Assessment of coronary spasms with transluminal attenuation gradient in coronary computed tomography angiography.

PURPOSE: To evaluate the imaging features of coronary spasm, including transluminal attenuation gradient (TAG) on coronary computed tomography angiography (CCTA), in patients with vasospastic angina (VA).
METHODS: A total of 43 patients with a high clinical likelihood of VA were included in the study. All the subjects underwent double CCTA acquisition: CCTA without a vasodilator ('baseline CT') and CCTA during continuous intravenous nitrate infusion ('IV nitrate CT'). A catheterized ergonovine provocation test was used to determine true VA patients. Coronary spasm is classified into focal- and diffuse-types according to morphological differences. We measured TAG and contrast enhancement of the proximal ostium (ProxHU) of each coronary artery for both the baseline and IV nitrate CT.
RESULTS: Twenty-four patients (55.8%) showed positive results of coronary vasospasm on the provocation test. Thirty-eight vessels showed coronary spasms (29.5%): Focal-type in nine vessels (24%), and diffuse-type in 29 (76%). In the baseline CT, LCX showed significantly lower (steeper) TAG in spasm(+) vessels than in spasm(-) vessels, while LAD and RCA showed no significant differences in TAG. The ProxHU of LAD showed significantly lower values in spasm(+) vessels than in spasm(-) vessels, while the other vessels did not show significant differences in ProxHU. For IV nitrate CT, there were no significant differences in either the TAG and ProxHU between spasm(+) and (-) vessels for all the three vessel types. In subgroup analysis for spasm(+) vessels, diffuse spasms showed significantly lower TAG than focal spasms, while the ProxHU did not differ between the two types of spasm.
CONCLUSIONS: A relatively large percentage of coronary spasms present as diffuse type, and the TAG values significantly differed according to the morphological type of the coronary spasm.

Introduction

Coronary artery spasm is a frequent cause of acute chest pain. It can cause angina pectoris, various ischemic diseases such as acute myocardial infarction, and even sudden cardiac death [1-4]. Catheterized coronary angiography (CAG) with a provocation test using acetylcholine or ergonovine is essential for diagnosing coronary artery spasms [5]. However, this procedure is invasive and involves a potential risk of severe myocardial ischemia or arrhythmia. Therefore, there is a need for less invasive diagnostic methods for coronary spasms. Coronary computed tomography (CT) angiography (CCTA) using multidetector CT has been widely used as a noninvasive imaging technique for evaluating coronary artery disease [6,7]. However, coronary spasms transiently occur during rest, especially in the early morning, and rarely during the day. Further, sublingual vasodilators are routinely administered before CCTA for coronary artery dilation. The sensitivity of CCTA is considerably lower as compared to its specificity. According to a study by Kang et al., the sensitivity of CCTA was 48% [8]. Taken together, this suggests that CCTA is inadequate as an initial screening tool for VA diagnosis. Previously, we adapted a double-acquisition CCTA protocol, which acquires CT at two different time points in the same patient. The first one is the baseline CT, performed in the early morning without a vasodilator, and the second is performed a few hours later using a vasodilator: a continuous intravenous nitrate infusion CT (IV nitrate CT) [9]. This protocol yielded a relatively high sensitivity (73%) for VA diagnosis [8,10]. However, this sensitivity was insufficient for predicting coronary spasms. Moreover, the CT protocol requires CCTA to be performed twice for each individual, which resulted in the use of more contrast medium and a higher radiation dose than that in single-acquisition protocols.

Transluminal attenuation gradient (TAG), which is a linear regression coefficient between the axial distance and luminal attenuation, allows the functional analysis of coronary stenosis without additional radiation exposure or use of contrast medium [11-13]. However, clinical validation studies have reported conflicting results of the usefulness of using TAG at determining coronary arterial flow [14,15], since TAG may be affected by changes in coronary luminal diameter and collateral vascular enhancement.

A focal type coronary spasm may occur as a focal stenotic lesion with negative remodeling; however, the distal vessel diameter is often normal. In the case of a diffuse type coronary spasm, the vessel shows a diffuse small diameter throughout the whole single vessel without normal diameter tapering. Therefore, diameter changes might not affect TAG values in both types of spasm. Moreover, collateral vessels, which develop in organic atherosclerotic lesions, do not develop in coronary spasms due to the transient occurrence and resolution of coronary spasms. To our knowledge, there have been no studies on TAG in coronary spasms. We aimed to examine the imaging features of coronary spasms, including TAG in CCTA, in patients with vasospastic angina (VA). Moreover, we aimed to evaluate differences in TAG between focal and diffuse coronary spasms.

Materials and methods

Subjects

We retrospectively reviewed 57 consecutive patients aged 30–73 years with a high clinical likelihood of VA between March 2017 and April 2019. All the subjects were part of the Dual-acquisition of Noninvasive Cardiac Imaging in Vasospastic Angina Korean Registry (NAVIGATOR study) [9,16]. These patients underwent baseline CCTA without a vasodilator (‘baseline CT’) early morning, followed by catheterized CAG with an ergonovine provocation test. Subsequently, they underwent repetitive CCTA during a continuous intravenous (IV) nitrate infusion (‘IV nitrate CT’) within 3 days.

Since TAG could be influenced by the vessel diameter and length, we included only right-dominant patients i.e., patients whose posterior descending artery is supplied by the right coronary artery (RCA)) [17]. We excluded eight patients with significant fixed stenosis, that was defined as ≥50% stenosis compared with the adjacent non-diseased arterial segment on conventional CAG. The diagnostic performance of CCTA for the detection of coronary spasm showed that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80%, 100%, 100%, 76%, and 87.76%, respectively. Per-vessel analysis results are shown in S1 Table.

For the analysis of TAG values on CCTA, we excluded 6 patients who showed inconsistent results on CCTA (negative) and the ergonovine provocation test (positive). Finally, a total of 43 patients (spasm(+) patients = 24, spasm(-) patients = 19) were enrolled in this study (Fig 1).

Fig 1

Patient flow diagram.

We excluded 14 patients from the initial 57 patients due to significant fixed stenosis (n = 8) or inconsistency between the CCTA and spasm provocation test (n = 6). Finally, 43 patients were selected for analysis. CCTA, coronary computed tomography angiography.

This retrospective multi-center study was approved by our institutional ethics committee, which waived the requirement for formal informed consent.

Catheterized ergonovine provocation test

VA was diagnosed based on findings from an invasive CAG and a positive result in the ergonovine provocation test [18]. Experienced cardiologists performed invasive CAG via radial access using a single coronary artery diagnostic catheter on the left coronary artery initially, followed by RCA (Tiger Catheter, Terumo Co.). In case the diagnostic CAG did not reveal substantial stenosis (≥50% diameter stenosis on visual estimation), an intracoronary ergonovine injection was administered to induce coronary spasms. First a right-sided spasm provocation was performed together with a right-sided CAG, and if a spasm was induced, an intracoronary nitroglycerin injection was administered for relief. If the right-sided provocation test did not induce a coronary spasm, a left-sided provocation test was attempted. We injected 10–20 μg of ergonovine thrice at 1 min intervals into each coronary artery. Even in the negative cases, oral and intracoronary nitroglycerin (100 μg) and nifedipine (10 mg) were administered before completing the procedure to prevent delayed coronary spasms. A positive ergonovine test, which was defined as total or subtotal occlusion (visually, >90% stenosis) compared to the dilated condition after nitroglycerin administration, was validated by an electrocardiogram shift (>2 mm ST depression or elevation) and/or the presence of concomitant chest pain [19].

CCTA acquisition and analysis

All CCTAs were conducted using a 320-detector row CT system (Aquilion One; Canon Medical Systems, Otawara, Japan) with two collimations of 320 × 0.5 mm, a gantry rotation time of 350 ms, and a temporal resolution of 175 ms. The protocol used for dual acquisition CT was according to the NAVIGATOR study [9,16]. A commercial software package (Sure Exposure 3D®, Canon Medical Systems) was used to control the tube voltage (120 kVp) and tube current (130 to 250 mA). A bolus of 50–70 mL of nonionic contrast material (iobitridol, Xenetix® 350 mg/mL; Guerbet, France) was intravenously infused at 4 mL/s, followed by infusion of 30 mL of a contrast/saline mixture (2:8 dilution) at 4 mL/s. The CT scans began with a 5-s delay after an automated bolus trigger in the ascending aorta (the triggering threshold was 100 Hounsfield units, HU). We did not administer additional beta-blockers or calcium channel blockers for decreasing the heart rate. All datasets were handled through iterative reconstruction (AIDR 3D, Canon Medical Systems). Axial images were reconstructed at a 0.5 mm slice thickness and 0.5 mm intervals in a field of view tailored to each patient’s heart size.

