Presence and extent of cardiac computed tomography angiography defined coronary artery disease in patients presenting with syncope
Presence and extent of cardiac computed tomography angiography defined coronary artery disease in patients presenting with syncope
S. Altintas 0 1 2 4 5
T. Dinh 0 1 2 4 5
N. G. H. M. Marcks 0 1 2 4 5
M. Kok 0 1 2 4 5
A. J. J. Aerts 0 1 2 4 5
B. Weijs 0 1 2 4 5
Y. Blaauw 0 1 2 4 5
J. E. Wildberger 0 1 2 4 5
M. Das 0 1 2 4 5
B. L. J. H. Kietselaer 0 1 2 4 5
H. J. G. M. Crijns 0 1 2 4 5
0 Department of Radiology, MUMC
1 Cardiovascular Research Institute Maastricht (CARIM), School for Cardiovascular Diseases , MUMC
2 Department of Cardiology, Maastricht University Medical Center
3 , Maastricht , The Netherlands
4 Department of Cardiology, University Medical Center Groningen , Groningen , The Netherlands
5 Department of Cardiology, Zuyderland Medical Center , Heerlen , The Netherlands
Background In syncope patients, presence of coronary artery disease (CAD) is associated with poor prognosis. However, data concerning CAD prevalence in syncope patients without known cardiovascular disease are lacking. Therefore, the aim of this study was to investigate presence and extent of CAD in syncope patients. Methods We included 142 consecutive patients presenting with syncope at the outpatient cardiology clinic who underwent coronary computed tomography (CT) angiography. Syncope type was ascertained by two reviewers, blinded for coronary CT angiography results. Of the patients, 49 had cardiac syncope (arrhythmia or structural cardiopulmonary disease) and 93 had non-cardiac syncope (reflex [neurallymediated], orthostatic or of unknown cause). Cardiac syncope patients were compared with matched stable chest
Coronary artery disease; Multidetector computed tomography; Cardiogenic syncope
pain patients regarding age, gender, smoking status,
diabetes mellitus type 2 and systolic blood pressure.
Results Distribution of CAD presence and extent in
cardiac and non-cardiac syncope patients was as follows: 72%
versus 48% any CAD; 31% versus 26% mild, 8% versus
14% moderate and 33% versus 7% severe CAD.
Compared with non-cardiac syncope, patients with
cardiac syncope had a significantly higher CAD presence and
extent (p = 0.001). Coronary calcium score, segment
involvement and stenosis score were also higher in cardiac
syncope patients (p-values 0.004). Compared to the chest
pain control group, patients with cardiac syncope showed
a higher, however, non-significant, prevalence of any CAD
(72% versus 63%) and severe CAD (33% versus 19%).
Conclusion Patients with cardiac syncope show a high
presence and extent of CAD in contrast to non-cardiac syncope
patients. These results suggest that CAD may play an
important role in the occurrence of cardiac syncope.
Syncope is defined as a transient loss of consciousness due
to transient global cerebral hypoperfusion and is
characterised by a rapid onset, short duration and complete
spontaneous recovery [1, 2]. It concerns a common medical
problem, with an incidence rate of 6.2 per 1000 person-years for
a first report . Syncope is a symptom with a wide
spectrum of potential aetiologies for which accurate diagnosis,
using additional testing, is of high importance [4–6]. Along
with the search for the underlying diagnosis, defining
progTable 1 Baseline characteristics of the study population
Cardiac syncope vs non-cardiac syncope
n = 142
Patient characteristics Cardiac syn- Non-cardiac
n = 49 n = 93
Continous variables are described as mean (±SD) or as median (interquartile range); categorical variables as number (%)
BMI body mass index
an = 19 lost to PROCAM risk score; bn = 34 lost to PROCAM risk score
nosis is crucial, whereby the risk of death, recurrence, as
well as life-threatening events should be considered [2, 4].
