Incremental Predictive Value of Coronary Calcium Score in Risk Stratification of Coronary Revascularization in Patients With Normal or Mild Ischemia Using Nuclear Myocardial Perfusion Single Photon Emission Computed Tomography

Abstract

Background: The incremental predictive value of the coronary artery calcium score (CACS) for risk stratification of coronary revascularization in patients with normal or mildly abnormal nuclear myocardial perfusion single photon emission computed tomography (MPS) scores is unknown.

Methods and Results: We analyzed 528 patients in whom CACS was calculated and who underwent stress MPS within 3 months. Patients with known coronary artery disease, prior coronary revascularization, and those undergoing hemodialysis were excluded. Patients were followed-up with coronary revascularization based on the evidence of physiological ischemia defined by fractional flow reserve or severe coronary stenosis (≥90%). CACS was significantly associated with the summed stress score (SSS) from MPS assessment. Multivariate logistic regression analysis showed that high CACS (≥300; odds ratio [OR] 5.44, 95% confidence interval [CI] 2.28–13.0) and SSS (OR 1.29, 95% CI 1.18–1.40) were significant (P<0.001) predictors of future coronary revascularization. The log-rank test showed that high CACS stratified coronary revascularization in normal SSS (0–3; P<0.001) or mildly abnormal SSS (4–8; P=0.028) groups, whereas high CACS did not significantly stratify coronary revascularization in moderate to severe SSS (≥9; P=0.757).

Conclusions: Risk stratification using CACS with a cut-off value 300 may have incremental predictive value for revascularization in patients with normal or mildly abnormal MPS.

Nuclear myocardial perfusion single-photon emission computed tomography (MPS) is one of the procedures used for the physiological assessment of myocardial ischemia. MPS quantifies and shows jeopardized coronary artery disease (CAD). The summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) are commonly used for the assessment of MPS. SSS and SRS are the sum of the stress and rest scores, respectively, of the 17-segment left ventricular model.¹ The SDS is used for visual assessment of ischemia in MPS, and is calculated by subtracting SRS from SSS.¹ SRS is used for the assessment of myocardial infarction or scar.² CAD risk is optimally estimated by the combination of SRS, reflecting a patient’s burden of disease, and SSS, reflecting a patient’s provocative ischemia. SSS is well known as a useful parameter to indicate the likelihood of future cardiac events.^3–5

Patients who have a normal (0–3) or mildly abnormal (4–8) SSS are considered to be at low risk for future cardiac events. Therefore, coronary revascularization is not usually associated with normal or mildly abnormal SSS.

The coronary artery calcium score (CACS), obtained from non-contrast electrocardiogram (ECG)-gated computed tomography (CT), is one of the non-invasive tests used for risk stratification of CAD. Agatston et al reported that a CACS cut-off of 300 diagnosed significant CAD, including coronary stenosis >50%.⁶ Berman et al also reported a positive correlation between an increase in CACS and SSS in MPS.⁷ The 2016 guidelines of the Society of Cardiovascular CT (SCCT) noted that CACS ≥300 (high CACS) was associated with a moderately to severely increased risk of CAD.⁸ CACS should predict significant stenosis in CAD, but the presence of anatomically significant CAD is not always associated with physiological ischemia and coronary intervention.

Others have reported that a combination of CACS and ⁸²Rb positron emission tomography (PET)/CT improved detection of significant CAD.^9,10 However, the incremental predictive value of high CACS for coronary revascularization in patients with normal or mildly abnormal risk based on MPS is unknown. Therefore, in the present study we investigated the incidence of coronary revascularization among patients with a high CACS in the normal or mildly abnormal SSS groups.

When considering CAD screening with CACS, it is important to clarify the relationship between CACS and chest symptoms. Typical chest symptoms, including shortness of breath, are known predictors of severe CAD.¹¹ We have investigated the relationship between a patient’s symptoms, CACS, and ischemia detected by MPS, and will report the results separately (unpublished data).

Methods

Study Population and Follow-up

Patients without known CAD, prior myocardial infarction, coronary revascularization, including percutaneous coronary intervention (PCI) or coronary bypass surgery (CABG), and hemodialysis were included in this study. All patients underwent a coronary calcium scan and MPS within 3 months of each other between October 2014 and June 2018. Patients were followed-up to determine the rate of revascularization, including PCI and CABG, for physiological ischemia detected by fractional flow reserve (FFR), proximal significant stenosis ≥90%, or left main disease. FFR <0.80 was defined as positive for physiological ischemia. Intravenous ATP (180 μg/kg/min) was injected to provoke a maximum hyperemia in the FFR study. The initial date of starting follow-up period was defined as the first date of CACS or MPS.