Regarding per-vessel analysis, positive spasm vessels were determined by comparing the baseline and IV nitrate CTs. The three main coronary branches (RCA, left anterior descending artery (LAD), and left circumflex artery (LCX)) with luminal diameters >1.5 mm were analyzed. For both the CTs, we evaluated curved multiplanar reconstruction images and cross-sectional images of each coronary artery. For the same patient, we attempted to compare baseline and IV nitrate CT images of the coronary arteries in similar cardiac phases. Regarding VA diagnosis, the following were the requirements for a positive finding on CCTA: (a) significant focal stenosis with negative remodeling on baseline CT without definite evidence of plaques in a completely dilated artery on IV nitrate CT (“focal-type”), or (b) diffuse small diameter (<2 mm) of a major coronary artery with lack of tapering and beaded appearance on baseline CT that showed complete dilation on IV nitrate CT (“diffuse-type”) (Figs 2 and 3) [10].

Fig 2

A representative case of the focal-type spasm on CCTA and the ergonovine provocation test.

A 59-year-old male patient presented with intractable recurrent chest pain. (A) Baseline CT (upper) revealed significant focal stenosis at the distal RCA on volume rendering and curved multiplanar images. IV nitrate CT (lower) revealed completely dilated coronary arteries without narrowing. (B) Baseline coronary angiography (left) revealed intermediate luminal stenosis of the distal RCA. Upon ergonovine infusion (middle), RCA showed complete luminal occlusion. After nitrate injection, RCA showed full dilation without evidence of a stenotic lesion (right). The TAG values were -8.80 and -0.90 for baseline CT and IV nitrate CT, respectively. CCTA, coronary computed tomography angiography; CT, computed tomography; IV, intravenous; RCA, right coronary artery; TAG, transluminal attenuation gradient.

Fig 3

A representative case of the diffuse-type spasm on CCTA and the ergonovine provocation test.

A 58-year-old male patient presented with chest pain. (A) Baseline CT (upper) revealed a diffuse small diameter with a beaded appearance throughout the coronary arteries at the distal RCA on volume rendering and curved multiplanar images. IV nitrate CT (lower) showed completely dilated coronary arteries without narrowing. (B) Baseline coronary angiography (left) demonstrated diffuse narrowing of the whole coronary branches, which was consistent with the findings on baseline CCTA (A). The TAG values were -19.87 and -13.89 on baseline CT and IV nitrate CT, respectively. CCTA, coronary computed tomography angiography; CT, computed tomography; IV, intravenous; RCA, right coronary artery; TAG, transluminal attenuation gradient.

All CCTA images were independently reviewed by two radiologists (E.J.K and H.S.Y) who were blinded to the patients’ clinical information, and discrepancies in results were resolved through consensus.

TAG and proximal enhancement measurements

All images were analyzed using commercial software (Vitrea®, Vital images, MN, USA). TAG values were measured using semi-automated methods on dedicated computer software (Canon Medical Systems) for each of the three major epicardial coronary arteries (RCA, LAD, and LCX) as previously reported [20]. The centerline and contouring of each major coronary artery were automatically identified and manually modified, if necessary. Cross-sectional images perpendicular to the vessels’ center-line were reconstructed. The mean luminal attenuation (HU) was measured at 1 mm intervals, from the ostium to distal levels where the cross-sectional minimal area fell below 2 mm2 [12]. Datapoints in segments with motion or blooming artifacts from luminal calcium were excluded when calculating TAG values [21]. TAG was defined as the linear regression coefficient between the intraluminal HU and the distance from the ostium. TAG values were calculated based on the change in CT attenuation (HU) per 10 mm length of the coronary artery. Representative examples are shown in Figs 2 and 3. Additionally, we assessed the contrast enhancement in the proximal ostium of the three major coronary arteries (“ProxHU”) by drawing a region of interest as broad as possible while carefully avoiding calcifications in the cross-sectional images of each vessel’s curved multiplanar planes.

Statistical analysis

We performed group comparisons of the clinical features. Moreover, the mean TAG and ProxHU values for each major coronary artery (LAD, LCX, and RCA) were compared according to the CT acquisition method (baseline or IV nitrate CT), presence of spasm (spasm(-) vs. spasm(+)), and spasm types (focal vs. diffuse). Continuous and categorical variables are shown as means with standard deviations and frequencies (percentages), respectively. Between-group comparisons were performed using the independent t-test, Mann Whitney U test, and paired t-test, as appropriate. One-way analysis of variance was used to test within-group differences based on the normality of the data distribution. Pearson’s correlation was used to examine the correlations between the TAG and ProxHU. Correlation coefficients of < 0.20, 0.20–0.39, 0.40–0.59, 0.60–0.79, and ≥ 0.80 indicate very weak, weak, moderate, strong, and very strong correlations, respectively. Interobserver agreement for decisions of coronary spasm was assessed using a kappa test. All statistical analyses were performed using SPSS (version 20.0; SPSS Inc., Chicago, IL, USA). Statistical significance was set at P < 0.05.

Results

Clinical characteristics

The mean age of the study population was 60.67±10.05 years, and 72.1% of the patients were male (31/43; Table 1). There were 11, 3, 9 and 21 patients with hypertension, diabetes, dyslipidemia, and smoking history, respectively. Among the 43 recruited patients, coronary vasospasm was found in 24 patients (55.8%) while 19 (44.2%) showed negative results of coronary spasm. Compared with the spasm(-) group, the spasm(+) group had a significantly larger proportion of males (87.5% vs 52.6%, P = 0.017) and patients with a smoking history (66.7% vs 26.3%, P = 0.011); however, there were no significant between-group differences with regards to age and other comorbidities. There were no significant between-group differences in the height, weight, body mass index, and mean coronary arterial calcium score (Agatston method); however, we only enrolled patients without significant luminal stenosis as revealed by conventional CAG.

Table 1

General characteristics of the enrolled subjects.

	Total	Spasm (–)	Spasm (+)	P
No. of patients	43	19	24
Age (years)	60.67 ± 10.05	61.42 ± 13.56	60.08 ± 6.32	0.67
Male sex (%)	31 (72.1)	10 (52.6)	21 (87.5)	0.017
Hypertension (%) a	11 (25.6)	2 (10.5)	9 (37.5)	0.077
Diabetes mellitus (%) b	3 (7.0)	1 (5.3)	2 (8.3)	1
Dyslipidemia c	9 (20.9)	5 (26.3)	4 (16.7)	0.477
Smoking history (%)				0.011
Never	22 (51.2)	14 (73.7)	8 (33.3)
Current/Past	21 (48.8)	5 (26.3)	16 (66.7)
Height (cm)	164.95 ± 8.43	164.21 ± 7.28	165.54 ± 9.35	0.613
Weight (kg)	65.32 ± 9.78	64.37 ± 9.96	66.08 ± 9.78	0.576
BMI (kg/m2)	23.95 ± 2.58	23.81 ± 2.61	24.06 ± 2.61	0.756
Agatston score	114.91 ± 223.67	159.15 ± 295.06	79.89 ± 142.57	0.253

Data are expressed as mean ± standard deviation or numbers of patients (%).

a Patients were considered hypertensive if their blood pressure was consistently > 140/90 mm Hg, or if they were currently taking anti-hypertensive medication.

b Patients were considered to have diabetes mellitus if their fasting glucose level was ≥ 126 mg/dL in, at least one assessment, or if they were currently taking oral hypoglycemic agents or insulin.

c Patients were considered to have dyslipidemia if they presented a range of lipid abnormalities in combination: increased total cholesterol (> 200 mg/dL), low-density lipoprotein cholesterol (> 140 mg/dL), and triglyceride levels (> 150 mg/dL) or decreased high-density lipoprotein cholesterol (< 40 mg/dL). Spasm (-), patients without vessels showing spasm; Spasm (+), patients with vessels showing spasm; BMI, body mass index.

