European Heart Journal Cardiovascular Imaging (2012) 13, 776–785
doi:10.1093/ehjci/jes060
Meaning of zero coronary calcium score
in symptomatic patients referred for coronary
computed tomographic angiography
Young Jin Kim, Jin Hur, Hye-Jeong Lee, Hyuk-Jae Chang, Ji Eun Nam, Yoo Jin Hong,
Hee Young Kim, Ji Won Lee, and Byoung Wook Choi*
Yonsei University Health System, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea
Received 3 January 2012; accepted after revision 6 March 2012; online publish-ahead-of-print 29 March 2012
Aims
The clinical implication of a zero coronary calcium score (CCS) in patients with chest pain syndrome has been under
debate. This study was undertaken to determine the meaning of a CCS of zero in a large sample of symptomatic
patients referred for coronary computed tomographic (CT) angiography.
.....................................................................................................................................................................................
Methods
We consecutively enrolled 2088 patients (age 58 + 10 years, 1028 men) who had undergone 64-slice cardiac CT due
and results
to chest pain syndrome. A CCS of zero was detected in 1114 patients (471 men and 643 women). Of these 1114
patients, obstructive coronary artery disease (CAD) was found in a total of 48 patients (4.3%); 35 men (7.4%) and 13
women (2.0%). Among the zero CCS patients with obstructive CAD, men had a higher prevalence of both premature
CAD (49 vs. 0%) and multivessel disease (20 vs. 8%) than women. During the follow-up period (1033 + 136 days),
early revascularization was done in 25 patients (2.2%, 18 men and 7 women) and there were 14 major adverse
cardiac events (1.3%, 8 men and 7 women) among the zero CCS patients. CAD severity was a strong prognostic
indicator in the zero CCS patients.
.....................................................................................................................................................................................
Conclusion
A CCS of zero cannot be used by itself to exclude obstructive CAD in symptomatic patients referred for coronary CT
angiography (CCTA). The prevalence of obstructive CAD and adverse cardiac events are not negligible in symptomatic
patients with a CCS of zero, and CAD severity by CCTA is associated with higher rates of adverse cardiac event.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Coronary CT † Coronary artery calcium † Chest pain syndrome † Prognosis
Introduction
Coronary artery calcium (CAC) is pathognomonic of coronary
atherosclerosis and represents atherosclerotic plaque burden.
Several large clinical trials have found a clear, incremental predictive value of CAC quantified with cardiac computed tomography
(CT) over the Framingham risk score; based on these findings,
the coronary calcium score (CCS) has been used for risk prediction of future cardiovascular events.1 – 3
The absence of CAC is generally taken to indicate a very low
risk of future cardiovascular events1,3 – 7 and the latest guidelines
published by the American College of Cardiology Foundation
(ACCF) and the American Heart Association (AHA) suggest
that a CCS of zero might exclude the need for coronary
angiography among symptomatic patients.8 However, some
researchers have reported conflicting results using multidetector
CT.9 – 13 In these studies, a considerable proportion of symptomatic patients with a CCS of zero had obstructive coronary artery
disease (CAD), as well as non-calcified plaques. As such, these
investigators found that a CCS of zero does not exclude clinically
important obstructive CAD in patients with chest pain syndrome.
These previous studies, however, included a relatively low
number of subjects with high probabilities of CAD and there
was no further investigation into the prognostic significance of
a CCS of zero.
Therefore, the current study aimed to determine the clinical
implication of a CCS of zero in a large number of symptomatic
patients undergoing coronary CT angiography (CCTA).
* Corresponding author. Tel: +82 2 2228 7400, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]
777
Zero CCS in symptomatic patients
Methods
Study subjects
This study was approved by our institutional review board and
informed consent was waived due to the retrospective study design.
This was an observational, single-centre study. Among the 3462
patients who underwent cardiac CT from January 2008 to May 2009
at our institution, a total of 2088 consecutive patients (mean age, 59
years; range, 19 – 86 years) with symptoms of suspected CAD were
enrolled in the study. Patients without chest pain syndrome or patients
with a previous history of myocardial infarction (MI), percutaneous
coronary intervention, or coronary bypass surgery were excluded.
