Study Population

We consecutively enrolled 792 patients who underwent their first coronary angiographic examinations from May 1, 2012, to November 1, 2014, at Tokushima University Hospital. In the present study, the analyzed population was patients who had no significant coronary artery stenosis but were suspected to have VSA (chest pain or chest discomfort at rest). Therefore, patients who demonstrated ≥50% stenosis on coronary angiography ( n = 482) or lacked typical VSA symptoms ( n = 212) were excluded. Subjects were also excluded if they refused to undergo the intracoronary acetylcholine (ACh) stress test ( n = 33). After these exclusions, 65 patients remained for the final analysis ( Figure 1 ). They were scheduled to undergo intracoronary ACh stress testing to diagnosis VSA. We also enrolled 30 age- and gender-matched healthy control subjects who were selected from our healthy volunteer database on the basis of a comprehensive history and physical examination, to determine the normal value of EAT. The study was approved by the institutional review board of Tokushima University Hospital (no. 2183-1), and written informed consent was obtained from all subjects.

Flowchart of the recruitment of patients.

All subjects were classified into either the VSA group or the non-VSA group. The VSA group was defined as patients who had coronary spasm in any coronary artery during the intracoronary ACh stress test. Hypertension was defined as systolic blood pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg or current treatment with antihypertensive medication. Diabetes mellitus was defined as fasting blood glucose 126 mg/dL, glycated hemoglobin ≥ 6.5%, and/or the need for oral hypoglycemic agents. Dyslipidemia was defined as plasma total cholesterol > 220 mg/dL or the use of lipid-lowering therapy. Smoking was defined as current or previous use of cigarettes.

Echocardiographic Examination

Echocardiography was performed using commercially available ultrasound machines (Vivid E9 [GE Healthcare, Milwaukee, WI], iE33 [Philips Healthcare, Best, The Netherlands]; Aplio 500 [Toshiba Medical Systems, Tochigi, Japan]; or α10, Preirus [Hitachi, Tokyo, Japan]) 1 day before coronary angiography. The details of EAT thickness measurements have already been described in our previous report. Using a high-frequency linear probe (7.5–11 MHz), EAT thickness was measured at end-systole in two locations: in the AIG, where the left anterior descending coronary artery (LAD) runs, and on the free wall of the RV, away from any major epicardial artery. While assessing EAT-AIG thickness, we searched for the distal portion of the LAD and carefully rotated the probe until a longitudinal section was identified. EAT-AIG thickness was measured as the distance from the outer wall of the myocardium to the visceral layer of the epicardium. EAT-RV thickness was measured using the method previously reported by Iacobellis and Willens. The thickness of pericardial adipose tissue over the free wall of the RV outside of the parietal pericardium was also measured at end-systole from the same image used to measure EAT-RV thickness. Measurements were performed during three cardiac cycles for each parameter, and the mean for each parameter was used for analysis. The reproducibility of EAT-AIG thickness, expressed as the intraclass correlation coefficient, has been described in detail by our group as 0.98 and 0.91 for intraobserver and interobserver variation.

Provocation Testing of VSA

The intracoronary infusion of ACh was performed according to the guidelines for diagnosis and treatment of patients with vasospastic angina. The administration of vasoactive drugs, including calcium channel blockers, nitrates, β-adrenergic blockers, and other vasodilators, was stopped for ≥2 days before angiography. Before performing vasospasm provocation testing with ACh, controlled coronary angiography was performed. ACh was injected from the same angle over a period of 20 sec into the right coronary artery (RCA; at a dose of 20 or 50 μg) and the left coronary artery (LCA; at a dose of 20, 50, or 100 μg) according to the clinical condition. Angiography was subsequently performed 1 min after the start of each injection. Angiography was also performed after presentation of ischemic changes on electrocardiography or chest pain. Coronary spasm was defined as total or subtotal occlusion (≥90% stenosis) accompanied by episodes of chest pain or ischemic ST-segment changes on electrocardiography ( Figure 2 ).

Representative recordings. VSA group: a 73-year-old woman presented with chest discomfort. EAT was thickened, and we suspected coronary artery disease or VSA. Coronary angiography revealed that there was no significant organic stenosis. We added ACh provocation testing. Significant coronary spasm was observed, and we diagnosed VSA. Non-VSA group: an 87-year-old man presented with chest discomfort. EAT was not thickened. The coronary artery had no significant stenosis, and ACh provocation testing was negative. PAT , Pericardial adipose tissue.