Nuclear MPS

A semiconductor scanner (D-SPECT; Spectrum Dynamics Medical, Caesarea, Israel) was used for MPS (single isotope rest/stress 1-day protocol with ^{99 m}Tc-tetrophosmin/-sestamibi or low-dose simultaneous acquisition dual-isotope protocol with 150 MBq ^{99 m}Tc agent and 50 MBq ²⁰¹Tl).^12–14 MPS (left ventricular short axis, vertical long axis, and horizontal long axis) scans were generated using Autoquant software (Media Cybernetics, Bethesda, MD, USA). Two experienced readers (Y.S. and N.M.) interpreted the MPS scans based on a 17-segment model and scored the SSS, adding a 5-point scale ranging from 0 to 4 (0, normal uptake; 1, mildly reduced uptake; 2, moderately reduced uptake; 3, severely reduced uptake; 4, almost no uptake) during stress, as described previously.¹⁵

Coronary Calcium Scan

An ECG-gated single shot scan was performed using 320 detector low CT scanner (Aqulion One Vision Edition; Canon Medical Systems, Tochigi, Japan) without a β-blocker with the following settings: tube voltage 120 kV, slice thickness 3 mm, and matrix size 512×512. CACS was semiautomatically calculated using Ziostation 2 (Ziosoft, Minato, Japan). In the present study, CACS was defined as the summed value of CACS in the left main, left anterior descending, left circumflex, and right coronary arteries.

Statistical Analysis

Data were analyzed using MedCalc ver. 19.1.5 and EZR ver. 1.40 were used.¹⁶ Continuous variables are expressed as the mean±SD. The Mann-Whitney U-test was used for comparisons of traditional risk factors and the frequency of revascularization between low (<300) and high (≥300) CACS groups in each SSS category (normal, SSS 0–3; mildly abnormal, SSS 4–8; moderate to severe, SSS ≥9). Spearman’s coefficient (r) was used to investigate correlations between CACS and SSS. The Bonferroni test was used for multiple comparisons of mean SSS in each CACS category (0, 1–99, 100–299, and ≥300). Log-rank tests were used to analyze the incremental predictive value of CACS for risk stratification of CAD in each SSS category using Kaplan-Meier curve analysis. Univariate and multivariate logistic regression analyses were used to calculate odds ratios (OR) and 95% confidence intervals (CIs) for high CACS, age, diabetes (DM), hypertension (HT), and SSS for revascularization. Significance was set at 2-tailed P<0.05.

Ethical Considerations

This study was performed in accordance with the Declaration of Helsinki and the ethical standards of the Review Board of Clinical Research of Nihon University Hospital (Reference no. 20190701). Written informed consent was obtained from all study patients.

Results

Among the 1,827 eligible patients in the study period, both CACS and MPS data were available for 528. No patients underwent coronary revascularization between the CT examination of CACS and the MPS assessment of SSS. The baseline characteristics of the study population are given in Table 1. Mean patient age was 69.0±10.8 years old, and 166 (31.4%) patients were female. The mean CACS was 367.9±836.2 and 161 patients (30.5%) had a CACS of 0. Of all study patients, 463 (87.6%) had normal SSS. CACS and SSS were weakly but significantly correlated (r=0.235, P<0.001; Figure 1A). The distribution of low and high CACS in each SSS category is shown in Figure 1B. The rates of high CACS increased with increasing SSS. Multiple comparison analysis revealed that mean SSS was significantly higher in the high CACS group (P<0.001), whereas there was no significant difference in mean SSS among the 3 groups with CACS <300 (Figure 2).

Table 1. Baseline Characteristics (n=528)

Age (years)	69.0±10.8
Female sex	166 (31.4)
BMI (kg/m2)	24.5±12.3
HT	329 (62.3)
Diabetes	141 (26.7)
Dyslipidemia	244 (46.2)
Smoking	43 (8.1)
Family history of CAD	27 (5.1)
Medication
CCB	197 (37.3)
β-blocker	134 (25.4)
ACEI	16 (3.0)
ARB	201 (38.1)
Statin	165 (31.2)
Aspirin	63 (11.9)
CACS	367.9±836.2
0	161 (30.5)
1–99	153 (29.0)
100–299	71 (13.4)
≥300	143 (27.1)
SSS
Normal (0–3)	463 (87.6)
Mildly abnormal (4–8)	39 (7.3)
Moderate to severe (≥9)	26 (4.9)

Data are presented as the mean±SD or as n (%). ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CACS, coronary artery calcium score; CAD, coronary artery disease; CCB, calcium channel blocker; HT, hypertension; SSS, summed stress score.

Figure 1.