Clinical symptoms and information regarding CAD risk factors,
including diabetes mellitus, hypertension, dyslipidaemia, and smoking,
were obtained from electronic medical records. Symptoms included
typical angina, atypical angina, or non-anginal chest pain. According
to ACC/AHA guidelines,14 typical angina was defined as: (i) substernal
chest discomfort with a characteristic quality and duration that is (ii)
provoked by exertion or emotional stress and (iii) relieved by rest
or nitroglycerin. Atypical angina was defined as chest discomfort that
lacks one of the above characteristics and non-anginal chest pain as
chest discomfort that met one or none of the typical angina characteristics. The pretest probability of CAD was calculated by using age, sex,
and symptoms;14,15 high indicates a probability of .90%; intermediate,
10 –90%; low, ,10%; and very low, ,5%. Hypertension was defined
as a self-reported history of hypertension, the use of antihypertensive
medication, or a blood pressure of ≥140/90 mmHg. Diabetes was
defined as a self-reported history of diabetes and/or receiving antidiabetic treatment, or a fasting glucose of ≥126 mg/dL. A history of
smoking was considered to be present if the patient currently
smoked or had smoked until 1 month prior to the study. Dyslipidaemia
was defined as a total cholesterol of ≥240 mg/dL, a low-density lipoprotein of ≥130 mg/dL, a high-density lipoprotein of ,40 mg/dL, a triglyceride level ≥200 mg/dL, and/or treatment with a lipid-lowering
agent. Premature CAD was defined as the development of obstructive
CAD in patients less than 45 years old. Females less than 50 years were
considered premenopausal.16
Computed tomographic protocol
Cardiac CT was performed using a 64-slice scanner (Sensation 64;
Siemens Medical Systems, Erlangen, Germany). To reduce heart rate
in patients with heart rates above 65 bpm, an oral b-blocker (50 mg
of metoprolol tartrate; Betaloc, Yuhan, Seoul, Korea) was administrated 1 h prior to examination. A 0.3 mg sublingual dose of nitroglycerin was administered before initiation of scanning. Before CCTA, a
non-enhanced prospective electrocardiography (ECG)-gated sequential scan was performed to measure CAC with the following parameters: a rotation time of 330 ms, a slice collimation of 0.6 mm, a
slice width of 3.0 mm, a tube voltage of 120 kV, and a tube current
of 50 mAs. CCTA was then performed using retrospective ECG
gating and the following scan parameters: a rotation time of 330 ms,
a slice collimation of 64 × 0.6 mm, a tube voltage of 100 kV (if the
patient’s body mass index was ,25 kg/m2) or 120 kV (if BMI was
.25 kg/m2), a tube current of 800 mAs, and a pitch factor of 0.2.
ECG-based tube current modulation was applied to 65% of the R-R
interval except in the case of arrhythmia. The mean radiation dose
for the CAC scan and CCTA was calculated as 1.1 (0.6 – 1.8) and 7.0
(2.8– 14.8) mSv, respectively.
A real-time bolus-tracking method was used to trigger the initiation
of the scan. Contrast enhancement was achieved with 70 mL of iopamidol (370 mg of iodine per millilitre, Iopamiro; Bracco, Milan, Italy)
injected at 5 mL/s, followed by an injection of 50 ml of saline at
5 mL/s with a power injector (Envision CT; Medrad, Indianola, PA,
USA) via the antecubital vein.
Image analysis
The CAC scan and CCTA images were evaluated using a dedicated
clinical workstation (Wizard, Siemens Medical Solutions, Erlangen,
Germany). The CCS was calculated by the Agatston method.17
Patients were divided into five subsets based on their CCSs;
CAC ¼ 0, 0 , CAC ≤ 10, 10 , CAC ≤ 100, 100 , CAC ≤ 400, and
CAC . 400.
Axial CCTA images were retrospectively reconstructed at 65% of
the R-R interval for each cardiac cycle by using a section thickness
of 0.75 mm and an increment of 0.5 mm, with a smooth kernel
(B25f). If artefacts appeared, additional image data sets were obtained
for various points of the cardiac cycle, and the data set with minimum
artefact was selected for further analysis. The CCTA images were evaluated independently by two experienced investigators who were
unaware of the clinical histories of the patients. After making independent evaluations, consensus interpretation was made to obtain a final
diagnosis. Semi-quantitative assessment was performed on all segments of the coronary artery, with the estimate of stenosis severity
calculated as the ratio of the minimum lumen over the normal reference lumen of an unaffected distal portion. Obstructive CAD was
defined as a luminal narrowing of ≥50%, whereas non-obstructive
CAD was defined as a luminal narrowing of ,50%. The extent of
obstructive CAD was categorized into one-, two-, and three-vessel
involvement. Obstructive CAD of the left main artery was considered
as two-vessel involvement.