Per-vessel spasm analysis using CCTA

Among the 24 patients with coronary vasospasm, 38 vessels showed coronary vasospasm (Table 2, Fig 4). Specifically, 10 patients had >2 vessels with spasm (one vessel, 14 patients; two vessels, 6 patients; three vessels, 4 patients). The most common location of vessels with spasm was LAD, followed by RCA and LCX (LAD, n = 21; RCA, n = 10; LCX, n = 7). For the subtype analysis of coronary spasm, the diffuse-type (n = 29, 76%) was more common than the focal-type (n = 9, 24%). In LAD, LCX, and RCA, 14 (33%), 7 (16%), and 8 (18%) vessels showed the diffuse type, respectively, while the corresponding values for the focal type were 7 (16%), 0 (0%), and 2 (5%) vessels, respectively. The interobserver agreements (weighted kappa) between the radiologists regarding the decision of coronary spasm were 0.781 (95% confidence interval (CI): 0.601 to 0.960) per patient and 0.759 (95% CI: 0.618 to 0.901) per vessel.

Table 2

Per vessel analysis for coronary spasm on CCTA.

Vessels	All (n)	Spasm (–)	Spasm (+)
LAD	43	22 (51.2%)	21 (48.8%)
LCX	43	36 (83.7%)	7 (16.3%)
RCA	43	33 (76.7%)	10 (23.3%)
Total	129	91	38

Data are expressed as numbers of vessels (%).

CCTA, coronary CT angiography; Spasm (-), patients without vessels showing spasm; Spasm (+), patients with vessels showing spasm; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

Fig 4

Per vessel analysis of spasm type for coronary spasm on CCTA.

A total of 43 patients (129 vessels) were analyzed based on their spasm types. In LAD, LCX, and RCA, 14 (33%), 7 (16%), and 8 (18%) vessels showed the diffuse type, while the corresponding values for the focal type were 7 (16%), 0 (0%), and 2 (5%) vessels. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; Spasm (-), patients without vessels showing spasm; Spasm (+), patients with vessels showing spasm; Focal (type), significant focal stenosis without definite plaques; Diffuse (type), diffuse small diameter (< 2 mm) with serrated margin and loss of diameter tapering.

Comparison of TAG and ProxHU values among vessel types and CT acquisition methods

The mean TAG values of each coronary artery showed significant differences between the baseline CT and IV nitrate CT (Table 3). In the baseline CT, RCA showed the highest TAG values (gentlest slope), followed by LAD and LCX (RCA, -11.50±7.08; LAD, -20.92±8.37; LCX, -29.56±17.37; P<0.001). In the IV nitrate CT, TAG values of each vessels showed a similar trend as the baseline CT group (P<0.001). There were no significant among-group differences in the ProxHU values among the three major coronary arteries for both the CT protocols (baseline CT group, P = 0.730; IV nitrate group, P = 0.795). The mean TAG values were significantly lower (steeper slop) for baseline CT than that for IV nitrate CT, especially for LAD and LCX (LAD, -20.92±8.37 vs. -16.71±6.90; P<0.001; LCX, -29.56±17.37 vs. -22.75±11.97; P = 0.001; RCA, -11.50±7.08 vs. -9.94±5.67; P = 0.068; Table 3). The ProxHU values were higher for IV nitrate CT than that for baseline CT for all three vessels (LAD, 410.70±73.60 vs 450.93±89.13; P = 0.003; LCX, 407.11±62.82 vs 451.23±80.93; P<0.001; RCA, 399.11±73.41vs 440.20±90.21; P = 0.004; Table 3).

Table 3

TAG and ProxHU values for the vessel types on baseline CT and IV nitrate CT.

	Baseline CT	IV nitrate CT	P
TAG
LAD	-20.92±8.37	-16.71±6.90	<0.001
LCX	-29.56±17.37	-22.75±11.97	0.001
RCA	-11.50±7.08	-9.94±5.67	0.068
P	<0.001	<0.001
ProxHU
LAD	410.70±73.60	450.93±89.13	0.003
LCX	407.11±62.82	451.23±80.93	<0.001
RCA	399.11±73.41	440.20±90.21	0.004
P	0.730	0.795

Data are expressed as mean ± standard deviation.

TAG, transluminal attenuation gradient; ProxHU, most proximal CT number of each coronary arteries; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

ProxHU values were negatively correlated with the TAG values (baseline CT, r = -0.360; P<0.001; IV nitrate CT, r = -0.385; P<0.001; Fig 5). This trend was independent of the CT acquisition method.

Fig 5

Correlation between the TAG and ProxHU values of coronary arteries.

ProxHU values showed a weak negative correlation with TAG values (Baseline CT, r = -0.360; P<0.001; IV nitrate CT, r = -0.385; P<0.001). This trend was observed regardless of the CT acquisition method.

Comparison of TAG and ProxHU values between spasm(-) and spasm(+) vessels

In the baseline CT, the TAG and ProxHU values showed partial differences. Regarding TAG, LCX exhibited lower values in spasm(+) vessels than in spasm(-) vessels (-27.80±15.07 vs -44.62±22.04; P = 0.016); however, there were no significant differences in TAG values for LAD and RCA (LAD, P = 0.449; RCA, P = 0.224, respectively; Fig 6). The ProxHU values of LAD exhibited lower values in spasm(+) vessels than in spasm(-) vessels (445.00±67.73 vs 375.00±64.79; P = 0.001), while the other vessels did not show significant differences in baseline CT (LCX, P = 0.579; RCA, P = 0.532, respectively). In the IV nitrate CT, there were no significant differences in either the TAG and ProxHU values between spasm(-) and (+) vessels for all the three major coronary arteries (P>0.05).

Fig 6

Comparison of TAG and ProxHU values between spasm(-) and spasm(+) vessels in baseline CT (A, B) and IV nitrate CT (C, D). In the baseline CT, the TAG of LCX was significantly lower values in spasm(+) vessels than in spasm(-) vessels; however there was no significant difference for that of LAD and RCA. The ProxHU values of LAD exhibited lower values in spasm(+) vessels than in spasm(-) vessels, while the other vessels did not show significant differences in baseline CT. For IV nitrate CT, there was no significant difference in the TAG or ProxHU values between the spasm(+) and (-) vessels for all three vessels. Spasm (-), patients without vessels showing spasm; Spasm (+), patients with vessels showing spasm; TAG, transluminal attenuation gradient; ProxHU, most proximal CT number of each coronary arteries; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.

Subgroup analysis of spasm(+) vessels on baseline CT

We performed subgroup analysis for spasm(+) vessels according to spasm type. Diffuse spasms showed significantly lower TAG values than focal spasms on the LAD and RCA (LAD, -14.02±4.49 vs. -23.02±10.45; P = 0.044; RCA, -8.77±0.04 vs. -15.22±6.62; P = 0.037; Table 4). There was no significant difference in the ProxHU values between the spasm types for the LAD and RCA. For LCX, all spasm(+) vessels were diffuse-type (TAG, -44.62±22.04); moreover, they showed the lowest TAG values compared with the other vessels.

Table 4

Subgroup analysis of spasm (+) vessels on baseline CT.

	Total spasm (+)	Focal type	Diffuse type	P
TAG
LAD	-20.02±9.79	-14.02±4.49	-23.02±10.45	0.044
LCX	-44.62±22.04	-	-44.62±22.04	-
RCA	-13.93±6.44	-8.77±0.04	-15.22±6.62	0.037
ProxHU
LAD	375.00±64.79	388.00±49.80	368.50±71.95	0.529
LCX	405.19±67.18	-	405.19±67.18	-
RCA	388.70±50.73	417.50±74.25	381.50±47.17	0.428

Data are expressed as mean ± standard deviation.

TAG, transluminal attenuation gradient; ProxHU, most proximal CT number of each coronary arteries; Spasm (+), patients with vessels showing spasm; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; Focal type, significant focal stenosis without definite plaques; Diffuse type, diffuse small diameter (< 2 mm) with serrated margin and loss of diameter tapering.

