Methods

Women with systemic hypertension and chest pain, who had presented for diagnostic coronary angiography were prospectively recruited into the present study if they had no historical or electrocardiographic evidence of previous myocardial infarction. After the exclusion of those with unstable angina, global left ventricular (LV) dysfunction (ejection fraction <55%), severe valvular disease, or previous revascularization, 76 hypertensive women (from 198 screened hypertensive patients) consented to undergo treadmill exercise ECG, exercise 99m-technetium sestamibi (MIBI) single photon emission computed tomography, and dobutamine and dipyridamole stress echocardiography. To avoid interference with the study investigations, anti-ischemic drugs were discontinued for the entire study duration. To control the patients’ blood pressure during the study period, the patients were given angiotensin-converting enzyme inhibitors or sartans, as necessary. For clinical reasons, 5 patients were still receiving antianginal therapy, and 2 of these patients were taking β-adrenoceptor blocking agents during the tests. The baseline characteristics of patients are listed in Table 1 .

Treadmill exercise ECG, exercise MIBI scanning, and dobutamine and dipyridamole stress echocardiography were performed within 4 weeks (30 ± 9 days) before coronary angiography. The sequence varied according to the clinical commitments of the patients but normally involved dobutamine echocardiography before dipyridamole echocardiography on separate days. All patients gave written informed consent.

Treadmill exercise was performed according to the modified Bruce protocol. The following criteria were used for discontinuing the test: (1) achievement of the maximal predicted heart rate; (2) the occurrence of diagnostic (≥2.0-mm rectilinear or downsloping) ST-segment depression on ≥1 precordial or 2 peripheral leads, with or without angina; (3) severe dyspnea or fatigue; (4) repetitive ventricular arrhythmias; and (5) a >20-mm Hg decrease in systolic blood pressure at any exercise step. The test results were considered positive when >1 mm horizontal or downsloping ST-segment depression occurred 80 ms after the J point. If a lead exhibited pre-exercise ST-segment abnormalities (ST-segment depression of ≥0.5 mm at rest), any additional ST-segment depression had to be ≥1 mm.

For the MIBI scan, the tracer (925 Mbq) was given intravenously immediately after exercise discontinuation and again 48 hours after exercise, with the patient at rest. Single photon emission computed tomography scans were performed 90 minutes after tracer injection, with a large field of view, single-head rotating gamma camera. A total of 64 angular projections (64 × 64 matrix) were obtained within approximately 40 minutes over 360°. Transaxial slices, 6.2 cm thick, were reconstructed using a filtered back projection algorithm with a Butterworth filter (cutoff frequency 0.4 cycles/pixel). From the raw scintigraphic data, horizontal long-axis, vertical long-axis, and short axis tomograms were reconstructed. The LV myocardium was divided into 6 segments: anterior, apical, septal, inferior, posterior, and lateral. The images were displayed in random order and graded using a 4-point score (0, normal; 1, moderate uptake reduction; 2, severe uptake reduction; and 3, absent uptake). A test was considered positive when ≥1 point score change was found between the at rest and stress images in ≥2 adjacent tomographic slices.

For dobutamine echocardiography, dobutamine, 5 to 40 μg/kg/min, was infused intravenously, with 3 minutes for each step. For dipyridamole echocardiography, dipyridamole was infused at 0.56 mg/kg within 4 minutes, followed by 4 minutes of no dose and then 0.28 mg/kg within 2 minutes. In patients not achieving 85% of their maximal predicted heart rate at the peak dose of dobutamine or dipyridamole, 0.5 mg of atropine was given intravenously and repeated to a maximum of 1.0 mg. Echocardiographic images were continuously recorded and were obtained from the standard parasternal long-axis and short-axis views and the apical 4- and 2-chamber views. The end points for the termination of the tests were (1) achievement of the maximum dose of dobutamine or dipyridamole (with or without atropine) or 85% of the maximum predicted heart rate, (2) hypertension (systolic pressure >220 mm Hg, diastolic pressure >120 mm Hg) or hypotension (>30 mm Hg decrease in systolic pressure), (3) development of severe ischemia (severe angina, ST-segment depression ≥2 mm, or new or worsening abnormality in systolic wall motion or wall thickening), or (4) significant ventricular or supraventricular arrhythmia (≥10 beats for supraventricular tachycardia or ≥3 beats for ventricular tachycardia). The left ventricle was divided into 16 segments. For each segment, the systolic wall motion and thickening was graded visually using a semiquantitative 4-grade scoring system (normal or hyperkinetic, 1; hypokinesia, 2; akinesia, 3; and dyskinesia, 4). Deterioration in regional wall motion was considered myocardial ischemia when the wall motion score increased by ≥1 grade at peak testing. In our center, the intra- and interobserver variability in the interpretation of regional function has been 7.1% and 4.2%, respectively.