Follow-up
Patient follow-up data for composite major adverse cardiac events
(MACEs) were collected by reviewing electronic medical records
and/or standardized telephone interviews. Early elective revascularization within 60 days after the index CT examination was excluded
from the analysis of composite MACEs to avoid treatment bias.
MACE was defined as cardiac death, non-fatal MI, unstable angina
requiring hospitalization, and late revascularization. Patient death
status was ascertained by querying the National Health Insurance
Corporation.
Statistical analysis
Continuous data were expressed as the mean values + standard
deviation. All categorical data were presented as a percentage or
an absolute number. The Student t-test was used to assess differences in mean values, and proportion comparisons were performed
by x 2 tests. Multivariate logistic regression analysis was undertaken
to determine associations between the presence of obstructive
CAD and other patient characteristics. A composite MACE
(cardiac death, non-fatal MI, unstable angina requiring hospitalization,
and/or late revascularization) was used as an endpoint. The Cox
regression analyses were used to identify associations between
clinical CT parameters and outcomes and were also used to identify
potential predictors. Hazard ratios were calculated as an estimate of
a risk associated with a particular variable, with 95% confidence
intervals. Statistical analyses were performed using commercially
available software (MedCalc for Windows, version 11.6.1.0;
MedCalc Software, Mariakerke, Belgium). A P-value of ,0.05 was
considered to be statistically significant.
778
Y.J. Kim et al.
Results
Coronary artery disease in patients
with zero coronary calcium score
Patient characteristics
The study cohort was comprised of 1028 men (mean age, 57 years;
range, 23– 82 years) and 1060 women (mean age, 60 years; range,
23 –86 years). Most of these patients presented to the hospital
with atypical angina or non-anginal chest pain, with the majority
of individuals having intermediate pretest probability. The pretest
probability of CAD could not be assessed in patients younger
than 30 years (0.6%, 12/2,088) or patients older than 70 years
(9%, 181/2,088).
The prevalence of CAC in our cohort was 47% (974/2088)
and the average CCS was 100 + 311 (range, 0–3890). Men
had both a higher prevalence of CAC and a higher mean
CCS than women (54.2 vs. 39.3%, P , 0.0001, and 138.2 vs.
63.8, P , 0.0001). A total of 444 patients (21%) had obstructive
CAD by CCTA and men were more likely to have obstructive
CAD than women (29.1 vs. 13.6%, P , 0.0001; Table 1). Men
had a higher prevalence of obstructive CAD than women
irrespective of chest pain type (Figure 1A). When patients
were divided into five subsets based on the CCS; CAC ¼ 0
(n ¼ 1,114),
0 , CAC ≤ 10
(n ¼ 205),
10 , CAC ≤ 100
(n ¼ 380), 100 , CAC ≤ 400 (n ¼ 242), and CAC . 400 (n ¼
147), the prevalence of obstructive CAD increased with their
CCS values. Statistically significant differences in obstructive
CAD prevalence between the sexes were only noted in patients
with a CCS of zero (Figure 1B).
Table 1
Among 2088 symptomatic patients, the CCS was zero in 1114
patients (471 men and 643 women). Coronary artery plaques
were detected in 158 (14%) of these zero CCS patients. Men
with a CCS of zero had more plaques compared with women
with a CCS of zero (17.8 vs. 10.7%, P ¼ 0.0052). Obstructive
CAD was found in 48 (4.3%) of these zero CCS patients. The
prevalence of obstructive CAD was also significantly higher in
males than females in this subset (7.4 vs. 2.0%, P , 0.0001; Table 2).
Most (40/48, 83%) patients with a CCS of zero and with
obstructive CAD had one-vessel disease. However, more men
(7/35, 20%) with a CCS of zero and with obstructive CAD had
multivessel disease, compared with women (1/13, 8%; Table 3).