Comparison of intra-subject differences in TAG values between baseline CT and IV nitrate CT

The intra-subject difference in TAG value between the baseline CT and IV nitrate CT shows relatively larger value in diffuse type spasm vessels than in focal type spasm or negative spasm vessels, but statistically insignificant (diffuse type vs focal type vs normal, 6.20±13.77 vs 2.05±6.13 vs 3.83±7.04; P = 0.35; Table 5). Among vessel subtypes, LCX, of which all spasm(+) vessels were diffuse type, showed a greater TAG difference for diffuse spasm(+) than for normal type, although this was not significant (diffuse type vs normal, 15.11±25.68 vs 5.38±7.07; P = 0.052; Table 5). The other two vessels, LAD and RCA, did not show significant TAG difference values among normal, focal spasm, and diffuse spasm vessels (LAD, P = 0.326; RCA, P = 0.433; Table 5).

Table 5

Comparison of intra-subject differences in TAG values among normal, focal and diffuse spasm (+) vessels.

	Spasm (-)	Spasm (+), Focal type	Spasm (+), Diffuse type	P
TAG difference a
Total	3.83±7.04	2.05±6.13	6.20±13.77	0.35
LAD	5.46±7.60	0.93±6.50	3.86±6.00	0.326
LCX	5.38±7.07	-	15.11±25.68	0.052
RCA	1.07±5.88	5.97±2.74	2.48±4.52	0.433

Data are expressed as mean ± standard deviation.

TAG difference

a, subtraction of TAG value of baseline CT from TAG value of IV Nitrate CT; TAG, transluminal attenuation gradient; Spasm (+), patients with vessels showing spasm; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; Focal type, significant focal stenosis without definite plaques; Diffuse type, diffuse small diameter (< 2 mm) with serrated margin and loss of diameter tapering.

Discussion

In our study, 55.8% (24/57) of the patients were diagnosed with coronary spasms based on the spasm provocation test. There were significant differences in TAG values among the major coronary arteries, regardless of the CT acquisition method, with RCA showing the highest TAG value (RCA > LAD > LCX). Further, TAG values were significantly lower (steeper) in the baseline CT than in the IV nitrate CT. More vessels showed diffuse spasms than focal spasms (76% vs. 24%), with diffuse spasms exhibiting significantly lower TAG values than the focal spasms.

The TAG value is positively correlated with the vessel diameter and length [12,22]. In our study, there were significant differences in the mean TAG values among the three major coronary arteries for both CT protocols. Additionally, the TAG values were progressively lower for LCX, LAD, and RCA, which corresponds to the order of increasing vessel diameter. Furthermore, administration of a vasodilator increased the TAG values in all three major coronary arteries. LAD and LCX demonstrated more significant increase in TAG values than RCA. Both the diameter and the contrast gradient over distance in the major coronary branches showed a more significant change in the left side than in the right side [23,24]. This could be attributed to the smaller change in the vessel diameter of the RCA over the vessel distance compared with the left coronary artery, which could result from the RCA having a larger diameter and longer length, as previously reported [25].

In our study, IV nitrate CT showed higher TAG (gentler slope) and ProxHU values than baseline CT in all three major coronary arteries. We previously found that the TAG and ProxHU values of coronary arteries increased with vasodilator administration on CCTA, regardless of the administration method (IV or sublingual), which is consistent with the present findings [25]. Additionally, there was a weak negative correlation between TAG and ProxHU values in all major coronary arteries before and after vasodilator administration. Coronary arteries are dilated after vasodilator administration, which emphasizes the contrast enhancement effect of increasing TAG and ProxHU values [25,26].

Comparison of TAG values in baseline CT between spasm(-) and (+) vessels, only LCX exhibited significantly lower values in spasm(+) than in spasm (-), but not in LAD and RCA. Moreover, the intrasubject TAG difference in LCX was greater in diffuse spasm(+) than normal group. This could be attributed to the relatively hypoplastic nature of LCX, and the small LCX sample size which only included diffuse spasm(+) vessels.

According to conventional CAG-based studies, coronary spasm can be divided into two types, based on the spasm length on CAG induced by the provocation test as follows: “focal spasm”, i.e., vasoconstriction within one coronary segment, and “diffuse spasm”, i.e., vasoconstriction of more than one adjacent coronary segments [27,28]. It remains unclear whether there are differences in the prognosis and clinical course between the spasm types. Sato et al. [29] analyzed 5-year clinical outcomes and showed that diffuse spasms showed fewer major adverse cardiovascular events and a better prognosis than focal spasms. Conversely, Park et al. [30] analyzed 3 year clinical outcomes and found that diffuse coronary spasms were independent predictors of recurrent chest pain. Sueda et al. [31] suggested that diffuse spasms had poor responses to medical treatment. Akasaka et al. [32] reported that vessels with diffuse spasms had significantly lower coronary flow reserves than those with focal spasms, which suggested that focal spasms are associated with localized endothelial dysfunction of the epicardial coronaries with no significant effect on coronary microvascular function. This explains the better prognosis of focal-type spasms. However, most CCTA studies on coronary spasms only considered focal spasms as a morphologic feature [8,10,33]. Due to the significant individual differences in the vessel diameter and density on contrast enhancement, as well as the influence of the contrast injection protocol or clinical characteristics, it might be difficult to identify diffuse type spasms on conventional single-acquisition CCTA. Using the double-acquisition protocol, we could assess diffuse spasms and determine the spasm types on CCTA. Moreover, for spasm(+) LAD and RCA vessels, all diffuse-type vessels showed significantly lower TAG values than the focal-type vessels. Since TAG is positively correlated with the diameter [12], the relatively small diameters of diffuse-type spasm vessels could have resulted in lower TAG values as compared to those of focal-type spasm vessels which usually maintain a normal diameter from the distal to spasm site. We cannot conclusively determine whether the vessel diameter is the only factor influencing TAG in diffuse-type spasm vessels or that it may co-exist with other factors, including coronary microvascular function status. There is a need for further studies on the poor prognosis and low TAG values of diffuse spasms, to improve VA diagnosis and management.

In our previous study [9], we examined the feasibility of the double acquisition CCTA protocol, which showed a relatively higher sensitivity for diagnosing VA compared with previous conventional single acquisition CCTA protocols. Moreover, according to the present study, the differences in TAG values of coronary spasms depend on the morphological subtype, which may improve the detection of diffuse type spasm. However, due to numerous limitations, including the difficulty of performing CCTA twice for the same patient, variations in vasospasm timing, increased radiation exposure, increased amount of contrast material used, and the requirement of CAG for confirmatory diagnosis of VA, further research is needed to determine the clinical use of the double acquisition CCTA protocol.

This study had several limitations. First, we included a relatively small sample size; therefore, future large-scale prospective studies are needed to confirm our results. Second, we excluded patients with significant (>50%) fixed stenosis of the coronary artery. Stenotic vessels have lower TAG values than non-stenotic vessels [21], which suggests that the inclusion of stenotic vessels may have influenced our results. Nonetheless, given the difficulty of discriminating between stenotic and spastic vessels, we chose to exclude fixed stenotic vessels. Third, we excluded 6 patients with inconsistent results on CCTA (negative) and the ergonovine provocation test (positive) in the analysis of TAG values. These false-negative results could result from variations in vasospasm timing and its migratory nature, which make them unreliable for determining the existence of vasospasm at the time of CCTA acquisition. Thus, due to the possible effect of inconsistencies between CCTA and CAG in the TAG analysis, we only included concordant resulting vessels to achieve accurate TAG results. Fourth, the results regarding the TAG values in spasm(+) and (-) vessels, regardless of vessel and spasm types, could not support an improved VA diagnostic performance with the addition of TAG in the CCTA analysis. We therefore focused on presenting differences in the TAG values between the spasm types.

In conclusion, coronary spasms can be classified as diffuse and focal types on CCTA. Additionally, a relatively large proportion of coronary spasms present as diffuse spasms rather than focal spasms. The TAG values of coronary spasms significantly differed according to the morphological feature. Diffuse-type spasms showed significantly lower TAG values than focal-type spasms. There is a need for future large-scale prospective studies to reveal the diagnostic utility of TAG in discriminating coronary spasms on CCTA.