(A) Scatter plot of summed stress score (SSS) vs. coronary artery calcium score (CACS). There was a significant correlation between CACS and SSS. (B) Distribution of CACS for each SSS category (normal, SSS 0–3; mildly abnormal, SSS 4–8; moderate to severe, SSS ≥9). The number of patients with a high CACS increased with increasing SSS.

Figure 2.

Comparison of mean summed stress score (SSS) for different coronary artery calcium score (CACS) categories. Mean SSS was significantly higher in patients with CACS ≥300.

A comparison of traditional risk factors and the frequency of revascularization among the 3 SSS categories according to low or high CACS (cut-off 300) are given in Table 2. In the normal SSS group, age, the number of males, HT, DM, and revascularization were significantly higher in the high CACS group. In the mildly abnormal SSS group, the number of revascularizations was higher in high CACS group, whereas there were no significant differences in traditional risk factors between the low and high CACS groups. In the moderate to severe SSS group, there were no significant differences in any of the parameters between the low and high CACS groups.

Table 2. Comparison of Clinical Characteristics Between Low and High CACS Groups

	Low CACS	High CACS	P value
Normal SSS
No. patients	359	104
Age	67.0±10.8	74.0±8.8	<0.001
Male (%)	235 (65.5)	81 (77.9)	0.017
BMI (kg/m2)	24.3±14.7	24.0±3.9	0.708
HT (%)	215 (59.9)	75 (72.1)	0.028
Diabetes (%)	64 (17.8)	48 (46.2)	<0.001
Dyslipidemia (%)	158 (44.0)	48 (46.2)	0.737
Family history of CAD	20 (5.6)	6 (5.8)	1.000
Smoking	25 (7.0)	7 (6.7)	1.000
Revascularization	5 (1.4)	10 (9.6)	<0.001
Mildly abnormal SSS
No. patients	21	18
Age	66.7±13.6	70.8±9.5	0.292
Male (%)	12 (57.1)	11 (61.1)	1.000
BMI (kg/m2)	26.4±6.6	25.2±3.4	0.495
HT (%)	11 (52.4)	14 (77.8)	0.180
Diabetes (%)	6 (28.6)	8 (44.4)	0.337
Dyslipidemia (%)	11 (52.4)	9 (50.0)	1.000
Family history of CAD	1 (4.8)	0 (0.0)	1.000
Smoking	3 (14.3)	3 (16.7)	1.000
Revascularization	3 (14.3)	9 (50.0)	0.035
Moderate to severe SSS
No. patients	5	21
Age	65.6±8.6	72.1±9.1	0.158
Male (%)	5 (100)	18 (85.7)	1.000
BMI (kg/m2)	23.8±3.2	25.5±2.9	0.267
HT (%)	2 (40.0)	12 (57.1)	0.635
Diabetes (%)	3 (60.0)	12 (57.1)	1.000
Dyslipidemia (%)	4 (80.0)	14 (66.7)	1.000
Family history of CAD	0	0
Smoking	1 (20.0)	4 (19.0)	1.000
Revascularization	4 (80.0)	18 (85.7)	1.000

Unless indicated otherwise, data are presented as the mean±SD or as n (%). Abbreviations as in Table 1.

The results of univariate and multivariate logistic regression analyses for the prediction of future coronary revascularization in the whole group are shown in Table 3. Univariate analysis showed that high CACS (OR 10.8; 95% CI 5.4–21.5), DM (OR 3.93; 95% CI 2.15–7.17), and SSS (OR 1.39; 95% CI 1.27–1.51) were significant predictors of future coronary revascularization (all P<0.001), whereas multivariate analysis showed that high CACS (OR 5.44; 95% CI 2.28–13.0) and SSS (OR 1.29; 95% CI 1.18–1.40) were significant predictors of future coronary revascularization (both P<0.001).

Table 3. Univariate and Multivariate Logistic Regression Analysis of Risk Factors for Revascularization

Risk factor	Univariate analysis		Multivariate analysis
	OR (95% CI)	P value	OR (95% CI)	P value
High CACS	10.8 (5.4–21.5)	<0.001	5.44 (2.28–13.0)	<0.001
Age	1.02 (0.99–1.05)	0.193	0.98 (0.94–1.03)	0.506
Diabetes	3.93 (2.15–7.17)	<0.001	1.90 (0.87–4.13)	0.107
HT	1.41 (0.74–2.67)	0.285	1.12 (0.56–2.25)	0.740
SSS	1.39 (1.27–1.51)	<0.001	1.29 (1.18–1.40)	<0.001

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Results of the log-rank test for revascularization in each SSS category is shown in Figure 3. High CACS groups were significantly associated with future coronary revascularization in the normal or mildly abnormal SSS groups (log-rank test, P<0.001 and P=0.028, respectively), whereas high CACS did not stratify future coronary revascularization in the moderate to severe SSS group (P=0.757).