Moreover, premature CAD (obstructive CAD at an age of ,45
years old) was found in 49% (17/35) of men with zero CCS and
obstructive CAD, while premature CAD was not found in
women with a CCS of zero. Among 110 female patients younger
than 50 with zero CCS, obstructive CAD was found in only one
patient, who had diabetes.
In a multivariate logistic regression analysis of factors that
may be associated with the prevalence of obstructive CAD on
CCTA, male sex, diabetes, and typical angina were found to be
independently associated with obstructive CAD in patients
with a CCS of zero. The odds ratio for male sex was 3.98
(P ¼ 0.0002), for diabetes was 2.34 (P ¼ 0.03), and for typical
angina was 3.0 (P ¼ 0.008; Table 4).
Characteristics of the study cohort
Total (n 5 2088)
Men (n 5 1028)
Women (n 5 1060)
P-value
...............................................................................................................................................................................
Age, years
58.6 + 9.8
56.6 + 10.5
60.4 + 8.6
,0.0001
Body mass index, kg/m2a
Diabetes
24.8 + 3.0
340 (16)
25.0 + 2.7
188 (18)
24.5 + 3.2
152 (14)
0.001
0.044
Hypertension
1074 (51)
512 (50)
562 (53)
0.4270
988 (47)
271 (13)
506 (49)
259 (25)
482 (46)
12 (1)
0.3235
,0.0001
Typical angina
Atypical angina
325 (16)
923 (44)
154 (15)
451 (44)
171 (16)
472 (45)
0.5750
0.8820
Non-anginal chest pain
840 (40)
423 (41)
417 (39)
0.6107
Dyslipidaemia
Current smoker
Chest pain type
Pre-test CAD probabilitya
Very low
Low
Intermediate
High
39 (2)
0 (0)
39 (4)
,0.0001
227 (12)
46 (5)
181 (19)
,0.0001
1422 (75)
207 (11)
773 (81)
134 (14)
649 (69)
73 (8)
0.0222
0.0001
CT findings
Presence of CAC
Mean CCS
Obstructive CAD
974 (47)
100.4 + 310.7
444 (21)
557 (54)
138.2 + 365.7
299 (29)
417 (39)
63.8 + 240.4
145 (14)
Values are mean + SD or n (%). CAD, coronary artery disease; CAC, coronary artery calcium; CCS, coronary calcium score.
a
Pre-test CAD probability was not available in 193 patients who were older than 70 years or younger than 30 years.
,0.0001
,0.0001
,0.0001
Zero CCS in symptomatic patients
779
Figure 1 Prevalence by gender of obstructive CAD. (A) The prevalence of obstructive CAD according to chest pain type. (B) The prevalence
of obstructive CAD according to CCS.
Follow-up
Follow-up data were available in 99.3% (2073 of 2088) of patients, and
the mean follow-up period for the study population was 1033 + 136
days. During the follow-up period, elective revascularization on the
basis of CT results was done in 196 patients and 60 composite
MACEs occurred in this study cohort, for an event rate of 2.9%.
Among the 48 patients with zero CCS and with obstructive
CAD on CCTA, early elective revascularization therapy was
done in 25 patients. During follow-up of patients with a CCS of
zero, there were 14 composite MACEs, which consisted of
cardiac death in three patients, non-fatal MI in one patient, unstable
angina requiring hospitalization in three patients, and late revascularization in seven patients, for an event rate of 1.3% (14 of 1114).
Figure 2 and Table 5 demonstrate detailed follow-up data of
patients.
Unadjusted and adjusted hazard ratios for the composite MACE
in patients with a CCS of zero are shown in Table 6 and Figure 3.
Current smoking, the presence of typical angina, the presence of
780
Y.J. Kim et al.