Per-vessel analysis of diagnostic performance of CCTA.

(DOCX)

Click here for additional data file.

Minimal data set for Tables 1–5 and S1 and Figs 1–6.

(XLSX)

Click here for additional data file.

9 Feb 2022

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Reviewer #1: This manuscript is a well conceived and executed extension of prior work on the topic of using TAG in CCTA. It provides a potential novel tool for measuring/evaluating coronary vasospasm on CCTA. Below are specific comments and recommendations for revision:

1. Relatively high “false positive VA” (8/57 excluded for fixed stenoses) and “false negative VA” (6/57 excluded for negative CCTA but positive conventional angiogram) in the initial study population. The patients with fixed stenoses are addressed as the second limitation of the study. Please address and account for the false negative patients. These findings suggest that there is significant clinical overlap within the variant chest pain population.

2. For institutions that perform only CCTA with vasodilator, vasospasm will likely go undiagnosed. Would you recommend adding baseline CT to all variant chest pain CCT protocols in order to help diagnose VA?

3. Because hypertension and smoking are so significantly correlated with positive vasospasm patients, is TAG more useful in that population? Please comment on this in the discussion.

4. Nondiagnostic coronary segments were manually removed from the analysis (i.e, due to motion or blooming artifact) Can you include details about how many times was this necessary? Were there any entirely nondiagnostic CCTA exams?

5. Who performed the CCTA analysis. Was it one or more than one radiologist? If more than one, were there are any discrepant results and how were those adjudicated.

6. In the discussion, do you mean: We observed that IV nitrate CT shows (?higher?) TAG and higher ProxHU values than baseline CT in all three major coronary arteries. Can you clarify?

Reviewer #2: This is a very interesting paper with very good angiographic and CT correlation in patients with coronary vasospasm. I have only a few comments. Please see below.

1. Lines 71-75. I don't understand these sentences. I think the introduction warrants minor expansion to clarify the method of TAG measurement. Also, to explain the influence of vessel diameter on TAG measurement.

2. Line 140. Were beta blocker or calcium channel blockers used to lower heart rate for CT scans? Was there a difference in the use of these medications in the spasm and non spasm patients? Was the mean heart rate at the time of CT scan the same in both groups (with and without NTG?).

3. Line 121 and 122. I believe that the character "u" was omitted from the text. The text reads "10-20 g of ergonovine" and "nitroglycerin 100g". Perhaps simply use the abbreviation "ucg" or consult with the editorial staff regarding the use of greek characters.

4. Line 162. I assume that the analysis of TAG was terminated at the distal RCA prior to the bifurcation of the PDA and PLV branch. IF so, this should be clarified in the methods.

5. Line 185. I believe "distal levels" should be "distal vessels".

6. Line 188. I believe "ostium length" should be changed to "vessel length".

7. Line 266. Is there a minus sign missing from the baseline LAD TAG value?

8. Was there a difference in coronary dominance between spasm positive and spasm negative patients?

9. Figure 5. I believe these results are also reported in table 4. I would consider omitting table 4, and only use the figure. If you do this, you need to label the results of statistical analysis in the figure.

10. Figure 5. Panel B is incorrectly labeled as IV nitrate CT.

11. Figure 5. Panel C is incorrectly labeled as baseline CT.

12. Line 364, discussion. Please change "epithelial" to "endothelial".

Reviewer #3: The non-invasive diagnosis of patients with vasospastic angina is a worthy goal. This manuscript describes the imaging features, mainly transluminal attenuation gradient (TAG) and contrast enhancement of the proximal ostium (ProxHU), using dual (before and after iv nitroglycerin) coronary CT angiography (CCTA) of 43 enrolled in the NAVIGATOR study who had a high likelihood of vasospastic angina. 24 of 43 subjects of enrolled subjects had vasospasm on provocative invasive angiography. Of the 72 major coronary vessels in these 24 subjects, 76% demonstrated diffuse spasm on CCTA while 26% had discrete spasm. As expected, TAG was numerically less negative (i.e. less steep) and ProxHU greater in major vessels after administration of iv NTG (Table 3). The difference in TAG between vessels with and without spasm was only significant on the baseline was in the left circumflex artery (which was affected least often by spam as indicated in Table 1) and the only difference in ProxHU was observed in LAD. Not unexpectedly, there were no difference in vessels with and without spam after iv NTG administration. Also not unexpectedly, diffuse spasm was associated with a more negative TAG and lower ProxHU than discrete spasm. The authors conclude that a relatively large percentage of coronary spasms present as diffuse and TAG significantly differed according to the morphological type of the coronary spasm.

The concept of measuring TAG by CCTA before and after iv NRG administration to identify patients with vasospastic angina is intriguing and a potentially useful proposition. Unfortunately, the singularly descriptive and unsophisticated nature of the data presented in this manuscript does little to advance this aim. The authors have an opportunity to go well beyond that with their data set and determine if the change in TAG with iv NTG, both on a per patient and per vessel basis, correlates with vasospasm detected on the gold standard invasive provocative test. The impact of the manuscript would be far greater if they did. In addition, there are several other major criticisms of the manuscript. These include:

1. Subjects for this analysis were enrolled in the NAVIGATOR study but according to the references for that study, only 41 subjects with vasospastic angina were enrolled. The authors need to clarify the discrepancy with the reported 57 enrolled subjects. During what dates were subjects enrolled in the NAVIGATOR study?

2. The authors excluded 6 subjects with invasive evidence of vasospasm in whom the CCTA did not reveal spasm (false negative). This is a major source of bias, and these subjects should be included in the analysis.

3. Table 2 is incredibly confusing. I am assuming column 3 represents all vessels without and column 4 all vessels with spasm on CCTA. What one cannot tell from that table is how many vessels without spasm on invasive imaging had spasm on CCTA. If the goal of the table was to depict the proportion of spasm type (focal vs diffuse) in the specific arteries of patients with spasm detected by CCTA, a figure would likely be better. On a related note, what was the correlation spasm detected in the same arteries on invasive provocative testing and were the proportions of spasm type similar?

4. Table 3 shows mean TAG and ProxHU results and per vessel differences before and after iv NTG. Subjects with and without spasm on invasive testing are lumped together but would it not be more useful to determine if the change in each parameter with NTG is different between subjects with and without invasive evidence of spasm?

5. The information presented in Table 4 and Figure 4 are identical and therefore redundant. Furthermore, some of the same data is also presented in the text.

6. The manuscript would be greatly improved if the authors correlated TAG (or more specifically the change in TAG with iv NRG) to the gold standard invasive provocative testing. Calculation of sensitivity/specificity and positive/negative predictive value would help determine if measuring TAG (or ProxHU) by CCTA is a useful non-invasive method to diagnose vasospastic angina.

Minor comments:

1. The authors need to better clarify what type vasospasm to which they are referring. The reader finds it hard to know if they are talking about spasm detected by invasive provocative testing of by CCTA.

2. There are several grammatical errors that should be remedied.

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Reviewer #2: Yes: Timothy P. Fitzgibbons

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24 Mar 2022

Response to reviewers

Reviewer #1:

1. Relatively high “false positive VA” (8/57 excluded for fixed stenoses) and “false negative VA” (6/57 excluded for negative CCTA but positive conventional angiogram) in the initial study population. The patients with fixed stenoses are addressed as the second limitation of the study. Please address and account for the false negative patients. These findings suggest that there is significant clinical overlap within the variant chest pain population.

Answer: Thank you for this thoughtful advice. The six patients showed negative results on CCTA but positive results in the ergonovine provocation test. This could be attributed to individual differences and variations in the timing of CT acquisition. Given the variations in the timing and migratory nature of vasopasms, CCTA studies on coronary spasms have generally discarded such false negative results; accordingly, we exclude them from the results.

Line 517-521; Third, we excluded patients with inconsistent results on CCTA (negative) and the ergonovine provocation test (positive). False-negative results could result from variations in the timing and migratory nature of vasospasms; moreover, they are generally excluded in related studies.

2. For institutions that perform only CCTA with vasodilator, vasospasm will likely go undiagnosed. Would you recommend adding baseline CT to all variant chest pain CCT protocols in order to help diagnose VA?

