yokota 0 1 2 3
J. P. Ottervanger 0 1 2 3
M. Mouden 0 1 2 3
M. J. de Boer 0 1 2 3
P. L. Jager 0 1 2 3
J. R. Timmer 0 1 2 3
0 Department of Cardiology, Radboud University Medical Center , Nijmegen , The Netherlands
1 Department of Cardiology, Isala Hospital , Zwolle , The Netherlands
2 J. P. Ottervanger
3 Department of Nuclear Medicine, Isala Hospital , Zwolle , The Netherlands
Purpose Normal myocardial perfusion imaging (MPI) is associated with excellent prognosis. However, in patients with persisting symptoms, it may be difficult to determine the patients in whom invasive angiography is justified to rule out false negative MPI. We evaluated predictors for severe stenosis at invasive angiography in patients with persisting symptoms after normal MPI. Methods 229 consecutive patients with normal MPI, without previous bypass surgery, underwent invasive angiography within 6 months. Older age was defined as >65 years. Multivariable analyses were performed to adjust for differences in baseline variables. Results Mean age was 62 ± 11 years, 48% were women. Severe stenosis was observed in 34%, and of these patients 60% had single-vessel disease (not left main coronary artery disease). After adjusting for several variables, including diabetes, smoking status, hypertension and hypercholesterolaemia, predictors of severe stenosis were male gender, odds ratio (OR) 2.7 (95% confidence interval (CI) 1.5-4.9), older age, OR 1.9 (95% CI 1.02-3.54) previous PCI, OR 2.0 (95% CI 1.0-4.3) and typical angina, OR 2.5 (95% CI 1.4-4.6). Conclusions Increasing age, male gender, previous PCI and typical symptoms are predictors of severe stenosis at invasive coronary angiography in patients with normal MPI. The majority of these patients have single-vessel disease.
Single photon emission computed tomography; Myocardial perfusion imaging; Coronary artery disease; Gender
Myocardial perfusion imaging (MPI) using single photon
emission computed tomography (SPECT) is a frequently
used non-invasive modality in patients with suspected
angina. A normal MPI is associated with an excellent
]. Although the diagnostic accuracy of MPI is
good , the possibility of a false negative test should be
considered, particularly in patients with persisting
]. Since invasive coronary angiography (ICA) is
still the gold standard for ruling out obstructive coronary
disease, it can be considered in patients with normal MPI
with persisting symptoms. In daily clinical practice, it
remains, however, a challenge to determine in which patients
ICA is justified. There are only few studies concerning
predictors of abnormalities in patients with normal MPI,
and many are hampered by a small sample size [
The aim of our study was to assess independent
predictors of severe coronary stenosis as detected with ICA in
patients with normal MPI and persisting symptoms.
Materials and methods
We performed a retrospective analysis of all 11,402
consecutive patients who underwent MPI using
99mTc-Tetrofosmin SPECT in the Isala Hospital, in Zwolle, the
Netherlands between January 2006 and December 31st, 2009.
Subsequent ICA within six months was performed in 1,602
(14%) patients, including 256 stable patients with normal
MPI and persisting or worsening symptoms. After
excluding 27 patients with a history of coronary bypass surgery,
we analysed the remaining 229 patients in our current study.
We described the methods of the study in an earlier article
]. We performed the study in accordance with the
Declaration of Helsinki.
At the time of MPI, all patients completed a
questionnaire regarding demographic information, prior medical
history, cardiac risk factors and current medication use.
Furthermore, information regarding patient age, gender,
weight, height, blood pressure, heart rate and symptoms
were prospectively obtained by a nurse.
Typical angina was defined as the presence of substernal
chest pain or discomfort that was provoked by exertion or
emotional stress and relieved by rest and/or nitroglycerin
Left ventricle ejection fraction (LVEF) and dimensions
were assessed by echocardiography. LVEF <50% was
considered abnormal. End diastolic left ventricular internal
diameter was defined as dilated if the value was ≥59 mm (for
men) or ≥53 mm (for women).
Classification of coronary disease
Invasive angiography was performed with the Judkins or
radial approach. Two experienced interventionalists blinded
to MPI results retrospectively re-interpreted all angiograms
visually. A coronary stenosis of ≥70% was considered to
be severe for the left anterior descending artery (LAD), left
circumflex artery (LCx) and right coronary artery (RCA).