Table 2
Characteristics of patients with zero CCS
Total (n 5 1114)
Men (n 5 471)
Women (n 5 643)
P-value
Age, years
55.3 + 10.1
51.7 + 10.9
57.9 + 8.6
,0.0001
Body mass index, kg/m2
Diabetes
24.6 + 3.1
102 (9)
24.8 + 2.8
48 (10)
24.4 + 3.3
54 (8)
0.038
0.4521
Hypertension
454 (41)
167 (35)
287 (45)
0.0488
Dyslipidaemia
Current smoker
486 (44)
126 (11)
213 (45)
121 (26)
273 (42)
5 (1)
0.6160
,0.0001
Typical angina
Atypical angina
130 (12)
499 (45)
43 (9)
206 (44)
87 (14)
293 (46)
0.0545
0.7485
Non-anginal chest pain
485 (44)
222 (47)
263 (41)
0.2147
...............................................................................................................................................................................
Chest pain type
Pre-test CAD probabilitya
Very low
37 (4)
0 (0)
37 (6)
,0.0001
Low
192 (18)
43 (10)
149 (25)
,0.0001
Intermediate
High
747 (72)
68 (7)
366 (82)
37 (8)
381 (64)
31 (5)
0.0098
0.0787
158 (14)
110 (10)
86 (18)
51 (11)
72 (11)
59 (9)
0.0052
0.4684
48 (4)
35 (7)
13 (2)
CT findings
Non-calcified plaque
Non-obstructive CAD
Obstructive CAD
,0.0001
Values are mean + SD or n (%). CAD, coronary artery disease.
a
Pre-test CAD probability was not available in 193 patients who were older than 70 years or younger than 30 years.
Table 3
Detailed characteristics of patients with zero CCS and with obstructive CAD
Total (n 5 48)
Men (n 5 35)
Women (n 5 13)
P-value
56.1 + 11.1
24.3 + 2.5
55.2 + 12.4
24.3 + 2.2
8.4 + 6.7
24.2 + 3.3
0.3893
0.8248
...............................................................................................................................................................................
Age (years)
Body mass index (kg/m2)
Diabetes
9 (19)
4 (11)
5 (39)
0.1153
Hypertension
Dyslipidaemia
21 (44)
25 (52)
14 (40)
17 (49)
7 (54)
8 (62)
0.7493
0.8213
Current smoking
13 (27)
13 (37)
0 (0)
0.0523
Chest pain type
Typical angina
11 (23)
7 (20)
4 (31)
0.8073
19 (40)
17 (49)
2 (15)
0.2541
18 (38)
11 (31)
7 (54)
0.5295
1-vessel disease
40 (83)
28 (80)
12 (92)
2-vessel disease
3-vessel disease
7 (15)
1 (2)
6 (17)
1 (3)
1 (8)
0 (0)
Atypical angina
Non-anginal chest pain
CT results
Conventional coronary angiography
37 (77)
27 (77)
10 (77)
1-vessel disease
2-vessel disease
29 (60)
7 (15)
21 (60)
5 (14)
9 (69)
1 (8)
3-vessel disease
1 (2)
1 (3)
0 (0)
non-obstructive CAD, as well as obstructive CAD at CCTA had an
independent prognostic predictive power for MACEs. Patients
without any evidence of CAD at CCTA (zero CCS and no
plaque) revealed excellent prognosis, for an event rate of 0.1%
(1 of 1114).
Discussion
The objective of the current study was to evaluate the clinical
significance of a CCS of zero in patients with chest pain syndrome.
The main findings revealed that in symptomatic patients with a
781
Zero CCS in symptomatic patients
CCS of zero, the prevalence of obstructive CAD by CCTA was
not negligible (4.3%; 7% of the men and 2% of the women) and
that zero CCS could not guarantee their mid-term prognosis:
elective revascularization was done in 2.2% of the patients (3.8%
of the men and 1.1% of the women), and composite MACEs
occurred in 1.3% (1.7% of the men and 0.9% of the women).
The CCS has been used in clinical practice for risk stratification,
and the absence of CAC is generally accepted as indicating very
low risk for future cardiovascular events. According to a
Table 4 Multivariate logistic regression analysis of
factors that may be associated with the presence of
obstructive CAD in patients with a CCS of zero
Odds ratio
95% CI
P-value
Age
1.03
0.99, 1.06
0.0666
Male sex
Diabetes mellitus
3.98
2.34
1.95, 8.13
1.07, 5.12
0.0002
0.0333
Hypertension
0.99
0.53, 1.84
0.9770
Dyslipidaemia
Current smoking
1.42
1.99
0.78, 2.57
0.95, 4.16
0.2491
0.0688
Typical angina
Atypical angina
3.00
1.04
1.34, 6.73
0.53, 2.05
0.0077
0.9045
Non-anginal chest pain
1
................................................................................