Answer: Thank you for your suggestion. Although our double-acquisition CCTA protocol improved the sensitivity for diagnosing vasospastic angina compared with conventional single-acquisition CCTA protocols (sensitivity in per-patient, 73%; Eur Radiol. 2017;27: 1136–1147), it has several drawbacks in routine clinical practice (radiation dose, contrast media, etc.). Additionally, vasospasms show individual differences at various time during the day, which results in false negative results on CCTA. Moreover, since the spasm provoking test combined with invasive coronary angiography remains necessary for confirming variant angina, our double acquisition CCTA protocol cannot be used an independent diagnostic tool yet.

Line 501-509; In our previous study (9), we examined the feasibility of the double acquisition CCTA protocol, which showed a relatively higher sensitivity for diagnosing VA compared with previous conventional single acquisition CCTA protocols. Moreover, according to present study, we found difference of TAG values of coronary spasms depend on the morphological subtype which may improving the detection of diffuse type spasm. However, due to numerous limitations, including the difficulty of performing CCTA twice for the same patient, variations in the time of vasospasm, increased radiation exposure, increased amount of contrast material used, and the requirement of CAG for confirmatory diagnosis of VA, further research is needed to determine the clinical use of the double acquisition CCTA protocol.

3. Because hypertension and smoking are so significantly correlated with positive vasospasm patients, is TAG more useful in that population? Please comment on this in the discussion.

Answer: Thank you for your suggestion. Male sex, smoking, and hypertension are established clinical risk factors for coronary spams, which is consistent with our findings. Given our small sample size and the limited number of patients with those comorbidities (hypertension 11/57, smoking 21/43), we could not analyze the actual correlations between the patients’ characteristics and TAG values. Moreover, we observed that the TAG value is significantly dependent on the type of coronary spasm. Therefore, we cannot guarantee the utility of additional TAG analysis in the detection of coronary spasms on CCTA.

4. Nondiagnostic coronary segments were manually removed from the analysis (i.e, due to motion or blooming artifact) Can you include details about how many times was this necessary? Were there any entirely nondiagnostic CCTA exams?

Answer: Based on previous reports regarding TAG measurement, segments with motion or blooming artifacts are generally excluded when calculating the TAG values (JACC Cardiovasc Imaging. 2016;9(9):1074–83.; Radiology. 2016;279(1):75–83.); accordingly, we adapted the previously described methodology. Since these segments usually occupy only a small portion of the entire vessel, no vessels were excluded in this step. Therefore, all vessels were available for TAG analysis. We have revised the sentence for improved clarity.

Line 231-232; Datapoints in segments with motion or blooming artifacts from luminal calcium were excluded when calculating TAG values (21).

5. Who performed the CCTA analysis. Was it one or more than one radiologist? If more than one, were there are any discrepant results and how were those adjudicated.

Answer: Thank you for this thoughtful comment. In our study, two radiologists (EJ Kang, HS Yong) independently performed CCTA analysis, with discrepancies being reconciled through consensus. The weighted kappa for agreement between radiologist for decisions regarding coronary spasms were 0.781 (95% confidence interval (CI): 0.601 to 0.960) per patient and 0.759 (95% CI: 0.618 to 0.901) per vessel.

Line 218-220; All CCTA images were independently reviewed by two radiologists (E.J.K and H.S.Y) who were blinded to the patients’ clinical information, and discrepancies in results were resolved through consensus.

Line 257-258; Interobserver agreement for decisions of coronary spasm was assessed using a kappa test.

Line 303-306; The weighted kappa for agreement between the radiologists regarding decisions of coronary spasm were 0.781 (95% confidence interval (CI): 0.601 to 0.960) per patient and 0.759 (95% CI: 0.618 to 0.901) per vessel.

6. In the discussion, do you mean: We observed that IV nitrate CT shows (?higher?) TAG and higher ProxHU values than baseline CT in all three major coronary arteries. Can you clarify?

Answer : Thank you for pointing out this unclear point. In our study, the coronary arteries showed an increased TAG value (gentle slope) after vasodilator administration, which could be attributed to their dilatation emphasizing the contrast enhancement effects and increasing the TAG. We have revised this sentence for clarity.

Line 451-452; In our study, IV nitrate CT showed higher TAG (gentler slope) and ProxHU values than baseline CT in all three major coronary arteries.

Reviewer #2:

1. Lines 71-75. I don't understand these sentences. I think the introduction warrants minor expansion to clarify the method of TAG measurement. Also, to explain the influence of vessel diameter on TAG measurement.

Answer: Thank you for this thoughtful comment. We have modified this section for more clarity.

Line 82-84; However, clinical validation studies have reported conflicting results of the usefulness of using TAG at determining coronary arterial flow (14,15), since TAG may be affected by changes in coronary luminal diameter and collateral vascular enhancement.

2. Line 140. Were beta blocker or calcium channel blockers used to lower heart rate for CT scans? Was there a difference in the use of these medications in the spasm and non spasm patients? Was the mean heart rate at the time of CT scan the same in both groups (with and without NTG?).

Answer: Thank you for your thoughtful comment. In our research, we did not administer beta blockers or calcium channel blockers during CT acquisition. There was no significant difference in the heart rate during CT acquisition between the CT protocols.

Line 173-174; We did not administer additional beta-blockers or calcium channel blockers for decreasing the heart rate.

3. Line 121 and 122. I believe that the character "u" was omitted from the text. The text reads "10-20 g of ergonovine" and "nitroglycerin 100g". Perhaps simply use the abbreviation "ucg" or consult with the editorial staff regarding the use of greek characters.

Answer: Thank you for your careful observation. We have revised our manuscript accordingly.

Line 152-155; We injected 10–20 μg of ergonovine thrice at 1 min intervals into each coronary artery. Even in the negative cases, oral and intracoronary nitroglycerin (100 μg) and nifedipine (10 mg) were administered before completing the procedure to prevent delayed coronary spasms.

4. Line 162. I assume that the analysis of TAG was terminated at the distal RCA prior to the bifurcation of the PDA and PLV branch. IF so, this should be clarified in the methods.

Answer: Thank you for this thoughtful comment. We calculated the TAG of each vessels from the ostium to the distal vessels where the cross-sectional minimal area was < 2 mm2, regardless of the branching point, as previously described (JACC Cardiovasc Imaging. 2016 Sep;9(9):1074–83.). We have modified the sentence for more clarity.

Line 229-231; The mean luminal attenuation (HU) was measured at 1 mm intervals, from the ostium to distal levels where the cross-sectional minimal area fell below 2 mm2 (12).

5. Line 185. I believe "distal levels" should be "distal vessels".

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

Line 229-231; The mean luminal attenuation (HU) was measured at 1 mm intervals, from the ostium to distal levels where the cross-sectional minimal area fell below 2 mm2 (12).

6. Line 188. I believe "ostium length" should be changed to "vessel length".

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

Line 232-234; TAG was defined as the linear regression coefficient between the intraluminal HU and the distance from the ostium.

7. Line 266. Is there a minus sign missing from the baseline LAD TAG value?

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

Line 345-348; The mean TAG values were significantly lower (steeper slop) for baseline CT than that for IV nitrate CT, especially for LAD and LCX (LAD, -20.92±8.37 vs -16.71±6.90; P<0.001; LCX, -29.56±17.37 vs -22.75±11.97; P=0.001; RCA, -11.50±7.08 vs -9.94±5.67; P=0.068; Table 3).

8. Was there a difference in coronary dominance between spasm positive and spasm negative patients?

Answer: Thank you for this comment regarding coronary dominance, which is a very important point in coronary researches. We only included right-side dominant patients since TAG can be influenced by the vessel diameter and length (Br J Radiol. 2018 Jul; 91(1087): 20180043). We have clearly explained this in the revised manuscript.

Line 115-117; Since TAG could be influenced by the vessel diameter and length, we included only right-dominant patients i.e., patients whose posterior descending artery is supplied by the right coronary artery (RCA) (17).

9. Figure 5. I believe these results are also reported in table 4. I would consider omitting table 4, and only use the figure. If you do this, you need to label the results of statistical analysis in the figure.

Answer: We appreciate your important comment regarding overlapping data. We decided to omit table 4, keep figure 5 (in revised manuscript, figure 6), and add additional statistical analysis in the figure (Line 382).