Statistical Analysis

Data are presented as mean ± SD. Student’s t test was used to compare continuous variables between the two groups (VSA and non-VSA). When comparing between three groups (VSA, non-VSA, and normal), we added the control group to use the analysis of variance with the Bonferroni method. Logistic regression was used to calculate odds ratios and 95% CIs after adjustment for potential confounders. Potential confounders, such as smoking, diabetes mellitus, and dyslipidemia, were entered in multivariate models. The performance of clinical risk factors (smoking, diabetes mellitus, and dyslipidemia) plus various combinations of EAT-AIG thickness was assessed using the area under the curve in receiver operating characteristic analysis. To evaluate the correlation of EAT-AIG thickness and presence of VSA, two models were constructed and compared using receiver operating characteristic analysis. Model 1, the basic model, consisted of clinical risk factors alone. Model 2 included the variables in model 1 plus EAT-AIG thickness. The DeLong method was used to compare the C statistic. We conducted bootstrapping with 2,000 resamples to assess the internal validation. Statistical analysis was performed using standard statistical software packages (SPSS version 21.0 [SPSS, Chicago, IL], MedCalc version 15.8 [MedCalc Software, Mariakerke, Belgium], and R version 3.3.3 [R Foundation for Statistical Computing, Vienna, Austria]). P values < .05 were considered to indicate statistical significance.

Patient Characteristics

On the basis of the results of ACh provocation testing, subjects were divided into two groups with (VSA group: 30 patients; mean age, 66 ± 9 years; 19 men) and without (non-VSA group: 35 patients; mean age, 65 ± 12 years; 18 men) significant coronary spasm. We added age-matched healthy control subjects (control group: 30 patients; mean age, 65 ± 10 years; 17 men) in the analysis. Clinical characteristics of the patients in the VSA group, non-VSA group, and control group are presented in Table 1 . There were no significant differences in age, gender, body mass index, and blood pressure among all three groups. Neither were there any differences in cardiovascular risk factors between the VSA and non-VSA groups. In the non-VSA group, all patients underwent provocative testing with ACh 50 μg in the RCA and ACh 100 μg in the LCA. In the VSA group, for the provocative test in the RCA, two subjects received ACh 20 μg and 22 subjects ACh 50 μg. For the provocative test in the LCA, no subjects received ACh 20 μg, three received ACh 50 μg, and 17 received ACh 100 μg. Thus, many patients underwent provocative testing with the maximum dose of ACh.

Echocardiographic Parameters and Measurements of EAT Thickness

We were able to measure EAT thicknesses using echocardiography in all subjects. Echocardiographic parameters and measurements of EAT thicknesses are presented in Table 2 . There were no significant differences in left ventricular and left atrial size and Doppler findings between the VSA and non-VSA groups. EAT-AIG thickness was significantly greater in the VSA group than in the non-VSA group (8.2 ± 2.7 vs 6.1 ± 2.5 mm, P = .002). Interestingly, there was no difference of EAT-AIG thickness between the control and non-VSA groups.

Table 2

Echocardiographic examination result

	Healthy control ( n = 30)	VSA ( n = 30)	Non-VSA ( n = 35)	P value for VSA vs non-VSA
LV and LA size
LV EDV (mL)	86 ± 22	82 ± 24	81 ± 18	.871
LV ESV (mL)	30 ± 9	29 ± 9	28 ± 8	.576
LV mass index (g/m 2 )	82 ± 16	83 ± 19	80 ± 23	.654
LA volume index (ml/m 2 )	29 ± 9	27 ± 7	29 ± 8	.302
LV ejection fraction (%)	66 ± 6	65 ± 5	66 ± 5	.389
Doppler findings
E (cm/sec)	61 ± 13	60 ± 20	63 ± 13	.430
DT (msec)	228 ± 38	240 ± 69	239 ± 60	.927
A (cm/sec)	71 ± 18	70 ± 13	76 ± 23	.193
E/A ratio	0.89 ± 0.23	0.89 ± 0.39	0.91 ± 0.35	.860
Lateral s′ (cm/sec)	8.3 ± 3.0	8.8 ± 3.0	8.1 ± 2.6	.334
Lateral e′ (cm/sec)	9.5 ± 2.4	8.5 ± 2.3	9.6 ± 2.5	.089
Lateral a′ (cm/sec)	10.1 ± 2.4	11.2 ± 3.2	10.3 ± 2.6	.958
E/e′ ratio	7.1 ± 2.7	7.5 ± 3.3	7.0 ± 2.4	.491
Adipose tissue thickness
EAT-AIG thickness (mm)	6.1 ± 2.4	8.2 ± 2.7 ∗	6.1 ± 2.5	.002
EAT-RV thickness (mm)	4.0 ± 2.3	4.6 ± 2.0	4.5 ± 1.8	.822
PAT thickness (mm)	4.3 ± 2.4	5.0 ± 2.0	4.5 ± 2.7	.388

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