Chest pain type
CI, confidence interval.
meta-analysis of large population studies of CAC, the cumulative
incidences of cardiovascular events are 0.1 –0.5% during 3–5
years of follow-up in asymptomatic patients with zero CCS, irrespective of gender and risk factors, such as smoking or diabetes.18
However, there is still controversy regarding the use of this standard in symptomatic patients, as to whether or not a CCS of zero
can be used as a filter to rule out obstructive CAD when CAD is
clinically suspected. The latest ACCF/AHA Expert Consensus
Documents8 states that ‘For the symptomatic patient, exclusion
of measurable coronary calcium may be an effective filter before
undertaking invasive diagnostic procedures or hospital admission’.
However, several recent studies reported that a CCS of zero
does not reliably exclude obstructive CAD among patients
with a high suspicion of CAD referred for coronary angiography10,19 or patients presenting to the emergency department
with chest pain.20
During this ongoing debate, the indications of CCTA are
expanding, and it is being increasingly used to detect CAD due
to its non-invasiveness and diagnostic accuracy.21 Consequently,
patients referred for CCTA usually have a low-to-intermediate
pretest probability of CAD when compared with patients referred
for coronary angiography who generally have an intermediateto-high pretest probability. In a recent related study with patients
referred for CCTA, Sosnowski et al.13 found obstructive CAD in 3
(2%) of 166 subjects who had both a CCS of zero and an intermediate probability of CAD. Although its outcome was concluded
from fewer subjects than our own study, it is still concordant with
our results. The majority of our study subjects also had an intermediate probability of CAD; obstructive CAD was found in 48
(4.3%) of the 1114 patients with a CCS of zero and 158 patients
Figure 2 Flow chart showing prognosis of entire study cohort during follow-up.
782
Y.J. Kim et al.
Table 5
Follow-up data of patients in the entire study cohort
Total
(n 5 2088)
CCS
.....................................................................................................................
Zero
........................................................
Non-zero
.......................................................
Total
(n 5 1114)
Men
(n 5 471)
Women
(n 5 643)
Total
(n 5 974)
Men
(n 5 557)
Women
(n 5 417)
25 (2.2)
14 (1.3)
18
8
7
6
171 (17.6)
46 (4.7)
111
32
60
14
...............................................................................................................................................................................
Elective revascularization
Composite MACE
196 (9.4)
60 (2.9)
Cardiac death
9 (0.4)
3 (0.3)
3
0
6 (0.6)
4
2
Non-fatal MI
Unstable angina
5 (0.2)
9 (0.4)
1 (0.1)
4 (0.4)
0
1
1
3
4 (0.4)
5 (0.5)
3
4
1
1
37 (1.8)
6 (0.5)
4
2
31 (3.2)
21
10
24 (1.1)
8 (0.7)
5
3
16 (1.6)
10
6
Late revascularization
All-cause mortality
Table 6
Hazard ratios of composite MACEs according to risk factors in patients with a CCS of zero
Univariate analysis
............................................................
Variable
HR
95% CI
P-value
Multivariate analysis
...........................................................
HR
95% CI
P-value
...............................................................................................................................................................................
Age
0.99
0.94, 1.04
Male sex
1.88
0.65, 5.44
0.6864
0.2346
0.65
0.16, 2.66
0.5491
Diabetes mellitus
Hypertension
1.70
3.68
0.27, 10.63
1.27, 10.72
0.4839
0.0181
0.68
2.70
0.12, 3.89
0.78, 9.35
0.6695
0.1193
Dyslipidaemia
0.73
0.25, 2.09
0.5627
Current smoking
Chest pain type
4.62
0.85, 25.05
0.0026
4.68
1.13, 19.3
0.0337
Typical angina
3.19
0.86, 11.81
0.0836
5.15
1.16, 22.9
0.0318
Atypical angina
Non-anginal chest pain
0.98
1.00
0.29, 3.38
0.9797
0.74
1.00
0.20, 2.72
0.7444
CAD on CCTA
Obstructive CAD
Non-obstructive CAD
No CAD
324.1
52.6
40.28, 2608.2
6.40, 432.2
1.00
,0.0001
0.0002
423.7
51.3
47.0, 3817.4
6.12, 429.7
,0.0001
0.0003
1.00
CI, confidence interval.