10. Figure 5. Panel B is incorrectly labeled as IV nitrate CT.

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

.

11. Figure 5. Panel C is incorrectly labeled as baseline CT.

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

12. Line 364, discussion. Please change "epithelial" to "endothelial".

Answer: Thank you for this thoughtful comment. We have revised our manuscript accordingly.

Line 476-480; Akasaka et al. (32) reported that vessels with diffuse spasms had significantly lower coronary flow reserves than those with focal spasms, which suggested that focal spasms are associated with localized endothelial dysfunction of the epicardial coronaries with no significant effect on coronary microvascular function.

Reviewer #3:

1. Subjects for this analysis were enrolled in the NAVIGATOR study but according to the references for that study, only 41 subjects with vasospastic angina were enrolled. The authors need to clarify the discrepancy with the reported 57 enrolled subjects. During what dates were subjects enrolled in the NAVIGATOR study?

Answer: Thank you for this thoughtful comment. Among the 57 enrolled participants, we excluded 8 patients with significant fixed stenosis and 6 patients who showed contradictory results on the CCTA (negative) and ergonovine provocation test (positive), which implies false negative results. Finally, we included 43 patients. The enrolled patients participated in the NAVIGATOR study from March 2017 to April 2019 rather than the study you mentioned (Eur Radiol. 2017 Mar;27(3):1136–47; Cardiology. 2018;139(1):25–32).

2. The authors excluded 6 subjects with invasive evidence of vasospasm in whom the CCTA did not reveal spasm (false negative). This is a major source of bias, and these subjects should be included in the analysis.

Answer: Thank you for this thoughtful comment. Accordingly, we have enhanced our discussion regarding false negative. The six patients showed negative results on CCTA but positive results on the ergonovine provocation test, which could be attributed to individual differences and variations in the timing of CT acquisition. Given the variations in the timing and migratory nature of vasopasms, CCTA studies on coronary spasms have generally discarded such false negative results; accordingly, we exclude them from the results.

Line 517-521; Third, we excluded patients with inconsistent results on CCTA (negative) and the ergonovine provocation test (positive). False-negative results could result from variations in the timing and migratory nature of vasospasms; moreover, they are generally excluded in related studies.

3. Table 2 is incredibly confusing. I am assuming column 3 represents all vessels without and column 4 all vessels with spasm on CCTA. What one cannot tell from that table is how many vessels without spasm on invasive imaging had spasm on CCTA. If the goal of the table was to depict the proportion of spasm type (focal vs diffuse) in the specific arteries of patients with spasm detected by CCTA, a figure would likely be better. On a related note, what was the correlation spasm detected in the same arteries on invasive provocative testing and were the proportions of spasm type similar?

Answer: Thank you for this thoughtful comment. No vessels showed spasms on CCTA without spasms on the ergonovine provocation test. We modified table 2 more simply, and have added a diagram showing the proportion of spasm types in the specific arteries (Table 2 and Figure 4). We defined focal and diffuse type on CCTA; moreover, we classified spasm-positive vessels according to the aforementioned types.

4. Table 3 shows mean TAG and ProxHU results and per vessel differences before and after iv NTG. Subjects with and without spasm on invasive testing are lumped together but would it not be more useful to determine if the change in each parameter with NTG is different between subjects with and without invasive evidence of spasm?

Answer: Thank you for this thoughtful suggestion regarding the evaluation of TAG and ProxHU values according to the presence of spasms. Accordingly, we have added further results and statistical analyses. Regarding the comparison of the TAG values within the same spasm group [spasm (-) and (+) separately] between the baseline and IV nitrate CT, the spasm (+) group showed a larger difference in the mean TAG value than the spasm (-) group in the LCX and RCA [LCX, 43.5% vs. 19.4%; RCA, 22.8% vs. 9.7%; spasm (+) vs. spasm (-)]. Contrastingly, the LAD showed a smaller change in the TAG value in the spasm (+) group than in the spasm (-) group (14.4% vs. 24.8%). Compared with the LAD, the LCX and RCA showed a higher proportion of the diffuse type than the focal type (diffuse type: 100%, LCX; 80%, RCA; 67%, LAD), which could have contributed to our findings

Line 458-465; Comparison of TAG values in baseline CT between spasm(-) and (+) vessels revealed significant differences in LCX, but not in LAD and RCA. This could be attributed to the relatively hypoplastic nature of LCX, and the small sample size which only included diffuse spasm (+) vessels in the LCX. The spasm (+) group showed a larger mean TAG difference than the spasm (-) group for all coronary arteries except for LAD, which showed a smaller change in the spasm (+) group than in the spasm (-) group. Compared with LAD, LCX and RCA showed a higher proportion of the diffuse type than the focal type (diffuse type: 100%, LCX; 80%, RCA; 67%, LAD), which could have contributed to our findings.

5. The information presented in Table 4 and Figure 4 are identical and therefore redundant. Furthermore, some of the same data is also presented in the text.

Answer: We appreciate your important comment regarding overlapping data. We decided to omit table 4, keep figure 5 (in revised manuscript, figure 6), and add additional statistical analyses in the figure.

6. The manuscript would be greatly improved if the authors correlated TAG (or more specifically the change in TAG with iv NRG) to the gold standard invasive provocative testing. Calculation of sensitivity/specificity and positive/negative predictive value would help determine if measuring TAG (or ProxHU) by CCTA is a useful non-invasive method to diagnose vasospastic angina.

Answer: Thank you for this important comment. Indeed, we desired to calculate more precise and meaningful results, including sensitivity or specificity. However, our primary goal was determining the relationship between the TAG value and spasm types. There were obstacles impeding more elaborate analysis, including the lack of data volume. Moreover, the TAG value only showed significant differences in the LCX, which further impeded analysis of sensitivity or specificity. Therefore, we focused on presenting differences in TAG values between spasm types, rather than calculating statistically precise values. However, we anticipate further research on the feasibility of TAG compared with conventional CAG in VA diagnosis. We have added an additional comment regarding this limitation.

Line 521-524; Fourth, TAG values showed significant differences only in the LCX. Therefore, we focused on presenting differences in the TAG values between the spasm types, rather than presenting the sensitivity or specificity of the CCTA or TAG values in VA diagnosis.

Minor comments:

1. The authors need to better clarify what type vasospasm to which they are referring. The reader finds it hard to know if they are talking about spasm detected by invasive provocative testing of by CCTA.

Answer: Thank you for your comment. We defined the focal- and diffuse-type in CCTA; moreover, we classified spasm¬-positive vessels according to the aforementioned types.

Line 185-190; Regarding VA diagnosis, the following were the requirements for a positive finding on CCTA: (a) significant focal stenosis with negative remodeling on baseline CT without definite evidence of plaques in a completely dilated artery on IV nitrate CT (“focal-type”), or (b) diffuse small diameter (<2 mm) of a major coronary artery with a beaded appearance on baseline CT that showed complete dilation on IV nitrate CT (“diffuse-type”) (Figs 2 and 3) (10).

2. There are several grammatical errors that should be remedied.

Answer: The manuscript has been carefully rechecked; also we conducted an English editing service to improve the manuscript.

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

Answer: We agree to publish the peer review history of the article

Submitted filename: Response to reviewers.docx

Click here for additional data file.

9 May 2022

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Academic Editor

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Additional Editor Comments (if provided):

The manuscript has been reviewed by three experts. While all Reviewers recognize the potential value of the work, Reviewer 3 pointed out to important limitations that were not sufficiently addressed in the revision and that need to be addressed before the manuscript can be considered for publication. I would ask the authors to carefully respond all issues raised by R3 and R4.

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Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

Reviewer #4: All comments have been addressed

**********

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Reviewer #3: No

Reviewer #4: Yes

**********

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Reviewer #3: I Don't Know

Reviewer #4: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: No

**********

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Reviewer #3: (No Response)

Reviewer #4: Yes

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6. Review Comments to the Author

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Reviewer #1: (No Response)

Reviewer #3: As mentioned in my previous review, the non-invasive diagnosis of patients with vasospastic angina is a worthy goal. As the authors point out in the Introduction “there have been no studies on TAG in coronary spasm” and therefore a study that adequately explores it utility would be useful. The hypothesis underlying this study is that “TAG for CCTA may allow a higher diagnostic performance for coronary spasm than CCTA alone.” Unfortunately, persistent major flaws in this study preclude confirming or refuting that hypothesis. These include:

1. The authors excluded 6 subjects with invasive evidence of vasospasm in whom the CCTA did not reveal spasm (false negative). This is a major source of bias, and these subjects continue to be excluded by the authors in this revised manuscript. One cannot accurately assess the diagnostic performance of using CCTA with TAG compared to invasive coronary angiography by excluding these subjects.