Within the current European Society of Cardiology
Guidelines for the diagnosis and management of syncope,
only limited guidance is offered for diagnostic strategies
to detect CAD . Ischaemia evaluation is recommended
within the current guidelines of the American College
of Cardiology/American Heart Association (ACC/AHH)
for syncope patients with known, or who are at risk for,
coronary artery disease (CAD) . However, there is no
guidance regarding anatomical imaging techniques to
detect CAD in syncope patients despite the evidence that
arrhythmic causes for syncope, such as atrial fibrillation
or ventricular tachycardia, have a higher risk of major
adverse cardiovascular and cerebral events in the presence
of CAD [7, 8]. Additionally, all patients with syncope and
ischaemic heart disease have an increased risk of death [1,
Currently, coronary computed tomography (CT)
angiography (CCTA) is a widely implemented non-invasive
imaging modality to diagnose CAD [10–12]. Conventional
CCTA reading includes assessment of the coronary calcium
score (CCS), luminal stenosis severity and extent of CAD
with high sensitivity and specificity [10, 12]. It may be
considered in stable chest pain patients with an intermediate
pre-test probability of ischaemic heart disease . Despite
the wide use of CCTA in patients with stable chest pain,
there are no recommendations for CAD detection with
CCTA in patients presenting with syncope. Nevertheless,
diagnosing CAD within syncope patients in an early stage
could have important prognostic and therapeutic clinical
implications. Therefore, the aim of the present study was to
investigate the presence and extent of CAD, as defined by
CCTA, in patients presenting with syncope at the outpatient
This was an observational single-centre study analysing
142 retrospectively collected consecutive patients
presenting with syncope at the outpatient cardiology department
between May 2007 and April 2015 who were referred for
CCTA within their diagnostic workup. Patients were
selected if they met the definition of syncope, which was
defined as transient loss of consciousness due to global
cerebral hypoperfusion with rapid onset, short duration and
spontaneous complete recovery .
General exclusion criteria for CCTA examination were:
haemodynamic instability, pregnancy, renal insufficiency
(defined as glomerular filtration rate <45 ml/min/1.73 m)
and known severe allergic reactions regarding iodine.
This study was approved by the Institutional Review
Board (METC 15-4-091) and complies to the ethical
guidelines of the 1975 Declaration of Helsinki. Written informed
consent was waived, because the data were anonymously
recorded and analysed in accordance with guidelines of our
Data collection and definitions
Data regarding syncope type, age, gender, cardiovascular
risk factors, medication use, additional diagnostic testing
and CCTA results were collected from the patients’ charts
and electronic medical records.
Table 2 Distribution of conventional CT parameters across cardiac syncope patients versus non-cardiac syncope patients and matched chest
pain control group
CT computed tomography, CAD coronary artery disease, AU Agatston Unit
The type of syncope was ascertained by chart review by
two reviewers (N.M., T.D.), blinded for CCTA results. The
definitive syncope type was ascertained by consensus
between the two reviewers. The following pathophysiological
classification and sub-classification was used to adequately
define the syncope types in each individual patient :
1. Cardiac syncope (cardiovascular): arrhythmia or struc
tural cardiopulmonary disease as primary cause,
2. Reflex (neurally-mediated) syncope: vasovagal, situa
tional or carotid sinus syncope,
3. Syncope due to orthostatic hypotension: primary or sec
ondary autonomic failure, drug-induced orthostatic
hypotension or volume depletion,
4. Syncope of unknown cause: defined as an unknown cause
despite additional diagnostic testing.
Subsequently, patients with reflex syncope, orthostatic
syncope and syncope of unknown cause were classified as
having ‘non-cardiac syncope’, which led to two main
syncope categories: cardiac and non-cardiac syncope.
Diabetes mellitus was defined as fasting glucose levels
of ≥7 mmol/l or treatment with either diet intervention, oral
glucose lowering agent or insulin ; smoking was defined
as current smoking. A positive family history was defined
as having a first-degree relative with a history of myocardial
infarction or sudden cardiac death before the age of 60.
The PROCAM risk score was determined according to
the following parameters: age, LDL cholesterol, smoking,
HDL cholesterol, systolic blood pressure, family history
of premature myocardial infarction, diabetes mellitus, and
triglycerides . This risk score predicts the absolute
10year risk for the occurrence of an acute coronary event
(fatal or non-fatal myocardial infarction or acute coronary
death). A score <10% is estimated as low risk, 10–20% as
intermediate risk, and >20% as high risk.
To further study the impact of cardiac syncope symptoms
on detection of CAD, we compared the cardiac syncope
patients with stable chest pain patients. The cardiac syncope
patients were compared (1:2 ratio) with stable chest pain
patients, referred for CCTA from the outpatient cardiology
clinic to compare the prevalence and extent of CAD in
cardiac syncope patients with stable chest pain patients.