(14.2%) had non-calcified plaques. Corresponding with our expectations, a higher prevalence of obstructive CAD and non-calcified
plaque was observed in our study’s symptomatic patients than was
observed in asymptomatic Korean subjects included in a recent
CCTA study.22 In that study, 1.2% of its asymptomatic participants
had obstructive CAD and 5% had non-calcified plaques.
According to our results, a CCS of zero cannot be used by itself
to exclude obstructive CAD in patients with chest pain syndrome
who are referred for CCTA because the prevalence of obstructive
CAD by CCTA was not negligible. Moreover, during mid-term
follow-up (2.8 + 0.4 years), revascularization or cardiac events
occurred in quite a few patients (3.5%, 39 of 1114) compared
with previously reported asymptomatic patients with zero CCS.
In terms of patient outcome, Min et al.,23 recently reported an
important prognostic study using CCTA. In their study, nonobstructive and obstructive CAD by CCTA were associated with
higher all-cause mortality among individuals without known
CAD, and the absence of CAD was associated with a very favourable prognosis. Our study shows concordant results with their
study, in that the severity of CAD by CCTA is a powerful prognostic predictor. While the study by Min et al. 23 analysed both
non-zero CCS patients and zero CCS patients together, our
study revealed that the severity of CAD confirmed by CCTA
can be equally applied to a separate group of patients with a
CCS of zero as well as to patients with CAC.
Another aspect to consider was the difference between the
male and female subjects. It is well known that there are gender
differences in CAD. Epidemiological data demonstrate that
women develop clinical coronary heart disease 10 years later, on
average, than men and the occurrence of coronary calcification
tracks with this later onset.24,25 Men and women also have different clinical presentations and outcomes of CAD; additionally,
emerging data suggest that there may be actual gender differences
in the anatomy of atherosclerosis.26 – 29 Thus, it is important to
Zero CCS in symptomatic patients
783
Figure 3 The Kaplan– Meier event-free survival curves by CAD severity. (A) An event-free survival curve by CAD severity for entire study
cohort. (B) An event-free survival curve by CAD severity for patients with zero CCS.
consider gender-specific data when evaluating CAD. In our study,
in which the gender ratio was 49% males and 51% females, the
prevalence and mean CCS were significantly higher in men than
in women and coronary artery calcification occurred at a later
age in women, as has been previously shown in other
studies.24,25 Men also had a much higher prevalence of obstructive
CAD than women. Interestingly, when patients were classified into
five groups according to their CCSs, this gender difference was
notably higher in the group with a CCS of zero than other CCS
groups. Further inspection of zero CCS patients with obstructive
CAD revealed a higher prevalence of premature CAD and multivessel involvement in men than in women. Revascularization
therapy and adverse cardiac events were more common in men
than in women. Our results suggest that a CCS of zero has different implications in symptomatic men and women. Fundamental
questions about the pathophysiology causing this gender difference
remain unanswered, though many biological factors including hormonal factors such as oestrogen and testosterone, autonomic
function, and the immune system and non-biological factors have
been suggested during the past decades.30 Among non-biological
factors, there was a large difference in the smoking rate between
sexes in our study population. This factor might be one of the
most important reasons for the gender discrepancy noted.31,32
Another issue to be mentioned is that recent CCTA no longer
delivers the higher radiation doses reported in our study using
64-slice CT as recent CCTA works with new radiation dose
saving techniques such as prospective ECG gating and iterative
reconstruction. It can now be performed with a low dose of
,1 mSv, which is comparable to that of a CAC scan.33,34 Therefore, the clinical value of performing both CAC scan and CCTA,
784
especially in symptomatic patients requires further study in terms
of diagnosis and prognosis.35,36
Several limitations of the current study should be acknowledged.