Severe left main coronary artery disease (LMCAD) was
defined as >50% diameter stenosis [
]. Patients were
categorised as having LMCAD (both isolated and
non-isolated), single-vessel disease without LMCAD, two-vessel
disease without LMCAD and three-vessel disease without
LMCAD. Performance of fractional flow reserve (FFR) was
at the discretion of the operator. We used an FFR cut-off
value of 0.80.
SPECT MPI data acquisition and analysis
All patients underwent a 1-day stress 99mTc-Tetrofosmin
MPI protocol. Owing to logistic reasons we routinely use
adenosine for stress unless contraindicated. We used
adenosine in 219 patients, dobutamine in 3 patients and
physical exercise (bicycle) in 7 patients. All MPI scans were
analysed by experienced readers as previously reported [
Transient ischaemic left ventricular dilatation was defined
as abnormal if the value was >1.36 for adenosine stress [
Scans were considered normal if perfusion was assessed to
be homogenous throughout the myocardium and summed
stress score was 3 [
]. Two readers retrospectively
reanalysed all scans to unmask any potential abnormality that
was initially missed.
Survival status was evaluated in August 2015 using the
‘Gemeentelijke Basis Administratie’ system, a decentralised
Dutch population registration system that contains
information about all inhabitants of the Netherlands. Since no
data are erased from this system, new data, such as death
and emigration, are registered in the register. The data were
considered right-censored if patients were still alive at the
time of evaluation. In addition, data on symptom status
were obtained from medical chart records for patients who
underwent revascularisation to assess the impact from the
Statistical analysis to compare baseline characteristics was
performed with a Chi-Square test and one-way analysis
of variance (ANOVA) as available in SPSS software
(version 20 for Windows; SPSS Inc., Chicago, Illinois, USA).
Comparison of continuous data between both groups was
performed using the two-sided student’s t-test.
Quantitative variables were expressed as mean ± SD and
categorical variables as frequencies, or percentages. Logistic
regression analyses were performed to assess independent
predictors of severe stenosis at angiography. The
KaplanMeier method was used for univariate survival analysis.
Cox proportional hazards regression model was used to
assess whether abnormal findings at angiography were
independent predictors of mortality. P-values of <0.05 were
considered statistically significant.
Mean age of the 229 patients was 62 ± 11 years, 48% were
women and mean body mass index (BMI) was 28 ± 5 kg/m2.
Hypertension and hypercholesterolaemia were found in
more than 50% of patients. A total of 20% of patients
had a previous percutaneous coronary intervention (PCI).
Aspirin, beta blockers and statins were prescribed to the
majority of patients before referral for ICA. In 52% of the
patients, the symptoms were interpreted as typical angina;
there was no difference between men (51%) and women
(53%, p = 0.82). We observed abnormal LVEF in 78 patients
Mean time between MPI and ICA was 66 ± 44 days (range
2–182 days). A total of 78 patients (34%) had severe
coronary stenosis. In 9 patients, severity was confirmed by
measurement of FFR. Of the 78 patients with severe stenosis,
47 patients (60%) had single-vessel disease (not the left
main coronary artery), 18 patients (23%) had two-vessel
disease, whereas 13 patients (17%) had LMCAD and/or
three-vessel disease. There were no patients with isolated
stenosis of the left main coronary artery. An example of
a normal SPECT MPI in a patient with a severe stenosis
is displayed in Fig. 1. Of the 47 patients with one-vessel
disease, the stenosis was located in the LAD in 45%, in the
RCA in 30% and in the LCX in 26%.
Severe stenosis was more common in men (64%) and
in patients with older age, a history of PCI, and typical
anginal symptoms (Tab. 1). The prevalence rates of
abnormal LVEF, dilatation of left ventricle, atrial fibrillation or
left bundle branch block, and symptoms during
pharmacologic stress were not significantly higher in patients with
severe stenosis compared to those with non-severe
stenosis. Transient ischaemic left ventricular dilatation was only
observed in 2 patients (3%, p = 0.11%), both with severe
BMI body mass index, LVEF left ventricular ejection fraction, PCI percutaneous coronary intervention,
SPECT single photon emission computed tomography
*Denotes statistical significance. Adjusted for differences in the other variables
CI confidence interval, OR odds ratio, PCI percutaneous coronary intervention, SPECT single photon
emission computed tomography
*Denotes statistical significance. Adjusted for differences in the other variables
Independent predictors of severe stenosis
To assess independent predictors of severe stenosis,
multivariate analyses were performed. After adjusting for
several variables, including diabetes, smoking, hypertension
and hypercholesterolaemia, only male gender, odds ratio
(OR) 2.7 (95% confidence interval (CI) 1.5–4.9), older age,
OR 1.9 (95% CI 1.02–3.54) and typical angina, OR 2.5
(95% CI 1.4–4.6) were predictors of significant coronary
stenosis. Results of multivariable analyses are summarised
in Tab. 2.