Matching was based upon age, gender, smoking status, diabetes
mellitus type 2 and systolic blood pressure (±10 mm Hg).
Scans were performed using a 64-slice multidetector
computed tomography scanner (Brilliance 64; Philips
Healthcare, Best, The Netherlands) or a 2nd generation dual-source
CT scanner (Somatom Definition Flash, Siemens
Healthcare, Forchheim, Germany). Data acquisition parameters
for the Brilliance 64 were a 64 × 0.625 mm slice
collimation, a gantry rotation time of 420 ms and a tube
voltage of 80 or 120 kV depending on patients’ height and
weight. Data acquisition parameters for the Somatom
Definition Flash were a 2 × 128 × 0.600 mm slice collimation,
a gantry rotation time of 280 ms and a tube voltage of 100 or
120 kV depending on patients’ height and weight. A
noncontrast enhanced scan was performed using 120 kV and
3 mm slice thickness to determine the CCS . CCTA
was performed using 75–120 ml of contrast agent (Xenetix
350; Guerbet, France or Ultravist 300; Bayer Healthcare,
Berlin, Germany) injected in the antecubital vein at a rate
of 5.2–7.4 ml/s followed by 40 ml intravenous saline at the
same flow rates.
Scan protocols differed between both CT scanners. For
the 64-slice scanner, a prospectively gated ‘Step and shoot’
Fig. 1 CAD presence and
extent (percentages) within
cardiac syncope patients versus
non-cardiac syncope patients
protocol was used in patients with stable heart rate <65 bpm.
In patients with a heart rate >65 bpm, a retrospectively
gated ‘Helical’ protocol was used with dose modulation.
For the 2nd generation dual-source CT scanner, a
prospectively gated high-pitch spiral ‘Flash’ protocol was used
in patients with a stable heart rate <60 bpm. In patients
with a stable heart rate between 60–90 bpm, a
prospectively gated axial ‘Adaptive sequence’ protocol was used.
In patients with a heart rate >90 bpm or with an
irregular heart rhythm, a retrospectively gated ‘Helical’ protocol
was used. Dose modulation was switched on in all three
protocols using tube current modulation (CARE Dose4D,
Siemens Healthcare, Forchheim, Germany).
Patients received 50 mg Metoprolol tartrate orally
(AstraZeneca, Zoetermeer, the Netherlands), two hours
before CCTA, unless contra-indicated. If indicated, an
additional dose of 5–20 mg Metoprolol was administered
intravenously to lower the heart rate. All patients received
nitroglycerine (Pohl-Boskamp, Hohenlockstedt, Germany)
sublingually in a dose of 0.8 mg just prior to CCTA.
The Agatston method was used to define the CCS .
CCTA’s were independently analysed by a cardiologist
and a radiologist, both experienced in the assessment of
CCTA. In case of disagreement, consensus was reached
by discussion. The assessment was performed using the
source images on the provided software (Cardiac
Comprehensive Analysis, Philips Healthcare or Syngo CT 2010A,
Siemens Healthcare). The coronary artery tree was
analysed for the presence and extent of CAD, according to
the 16-segment classification of the American Heart
Association . Plaques were defined as visible structures
within or adjacent to the coronary artery lumen, which
could be clearly distinguished from the vessel lumen and
the surrounding pericardial tissue. The degree of stenosis
was visually defined and classified as no CAD (no
luminal stenosis), mild (<50% luminal stenosis), moderate
(50–70% luminal stenosis), severe (>70% luminal
stenosis). A segment involvement score was defined by counting
all coronary segments with plaques (irrespective of degree
of stenosis), which resulted in a score ranging from 0–16
. A segment stenosis score was the sum of the lesion
severity in all 16 coronary segments, resulting in a score
ranging from 0–48 .
Data were analysed using SPSS version 23.0 (SPSS Inc.,
Chicago, IL, USA). Continuous variables were checked
whether they were normally distributed using box plots,
histograms or by computing skewness and kurtosis.
Continuous data were reported as means and standard deviations
(SDs) if normally distributed. If data were not normally
distributed, continuous data were reported as medians and
boundaries of interquartile ranges (IQR). Proportions (%)
were used for categorical values.