The coronary arteries were selectively injected in multiple views and, to avoid overestimation of coronary stenosis due to vasoconstriction, left and right coronary injections were performed after intracoronary administration of nitroglycerin. All angiograms were analyzed by an investigator who had no knowledge of the other data. The minimal stenosis diameter was measured, and the severity is expressed as the percentage of reduction of the normal diameter. Significant CAD was considered >50% reduction in the luminal diameter of ≥1 major epicardial vessel. The stenotic lesion morphology was serially identified as either “simple” (with smooth border) type plaques or “complex” (with irregular border) type plaques, according to the classification by Ambrose and Israel.

The sensitivity, specificity, and positive and negative predictive values of the 4 noninvasive tests in detecting CAD were obtained in the usual fashion. Differences between the results of the tests were compared using the chi-square test; Fisher’s exact test was used as appropriate. Continuous variables are expressed as the mean ± SD and compared using a paired t test. A value of p ≤0.05 was considered statistically significant.

Results

All studies performed in the 76 hypertensive women who completed the protocol were interpreted and compared. Coronary angiography demonstrated significant CAD in 31 (41%) of the 76 hypertensive women. Of these 31 patients, 17 had single-vessel, 11 had 2-vessel, and 3 had 3-vessel CAD. The morphology of the stenotic lesion was simple (smooth) in 18 patients and complex (irregular) in 10 patients; 3 patients had both simple and complex lesions.

Of the 45 patients with normal coronary arteries, 22 had abnormal findings on the electrocardiogram at rest, 1 had left anterior fascicular branch block, and 21 had varying degrees of abnormal repolarization (ST-T abnormalities). On the at rest echocardiogram, 16 patients had LV hypertrophy (mean septum thickness 12.8 ± 1.0 mm) and 5 had mild regional dysfunction of the left ventricle. A perfusion defect at rest, as assessed by myocardial scintigraphy, was found in 17 patients.

Of the 31 patients with CAD, 17 had normal findings on the electrocardiogram at rest, 14 had abnormal repolarization, 20 had LV hypertrophy (mean septum thickness 13.2 ± 1.2 mm), 4 had LV regional dysfunction, and 13 had a perfusion defect at rest.

The diagnostic accuracy of the 4 stress tests is listed in Table 2 . The sensitivity of exercise ECG (25 of 31), MIBI scan (28 of 31), and dobutamine echocardiography (27 of 31) was similar and greater than that of dipyridamole echocardiography (19 of 31). However, the specificity of exercise ECG and MIBI scanning were poor and were significantly lower than that of dipyridamole and dobutamine echocardiography. However, the 2 stress echocardiography tests did not differ significantly from each other. Similarly, the positive predictive value of dobutamine and dipyridamole echocardiography were greater than that of exercise ECG and MIBI scanning, although their respective negative predictive values were not significantly different. Owing to its fair sensitivity and specificity, dobutamine echocardiography had the greatest overall diagnostic accuracy of the 4 tests. The excellent specificity of dipyridamole echocardiography and that the majority of study patients had no CAD were taken into account for a fair negative predictive value, comparable to that of the other tests.