First, our study was performed at a single centre and all subjects
were drawn from the same ethnic background. Thus, it is uncertain
whether its results can be equally applicable to the general practice. Further larger studies, including multicentre and multiethnic
studies, are needed to elucidate our findings. Secondly, a composite MACE was used as an endpoint to investigate prognostic significance of zero CCS because hard cardiac events (i.e. MI and cardiac
death) were small in number in our cohort. Therefore, we considered the possibility of treatment bias, in that patients with
obstructive CAD at CCTA are more likely to be treated aggressively by their physicians, resulting in increased revascularization,
which constituted the major proportion of the composite
MACE. To avoid this possible treatment bias, we excluded patients
who underwent elective revascularization within 60 days after the
index CT study from MACE measure. Finally, current 64-slice CT
techniques still offer limited spatial resolution when evaluating
coronary plaques even though the diagnostic accuracy for stenosis
detection is higher in patients with the absence of CAC than in
patients with a high CCS.37 As spatial resolution may impact the
ability to detect non-calcified plaques or to detect small amounts
of calcium, future studies using more advanced CT techniques
are required.
In conclusion, a CCS of zero cannot be used by itself to exclude
obstructive CAD in symptomatic patients referred for CCTA. The
prevalence of obstructive CAD and adverse cardiac events are not
negligible in symptomatic patients with a CCS of zero, and CAD
severity by CCTA is associated with higher rates of adverse
cardiac event.
Y.J. Kim et al.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Conflict of interest: none declared.
Funding
19.
This work was supported by a faculty research grant of Yonsei University College of Medicine (6-2011-0107).
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IMAGE FOCUS
doi:10.1093/ehjci/jes088
Online publish-ahead-of-print 24 April 2012
.............................................................................................................................................................................
Dehiscence of Freestyle aortic valve visualized by real-time
three-dimensional transoesophageal echocardiography and
dual-source computed tomography: a rare cause of aortic regurgitation
Shunsuke Sasaki1*, Hiroyuki Watanabe1, Nobuo Iguchi1, Hitoshi Kasegawa2, and Shuichiro Takanashi2
1
Department of Cardiology, Sakakibara Heart Institute, 3-16-1 Asahi-cho, Fuchu-shi, Tokyo 183-0003, Japan and 2Department of Cardiovascular Surgery, Sakakibara Heart
Institute, 3-16-1 Asahi-cho, Fuchu-shi, Tokyo 183-0003, Japan
* Corresponding author. Tel: +81 42 314 3111; fax: +81 42 314 3133, Email: [email protected]
A 54-year-old man was admitted because of
acute decompensated heart failure. Ten years
ago, he underwent implantation of a 27 mm
Freestyle aortic root stentless bioprosthesis
(Medtronic Inc., Minneapolis, Minnesota) with
a subcoronary technique for severe aortic regurgitation (AR) due to the bicuspid valve, combined with mitral valve repair for moderate
mitral regurgitation (MR) due to anterior
leaflet prolapse.
On admission, transthoracic echocardiography revealed a flap-like structure (asterisk) at
the non-coronary cusp (Panel A; Supplementary
data online, Movie A). Colour Doppler images
showed an AR jet between the left and right coronary cusps (Panels B and C; Supplementary data
online, Movies B and C), and moderate MR due to degenerative change. Aortic and mitral regurgitant fractions were 30 and 43%, respectively. Real-time three-dimensional transoesophageal echocardiography (RT3D-TEE) using iE33 (Philips Medical Systems,
Bothell, WA, USA) was conducted to evaluate the cause of AR. RT3D-TEE depicted a partial dehiscence of the Freestyle bioprosthesis
at the non-coronary cusp (Panel D; Supplementary data online, Movie D). A 128-slice dual-source computed tomography (DSCT) system
(Somatom Definition FLASH, Siemens Healthcare, Forchheim, Germany) with 4D volume rendering confirmed the RT3D-TEE finding
(Panel E; Supplementary data online, Movie E). We suspected that the dehiscence of the bioprosthesis at the non-coronary cusp induced
discoaptation of the leaflets, deforming the aortic valve and causing a gap between the left and right coronary cusps on the opposite side,
through which AR occurred.
Moderate AR and moderate MR were considered to have caused heart failure, and aortic and mitral valve replacements were
performed. The operative findings (Panel F) were consistent with the RT3D-TEE and DSCT findings. The patient recovered uneventfully and was discharged on the 23rd postoperative day.
Supplementary data are available at European Heart Journal – Cardiovascular Imaging online.
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]