Differences across groups were assessed using the
independent t-test for normally distributed data after performing
Fig. 2 CAD presence and
extent (percentages) within
cardiac syncope versus matched
chest pain control group
Levene’s test for equality of variance. The Mann-Whitney
test was used for data that were not normally distributed.
Categorical variables were tested with Fisher’s exact test.
All p-values were 2-sided, and a p-value below 0.05 was
considered statistically significant.
Between May 2007 and April 2015, 142 consecutive
patients presented with syncope at the outpatient cardiology
clinic who were referred for CCTA. The distribution of
syncope classifications was as follows: 49 (35%) cardiac
syncope, 63 (44%) reflex (neurally-mediated) syncope, 10
(7%) orthostatic syncope and 20 (14%) syncope of
unknown cause. Subsequently, patients with reflex syncope,
orthostatic syncope and syncope of unknown cause were
classified as having ‘non-cardiac syncope’ leading to two
main categories, with 49 (35%) cardiac syncope patients
and 93 (65%) non-cardiac syncope patients.
The baseline characteristics of the study population are
described in Table 1. When compared to non-cardiac
syncope patients, only age showed a statistically significant
difference between the cardiac and non-cardiac syncope
groups (mean (SD): 60 (13) versus 54 (12); p = 0.002).
The Online Supplemental Material provides further detailed
clinical information regarding the syncope patients.
Presence and extent of CAD in syncope
The distribution of CAD presence and extent in cardiac and
non-cardiac syncope patients was as follows: 72% versus
48% any CAD; 31% versus 26% mild CAD; 8% versus 14%
moderate CAD and 33% versus 7% severe CAD (Table 2).
Fig. 1 visualises CAD prevalence and distribution of
CAD in patients with cardiac and non-cardiac syncope.
CAD presence and extent was significantly higher in
patients with cardiac syncope in comparison with
non-cardiac syncope patients (Table 1; p = 0.001). Additionally,
all conventional CT parameters including CCS, segment
involvement and segment stenosis score were significantly
higher in patients with cardiac syncope compared to
noncardiac syncope (80 [0–387] versus 0 [0–79]; 2 [0–5]
versus 0 [0–2]; 3 [0–7] versus 0 [0–3]) (all p-values 0.004;
Presence and extent of CAD in patients with cardiac
syncope versus matched chest pain controls
Fig. 2 displays the presence and extent of CAD in both
cardiac syncope patients and matched chest pain controls.
Patients with cardiac syncope showed a higher prevalence
of any CAD (72% versus 63%, respectively) and percentage
of severe luminal stenosis (33% versus 19%). Interestingly,
no statistically significant difference was observed between
cardiac syncope patients and chest pain controls regarding
overall prevalence of CAD presence and its extent (p =
Table 2 shows that all other conventional CT parameters
including CCS, segment involvement score and segment
stenosis score were comparable between cardiac syncope
patients and chest pain controls (all p-values ≥0.272).
To our best knowledge, this is the first study dedicated to
investigating the prevalence and extent of CAD in patients
presenting with syncope. The main finding of this study
was that cardiac syncope patients showed a high presence
and extent of CAD in comparison with non-cardiac syncope
patients. In addition, all other coronary CT parameters like
CCS, segment involvement score and stenosis score were
also significantly higher in cardiac syncope patients
compared to non-cardiac syncope patients. When compared to
stable chest pain controls, patients with cardiac syncope
showed a higher, however, non-significant, prevalence of
any CAD (72% versus 63%, respectively) and percentage
of severe luminal stenosis (33% versus 19%). Taken
together, these results suggest that the non-invasive evaluation
of CAD, using CCTA, could be considered within the
diagnostic workup of patients presenting with cardiac syncope
at the outpatient cardiology clinic. Additionally, CCTA may
show alternative causes for cardiovascular syncope such
as congenital anomalies of coronary arteries, hypertrophic
cardiomyopathy, pulmonary embolism, obstructive valvular
heart disease, intracardiac masses and pericardial diseases.
Association and relevance of CAD in cardiac syncope
Meticulous history taking is essential in arriving at a
diagnosis in patients with syncope. Once cardiac syncope is
suspected, a wide range of different diagnostic tests can
be considered in patients presenting with syncope [2, 6].