Total follow-up duration in survivors was 7.0 years (range
5–9 years, SD 1.1 years). Coronary revascularisation was
performed in 70 patients (89%), in 47 patients (60%) by
PCI and in 23 patients (30%) by bypass surgery. Among
the 70 patients who underwent coronary revascularisation,
49 patients (70%) were free from symptoms, while 16
patients had unchanged persistent chest symptoms (23%).
Data on symptom status post intervention were lacking for
the remaining 5 patients (7%).
During follow-up, a total of 31 patients died (14%).
Mean age of patients who died was higher than of those
who survived (71.1 years SD 7.9 vs 60.9 years SD 10.2;
p < 0.001). After univariate analyses, long-term mortality
was 16.7% in patients with severe stenosis and 11.9% in
patients without severe stenosis (p = 0.32). Also, after
adjusting for differences in age, gender and typical angina
symptoms, severe stenosis demonstrated by ICA was still
not associated with increased mortality, OR 1.0 (95% CI
In our observational study, increasing age, male gender and
typical angina symptoms are predictors of severe stenosis
demonstrated by ICA in patients with normal MPI. The
severe stenoses in our patients were not associated with
increased long-term mortality.
MPI is well-validated and has proven value in
identifying patients at high risk of a serious cardiac event, whereas
a normal MPI study confers a benign prognosis with a low
annual serious cardiac event rate of 0.6% per year [
However, there can always be concern that MPI has missed
high-risk coronary disease as in patients with balanced
ischaemia due to flow-limiting three-vessel disease or
stenosis of the left main coronary artery. Although balanced
ischaemia was considered an important reason for false
negative MPI in previous studies [
], the majority of
patients with severe stenosis in our study had single-vessel
disease. This suggests that balanced ischaemia may be less
important as a cause of false negative MPI than previously
thought. Various explanations for discordant findings have
been suggested: false negative SPECT may be due to
inadequate vasodilatation during stress, for example due to
recent caffeine intake in an adenosine stress test or
inadequate exercise in a physical stress test. But FFR, which is
increasingly considered the new gold standard, can result
in incorrect diagnoses as well. Reasons may be insufficient
hyperaemia, guiding catheter related pitfall, electrical drift,
diffuse disease rather than focal stenosis, small perfusion
territory, severe microvascular disease, abundant collaterals
and severe left ventricular hypertrophy [
Since false negative findings may occur in every
diagnostic test, it is important to know which patients have the
highest risk of a false negative test, and who may
benefit from additional (invasive) testing. Accurate detection
of false negative findings may lead to initiation of
appropriate medical treatment that may improve outcome. Only
three studies have assessed predictors of severe stenosis in
patients with normal MPI (Tab. 3). The largest study was
performed in the US as recently reported [
]. As in our
study, they found that increasing age, male gender and
typical anginal symptoms are predictors of severe coronary
stenosis. Ghadri et al. demonstrated in a small study that
Fujimoto et al. [
Sharma et al. [
Nakanishi et al.
CAC coronary calcium score, CAD coronary artery disease, ECG electrocardiography, EF ejection fraction, SSS summed stress score, SPECT
MPI single photon emission computed tomography myocardial perfusion imaging, TID transient ischaemic dilatation, TPD total perfusion defect
a very high coronary calcium score is a predictor of severe
coronary stenosis in patients with normal MPI, but they did
not assess other potential risk factors [
Stable angina is the most common type of angina, and
it typically occurs with exertion and relieves with rest. Our
study highlights the importance of adequate history taking
in the evaluation of chest pain. This was also observed in
previous studies. Cooke and colleagues examined the
description of pain in 65 patients with normal angiograms
compared to 65 patients with significant coronary stenosis
]. The presence of two out of three specific symptoms
was noted in their study in 85% of patients with significant
disease while it was only observed in 26% of those with
normal angiograms. Also, other studies showed the
importance of medical history for both diagnosis and prognosis in
patients with suspected angina [
]. Similarly, in patients
referred for coronary computed tomography angiography,
the importance of symptoms was demonstrated [
Our study was too small to assess whether typical
symptoms predict severe stenosis in men and women. In general,
women have different symptoms, which are more frequently
not recognised as angina [
]. They often experience
symptoms such as nausea, shortness of breath, abdominal pain
or extreme fatigue, with or without chest pain. It is also
more difficult to demonstrate microvascular disease (which
is more common in women) with ICA.