2. In the places in text and their rebuttal, the Authors appear to shift the purpose of the manuscript and narrow it to a description of the imaging features of coronary spam on CCTA. Given that the performance of CCTA with TAG in diagnosing coronary vasospasm has not been validated against invasive coronary angiography, an analysis of the type of spasm (focal versus diffuse) in this highly selected population is of limited value in an of itself. Furthermore, if that really is the main purpose of this work, the authors need to compare the spasm on CCTA to that observed on coronary angiography, the goal standard.

3. The revised Table 3 snow shows the difference in group mean TAG and ProxHU results. A far more useful metric is the per subject differences that could potentially be able to identify subjects with vasospasm.

Reviewer #4: The authors present an interesting study and have addressed the previously raised criticisms in a satisfactory manner. Two points remain:

1) I don't see an explicit statement that the data is made available. Please add this.

2) Please have the manuscript reviewed by a native speaker. There are still language issues.

**********

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Reviewer #1: No

Reviewer #3: No

Reviewer #4: No

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30 May 2022

Response to reviewers

Reviewer #1:

Reviewer #3:

As mentioned in my previous review, the non-invasive diagnosis of patients with vasospastic angina is a worthy goal. As the authors point out in the Introduction “there have been no studies on TAG in coronary spasm” and therefore a study that adequately explores it utility would be useful. The hypothesis underlying this study is that “TAG for CCTA may allow a higher diagnostic performance for coronary spasm than CCTA alone.” Unfortunately, persistent major flaws in this study preclude confirming or refuting that hypothesis. These include:

1. The authors excluded 6 subjects with invasive evidence of vasospasm in whom the CCTA did not reveal spasm (false negative). This is a major source of bias, and these subjects continue to be excluded by the authors in this revised manuscript. One cannot accurately assess the diagnostic performance of using CCTA with TAG compared to invasive coronary angiography by excluding these subjects.

Answer:

Thank you for this valuable comment. In agreement, we have now included the six patients who showed negative results on CCTA but positive results on the ergonovine provocation test in the evaluation of the diagnostic performance of CCTA compared to invasive coronary angiography. The results of the per-patient analysis showed that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80%, 100%, 100%, 76%, and 87.76%, respectively. We also analyzed that with per vessel level, and added the results with supplement table (Table S1). However, based on our results, there was only partial differences of TAG values for regarding the spasm on diffuse type spasm on LCX. Also we found the differences of TAG values between the spasm subtypes (diffuse vs focal). Thus, we could not applied TAG for the additional diagnostic tool of spasm detection on CCTA. We added this on the discussion session for limitation.

Line 107-110; The diagnostic performance of CCTA for the detection of coronary spasm showed that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80%, 100%, 100%, 76%, and 87.76%, respectively. Per-vessel analysis results are shown in S1 Table.

Line 448-452; Fourth, the results regarding the TAG differences between spasm(+) and (-) vessels, regardless of vessel and spasm types, could not support an improved VA diagnostic performance with the addition of TAG in the CCTA analysis. We therefore focused on presenting differences in the TAG values between the spasm types.

2. In the places in text and their rebuttal, the Authors appear to shift the purpose of the manuscript and narrow it to a description of the imaging features of coronary spam on CCTA. Given that the performance of CCTA with TAG in diagnosing coronary vasospasm has not been validated against invasive coronary angiography, an analysis of the type of spasm (focal versus diffuse) in this highly selected population is of limited value in an of itself. Furthermore, if that really is the main purpose of this work, the authors need to compare the spasm on CCTA to that observed on coronary angiography, the goal standard.

Answer:

Thank you for your comment. As your comment, in the previous manuscript, we shifted the purpose from proving the hypothesis “that using TAG for CCTA may allow a higher diagnostic performance for coronary spasm than CCTA alone”, which was suggested in the introduction, to a description of the imaging features of coronary spam on CCTA. We agree with your comment that our results are insufficient to support the former purpose; therefore, we have deleted the sentence from the manuscript.

In addition to CCTA alone, we attempted to evaluate the usefulness of TAG and TAG difference values in diagnosing VA in CCTA. Unfortunately, both the TAG and TAG differences between any of the groups (i.e. normal vs spasm(+) or diffuse type vs focal type) were not significant, except for the analysis of baseline CT TAG values among normal vs focal vs diffuse type in LAD and RCA (Table 4). Thus, in the revised manuscript we have focused on presenting the differences in TAG values between spasm types.

Line 430-436; Moreover, according to the present study, the differences in TAG values of coronary spasms depend on the morphological subtype, which may improve the detection of diffuse type spasm. However, due to numerous limitations, including the difficulty of performing CCTA twice for the same patient, variations in vasospasm timing, increased radiation exposure, increased amount of contrast material used, and the requirement of CAG for confirmatory diagnosis of VA, further research is needed to determine the clinical use of the double acquisition CCTA protocol.

Line 448-452; Fourth, the results regarding the TAG differences between spasm(+) and (-) vessels, regardless of vessel and spasm types, could not support an improved VA diagnostic performance with the addition of TAG in the CCTA analysis. We therefore focused on presenting differences in the TAG values between the spasm types.

3. The revised Table 3 snow shows the difference in group mean TAG and ProxHU results. A far more useful metric is the per subject differences that could potentially be able to identify subjects with vasospasm.

Answer:

Thank you for your comment. Accordingly, we calculated the TAG difference values, the intra-subject difference in TAG value between the baseline CT and IV nitrate CT. The results showed non-significant differences in TAG difference values among normal, focal spasm, and diffuse spasm groups in all three vessels. Among vessel subtypes, LCX, of which all spasm(+) vessels were diffuse type, showed a greater TAG difference for diffuse spasm(+) than for normal type, although this was not statistically significant.

Line 349-357; The intra-subject difference in TAG value between the baseline CT and IV nitrate CT shows relatively larger value in diffuse type spasm vessels than in focal type spasm or negative spasm vessels, but statistically insignificant (diffuse type vs focal type vs normal, 6.20±13.77 vs 2.05±6.13 vs 3.83±7.04; P=0.35; Table 5). Among vessel subtypes, LCX, of which all spasm(+) vessels were diffuse type, showed a greater TAG difference for diffuse spasm(+) than for normal type, although this was not significant (diffuse type vs normal, 15.11±25.68 vs 5.38±7.07; P=0.052; Table 5). The other two vessels, LAD and RCA, did not show significant TAG difference values among normal, focal spasm, and diffuse spasm vessels (LAD, P=0.326; RCA, P=0.433; Table 5).

Line 397-399; Moreover, the intrasubject TAG difference in LCX was greater in the diffuse spasm group than in the normal group. This could be attributed to the relatively hypoplastic nature of LCX, and the small LCX sample size which only included diffuse spasm(+) vessels.

Reviewer #4:

The authors present an interesting study and have addressed the previously raised criticisms in a satisfactory manner. Two points remain:

1. I don't see an explicit statement that the data is made available. Please add this.

Answer: Thank you for your comment. All relevant data are within the manuscript, figures, and its Supporting Information files.

2. Please have the manuscript reviewed by a native speaker. There are still language issues.

Answer: Thank you for your comment. The manuscript has now been proofread and corrected by a professional editor.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

27 Jun 2022

Assessment of coronary spasms with transluminal attenuation gradient in coronary computed tomography angiography

PONE-D-21-39960R2

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Reviewer #1: All comments have been addressed

Reviewer #4: All comments have been addressed

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**********

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Reviewer #1: Yes

Reviewer #4: (No Response)

**********

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1 Jul 2022

PONE-D-21-39960R2

Assessment of coronary spasms with transluminal attenuation gradient in coronary computed tomography angiography

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