In the 45 patients without significant CAD, 20 and 21 had false-positive results from exercise ECG and MIBI scanning, respectively. However, only 4 and 8 had a false-positive response to dipyridamole and dobutamine echocardiography, respectively. The relevant clinical and angiographic findings for patients with a false-positive result by any technique are summarized in Table 3 . Patients with LV hypertrophy or repolarization abnormalities at rest were excessively represented among the patients with false-positive results from exercise ECG ( Table 3 ), which attained statistical significance when consider either alone or together. Patients with LV hypertrophy or baseline ST-T abnormalities considered together or separately correlated more closely with false-positive than true-negative results from exercise ECG (LV hypertrophy 11 of 20 vs 5 of 25, p <0.02; ST-T abnormalities 13 of 20 vs 8 of 25, p <0.03; both LV hypertrophy and ST-T abnormalities 18 of 20 vs 9 of 25, p = 0.001). However, using the MIBI scan, only LV hypertrophy, and not ST-T abnormalities, was more closely associated with false-positive than true-negative results (ST-T abnormalities 9 of 21 vs 12 of 24, p = NS; LV hypertrophy 11 of 21 vs 5 of 24, p <0.03; together 15 of 21 vs 12 of 24, p = NS). The percentage of abnormal perfusion at rest was 29% (6 of 21 patients) in false-positive group and 47% (11 of 24) in the remainder (p = NS). In 27 patients with either LV hypertrophy or ST-T abnormalities at rest and without significant CAD, the specificity of exercise ECG and MIBI scanning was only 33% and 44%, respectively. However, for the remainder, the specificity was 89% for exercise ECG (p <0.001) and 67% for MIBI scanning (p = NS; Figures 1 and 2 ). When we considered the specificity of exercise ECG alone, it ( Figure 1 ) was significantly greater in either patients without LV hypertrophy or those with normal findings at ECG at rest than in those with LV hypertrophy and those with ST-T abnormalities, respectively ( Figure 1 ). In contrast, the specificity of MIBI scanning was greater in patients without LV hypertrophy than in those with LV hypertrophy and was similar in patients with and without ST-T abnormalities ( Figure 2 ). The false-positive findings from scintigraphy were also not attributable to soft tissue attenuation. Of the 21 studies with false-positive findings, only 3 showed a perfusion defect at rest and 3 showed a combination of defects at rest and during stress.

Table 3

Clinical baseline data and stress test findings in patients with false-positive results

Pt. No.	Age (years)	LVH	ECG at Rest	LV Dysfunction at Rest	Perfusion Defect	Angiographic Stenosis	DOB Echocardiographic Positive Site	DIP Echocardiographic Positive Site	EET Positive Leads	MIBI Scan Positive Site
1	45	0	0	0	0	0	0	0	0	I-Ap
2	52	0	Multilead ST-T ↓	0	Ap	0	0	0	0	S
3	52	+	0	0	0	0	0	I	V 5 –V 6	S, L
4	55	+	ST-III, aVF ↓	0	0	0	L, I	0	0	L
5	55	0	ST-II, V 5 , V 6 ↓	0	0	0	0	0	V 4 –V 6	0
6	55	0	RBB,V 1 –V 3 ↓	0	Ap, S	0	0	0	V 4 –V 6	0
7	55	0	Multi-lead T flat	0	0	0	0	0	V 3 –V 6	0
8	56	0	0	0	0	0	0	0	V 4 –V 6	A, Ap
9	56	+	ST-aVL, V 5 , V 6 ↓	0	0	0	0	0	V 4 –V 6	AS
10	57	0	0	0	Ap, A, S	0	AS, S	AS, S	V 4 –V 6	0
11	57	+	ST-II, III, aVF ↓	0	0	0	0	0	V 4 –V 6	A, L
12	58	+	Multilead T flat	0	0	0	0	0	V 4 –V 6	AS
13	58	0	0	0	0	0	0	0	0	I-Ap
14	58	0	0	Ap, P	S	0	L, P	0	0	0
15	58	+	Multilead T negative	0	S, I	0	0	0	V 4 –V 6	0
16	59	0	ST-V 3 –V 6 ↓	0	0	0	0	0	V 4 –V 6	0
17	59	0	0	0	I	0	0	0	0	I, Ap
18	60	0	ST-II, III, aVF, V 4 –V 6 ↓	0	0	43% DI	0	0	V 5 , V 6	L
19	61	+	0	0	0	0	0	0	V 5 –V 6	I, A-Ap
20	62	+	ST-V 2 , V 6 ↓	A, L	0	30% LAD	A, L, A-S	A, L	V 4 –V 6	0
21	63	+	Multilead T flat	0	A, S	0	0	0	0	A, S
22	63	+	0	0	0	0	0	0	V 4 –V 6	P-L, A,S
23	64	+	Multilead ST-T ↓	Ap	0	0	A, L	I, L	0	0
24	65	+	0	0	0	0	0	0	V 3 –V 4	I–P
25	66	+	ST-V 2 -V 5 ↓	L, S	S, I, L	0	I	0	V 4 –V 6	0
26	67	0	ST-II, aVF, V 6 ↓	0	Ap	0	0	0	II, aVF, V 4 –V 6	AS, S
27	67	0	0	0	Ap, S, A	0	0	0	0	S, L
28	68	+	0	0	0	0	0	0	0	A, L
29	70	+	0	I	A, S	0	I	0	V 4 –V 6	I–P
30	71	0	ST-V 3 –V 4 ↓	0	0	30% RCA	0	0	II, aVF, V 6	I-Ap
31	72	0	0	0	0	0	P	0	0	I-Ap

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