We found that ICA in older patients with normal MPI
more commonly demonstrates stenosis. First, we should be
aware that the prevalence of abnormal ICA is high, even in
asymptomatic older patients. Second, it remains to be seen
whether the symptoms of older patients are always related
to specific and discrete coronary stenosis.
We demonstrated that mortality was low, and that severe
coronary stenosis was not associated with increased
longterm mortality in our population with normal MPI.
Importantly, the majority of these patients were prescribed aspirin
and statins. This confirms the generally good prognosis of
stable coronary disease, with an annual incidence of cardiac
death and non-fatal myocardial infarction between 0.6 and
1.4% and 0.6 and 2.7%, respectively [
In patients with persistent symptoms suggestive of
angina and recent normal non-invasive functional test
results an initial trial of optimal medical treatment combined
with lifestyle interventions should be considered. When
symptoms don’t improve despite medical treatment, further
intensification of medical treatment is recommended. If
symptoms persist, ICA with FFR measurement should be
considered as recommended in the ESC guideline [
patients with a high pre-test likelihood of coronary artery
disease false negative SPECT results may occur as Bayes’
theorem predicts that a high post-test likelihood will
remain as well. However, several studies have demonstrated
that current pre-test likelihood scores overestimate the
true prevalence of obstructive stenosis found in patients
with typical angina [
]. Therefore, non-invasive coronary
computed tomography angiography could be used as an
alternative to exclude the presence of relevant obstructive
CAD following a normal SPECT scan in patients with
persisting symptoms [
]. Other alternatives to depict false
negative SPECT may include quantitative positron
emission tomography MPI [
] or cardiac perfusion magnetic
resonance imaging (MRI) [
Our study has several limitations. First, we studied
a highly selected population, who had ICA after normal
MPI because of persisting symptoms, and had no data on
patients without subsequent ICA after normal MPI. Second,
the data were retrospectively collected. Hence,
misclassification of baseline characteristics may have occurred. Third,
FFR was performed in only few patients, and the
haemodynamic importance of stenosis can be discussed, particularly
in our selected patients with normal MPI. However,
European guidelines at the time of ICA recommended additional
FFR only in patients with intermediate coronary stenosis
(i. e. 50–70%), while coronary revascularisation could be
considered, based on symptoms, for patients with persisting
angina unresponsive to optimal medical treatment [
In 2009, Tonino et al. showed the superiority of FFR over
ICA in patients with multivessel disease [
]. Since then,
we have been using FFR at our hospital more often to assess
the severity of a stenosis, particularly in patients without
documented ischaemia. Fourth, intramural plaques cannot
be visualised by normal ICA, and neither intravascular
ultrasound nor optical coherence tomography was used in
our study. Fifth, further non-invasive cardiac evaluation by
means of either PET imaging or cardiac MRI was not
performed, but these investigations are routinely used in only
a few hospitals. Finally, the majority of our myocardial
perfusion procedures were performed without computed
tomography-based attenuation correction. However,
computed tomography-based attenuation, may possibly only
improve specificity of MPI in specific subgroups [
Increasing age, male gender, previous PCI and typical
symptoms are predictors of severe stenosis at invasive
coronary angiography in patients with persisting symptoms
after normal nuclear MPI. The majority of these patients
have single-vessel disease (not the left main coronary
Take home message
● Age, male gender, prior percutaneous coronary
intervention and typical angina are predictors of obstructive
coronary artery disease in patients with persisting symptoms
and normal single photon emission computed
● The majority of these patients have single-vessel disease
● Severe coronary stenosis was not associated with
increased mortality at long-term follow-up
Acknowledgements We thank Vera Derks for excellent editorial
Conflict of interest S. Yokota, J.P. Ottervanger, M. Mouden, M.J. de
Boer, P.L. Jager and J.R. Timmer declare that they have no competing
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