However, there is no guidance regarding anatomical
imaging techniques to detect CAD due to lacking evidence
describing the extent and nature of CAD in patients with
cardiac syncope. The relationship between cardiac ischaemia
and syncope is multiple, including induction of
non-sustained ventricular arrhythmias and sinoatrial or
atrioventricular block, or by triggering e. g. the Bezold-Jarisch-reflex
causing severe bradycardia and hypotension. Apart from
a direct relationship, indirect mechanisms may be
important, including old myocardial infarction with ventricular
remodelling as a basis for re-entrant or adrenergic
ventricular tachycardia; likewise, atrial remodelling leading to late
onset atrioventricular nodal tachycardia or atrial
tachycardias may at times occur with well-known haemodynamic
compromise eliciting syncope at the beginning of the
attack . In all of the above-mentioned aetiologies, CAD
may be causal or contributory for syncope whereby one
could conjecture that interventional and vascular
prophylactic management may help to reduce further syncope in
these patients. In all other cases, CAD presence should be
considered as coincidental wherefore vascular prophylactic
vascular management may not be indicated in the
management of syncope.
Within the European Society of Cardiology guidelines for
the diagnosis and management of syncope, exercise stress
testing is only recommended in patients with suspected
exercise-induced syncope, which concerns a rare condition
. Concurrently, ischaemia evaluation is recommended by
the American College of Cardiology/American Heart
Association (ACC/AHA) for patients with syncope and an
intermediate-to-high risk for coronary heart disease or known
CAD, but such strategy may underdiagnose the presence of
non-obstructive CAD, which still is associated with high
major adverse cardiac event rates [6, 20, 21]. On the other
hand, a previous report revealed a low-diagnostic yield for
stress myocardial perfusion imaging across all risk
categories in syncope patients without known CAD .
Previously, Soteriades et al. investigated the incidence and
prognosis of syncope among participants of the
Framingham Heart Study and found that patients with a cardiac
syncope were more likely to have a history of CAD and
were at an increased risk for death from any cause and
cardiovascular events . A more recent study of patients
presenting with syncope at the emergency department with
trauma, has shown that patients with a history of CAD are
four times more likely to have cardiac syncope in contrast
to non-cardiac syncope .
These previous reports support the high prevalence and
extent of CAD in patients presenting with cardiac syncope
compared to patients with non-cardiac syncope within the
present study. Furthermore, in the presence of obstructive
CAD in patients with syncope, treatment by either
percutaneous coronary intervention (PCI) or medical management
did not improve readmission rates due to syncope.
However, PCI did improve long-term mortality in patients with
syncope, suggesting the need for imaging of the coronary
Moreover, in syncope patients with left ventricular
dysfunction, inducible ventricular tachycardia was frequent in
the presence of CAD and associated with a bad prognosis
. Therefore, by diagnosing stable CAD and providing
additional treatment with vascular protective medication,
the prognosis of cardiac syncope patients could be
positively influenced. HMG-CoA reductase inhibitors (statins)
have become a cornerstone in the treatment of patients with
stable CAD due to their lipid-lowering characteristics and
additional atherosclerotic plaque stabilization, systemic
inflammation and thrombogenicity reducing effects . In
line with these findings, recent review articles summarise
that statins even reduce the incidence of ventricular
tachycardia/fibrillation and sudden cardiac death in patients with
CAD due to their anti-ischaemic, and possibly also by their
antiarrhythmic or anti-inflammatory, effects [26, 27].
This study has several limitations that should be mentioned.
Firstly, it concerns a study with a relatively small sample
size. Secondly, there was some degree of referral bias
considering that our institution is a tertiary centre for patients
with syncope. This is confirmed by the fact that within our
syncope study population, a higher relative prevalence of
cardiac syncope was observed in comparison to previous
reports [2, 3]. Thirdly, the syncope patients were included
if they were referred for CCTA, inducing some degree of
selection bias. The combination of referral as well as
selection bias could have contributed to the high prevalence
and extent of CAD within the cardiac syncope patients.
Also important is the fact that no direct causal relationships
could be identified regarding the presence and extent of
CAD and syncope due to the present study design, as this
would require a prospective interventional study.
Patients with cardiac syncope show a high presence and
extent of CCTA defined CAD in contrast to patients with
non-cardiac syncope. These results suggest that CAD may
play an important role in the occurrence of cardiac syncope
and should be considered in the diagnostic workup and
treatment of syncope patients.
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