Figure 3.

Kaplan-Meier curves for risk stratification of revascularization using low and high coronary artery calcium scores (CACS) for each summed stress score (SSS) category (normal, SSS 0–3; mildly abnormal, SSS 4–8; moderate to severe, SSS ≥9). CACS significantly stratified revascularization in patients with normal or mildly abnormal SSS, but not in patients with moderate to severe SSS.

Discussion

This study found that CACS is weakly but significantly associated with SSS. In addition, mean SSS was significantly higher in the high than low CACS group, and these findings are consistent with those of previous studies.^7,17 Furthermore, we showed that patients with high CACS were classified as candidates for revascularization based on evidence of physiological ischemia or severe coronary artery stenosis in the normal or mildly abnormal SSS groups. Chang et al reported that high CACS was associated with a more than 4-fold increase in relative long-term cardiac events in patients with normal MPS.¹⁸ However, Chang et al did not refer to the incremental predictive value of CACS for coronary revascularization. Previous studies reported that a combination of CACS and physiological assessment of myocardial blood flow using ⁸²Rb PET/CT improved the detection of CAD, but neither of these studies referred to the relationship between CACS and coronary revascularization in the group of low to intermediate risk of CAD.^9,10 Thus, it should be noted that high CACS is one of the significant predictors of coronary revascularization in patients with normal or mildly abnormal SSS. Importantly, false-negative results for significant CAD because of balanced ischemia based on multivessel or left main CAD in patients with normal or mildly abnormal SSS may miss patients who need to be revascularized.^19,20 Therefore, we emphasize that high CACS could be ideal to estimate CAD in patients with normal or mildly abnormal SSS, with minimal medical costs and radiation exposure.

Another issue is that myocardial perfusion imaging using PET/CT is not widely used in Japan compared with MPS, which is commonly used. For the first time, we used the combination of common MPS and CACS to successfully stratify patients requiring treatment among those with normal or mildly abnormal MPS in a Japanese population.

Our data revealed that risk stratification of coronary revascularization using CACS was significant only in patients with normal or mildly abnormal SSS (P<0.001 and P=0.028, respectively), whereas it was not significant in patients with moderate to severe SSS (P=0.757). That is, CACS data may not be necessary for patients with moderate to severe SSS. Although CACS is a potential test for screening of CAD, it may not be relevant to use from the outset in patients with a clearly high likelihood of the detecting of severe ischemia on MPS. However, unexpected normal or mildly abnormal cases of MPS with more than a moderate probability of CAD require a subsequent CACS test. Of course, it goes without saying that the patients will need to undergo CT coronary angiography. In addition, 2013 guidelines for appropriate multimodal detection and risk assessment of stable ischemic heart disease do not recommend CACS in patients with typical symptoms.²¹ Typical chest pain and shortness of breath are recognized as risks of CAD.¹¹ The relationship between CACS and the clinical information used to estimate the pretest probability of CAD in Japan is still unknown. Further study is required to clarify which patients should undergo CAD screening with CACS.

In the present study, the log-rank test showed that the timing of revascularization was different among the 3 SSS groups. In the normal or mildly abnormal SSS groups, high CACS predicted relatively delayed revascularization compared with the moderate to severe SSS group (P<0.001 and P=0.028, respectively). This remote revascularization could be explained by the following: (1) underestimation of the jeopardized myocardium at risk by MPS; (2) the presence of severe stenosis in coronary arteries or positive FFR by coronary angiography; and (3) new onset of angina or progression of atherosclerosis. However, the significance of high CACS in predicting future revascularization in patients in the moderate to severe SSS group could not be demonstrated (P=0.757).

Study Limitations

This study was an observational study performed in a single center. In the present study, the selected patients were unbalanced because 88% of patients were determined to have normal SSS. Thus, the findings should be interpreted with caution because of the possibility of selection bias. Multivariate logistic regression analysis could not performed in each SSS category because of the small number of patients. Further analysis with a larger population in multiple centers should be performed. In the present study, SSS was used for the semiquantitative assessment of ischemia by MPS. Automated quantification of ischemia using total perfusion deficit and a database of normal myocardial perfusion could be considered for more objective assessment of MPS.²²

Conclusions

Risk stratification using CACS with a cutoff value of ≥300 may have incremental predictive value of future coronary revascularization based on the evidence of physiological ischemia in patients with normal or mildly abnormal SSS detected by MPS.

Acknowledgments / Sources of Funding

None.

Disclosures

The authors do not have any conflicts of interest to declare.

IRB Information

This study was approved by the Review Board of Clinical Research of Nihon University Hospital (Reference no. 20190701).

Data Availability

The deidentified participant data will not be shared.

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