1. Introduction

Exercise-testing is an affordable and widely available tool for the detection of exercise-induced myocardial ischemia in subjects with intermediate pretest probability of coronary artery disease [Gibbons et al., 1997]. However, the diagnostic accuracy of this valuable method based on ST-segment deviation has been modest, mainly due to its low sensitivity for the diagnosis of single vessel disease and particularly for the diagnosis of right coronary artery stenosis [McHenry at al., 1972; Gianrossi et al., 1989]. Although the use of three additional right anterior chest leads has been reported to increase the sensitivity of exercise-testing to detect myocardial ischemia due to right coronary artery disease in patients referred for chest pain [Michaelides et al., 1999], the diagnostic performance of exercise-testing in a variety of clinical conditions, such as treatment with digitalis, conduction disturbances, abnormalities of the cardiac rhythm, history of myocardial infarction or revascularisation therapy, left ventricular hypertrophy and resting ST-segment depression remains problematic [Sketch et al., 1981; Whinnery et al., 1977].

During the last decades, the advances in radionuclide imaging techniques enabled us to improve diagnosis and risk stratification of patients with coronary artery disease. Indeed, thallium-201 scintigraphy, having gathered the largest experience in myocardial perfusion imaging, has been proved to be a very accurate technique for the management of patients with ischemic heart disease. Furthermore, thallium-201 scintigraphy has been found to be less susceptible to false results than exercise-testing, in the aforementioned, problematic clinical conditions. However, the specificity of thallium-201 scintigraphy for the detection of ischemia in the inferior wall has been reported to be modest, mainly due to the attenuation of the inferior wall activity by the left hemidiaphragm [DePasquale et al., 1988; DePuey and Garcia, 1989; DePuey, 1994].

We examined the ability of right chest leads during exercise-testing in identifying those individuals, who despite the positive results exclusively in the inferior myocardial wall on thallium-201 scintigraphy, are not likely to suffer from coronary artery stenosis and thus will not benefit from further evaluation with coronary angiography.

2. Materials and Methods

2.1. Study Population

In this pilot, evolving study, we have enrolled 94 patients who had undergone coronary angiography because of evidence of myocardial ischemia exclusively in the inferior myocardial wall, as depicted by thallium-201 scintigraphy. There were 75 males and 19 females with a mean age of 52±7 years. The studied patients were originally referred by their physicians for evaluation of their symptoms with thallium-201 scintigraphy, mainly due to inconclusive exercise tests and abnormal ECG findings at baseline, and consisted a group of individuals with moderate pretest probability of having clinically relevant coronary artery disease. Excluded from the study were patients with a history of myocardial infarction, left or right bundle branch block, ventricular hypertrophy, ventricular preexcitation, valvular or congenital heart disease and those receiving digitalis. The study was approved by our hospital ethics committee and informed consent was obtained from all participants.

2.2. Exercise Testing

All patients exercised on Quinton 5000 treadmill systems (Quinton Instruments Co., Seattle, WA, USA) according to the multistage Bruce protocol. We used two exercise systems (Fig. 1). The patients were walking on the treadmill of the one system. Two of the investigators were responsible for the simultaneous starting and ending of the exercise in both systems. A total of 20 leads were used. The position of the three right anterior chest leads (RV3, RV4 and RV5) has been previously described [Fisch, 1997] and is shown in Fig. 2. The usual 12-lead exercise testing was recorded on the first system, while the 3 right chest leads were recorded on the second system simultaneously but separately. All leads were simultaneously recorded every minute during exercise and up to ten minutes during the recovery period. Blood pressure was measured every two minutes during exercise by sphygmomanometry. Exercise was terminated because of severe angina, incapacitating fatigue, dyspnoea or severe arrhythmias. In the absence of symptoms each test was terminated at the occurrence of 3 mm ST segment depression or 2 mm ST segment elevation or a decrease in systolic blood pressure ³ 20 mmHg. All medications were discontinued at least five half-lives before the exercise testing. Ischemic exercise-induced ST segment changes in both usual 12-leads and/or right precordial leads, were considered significant if there was (1) a horizontal or downsloping ST segment depression ³ 1 mm, 60 msec after the J point; (2) an upsloping ST segment with at least 1.5 mm depression 80 msec after the J point; (3) in the presence of ST segment depression at rest an additional 2 mm of ST segment depression [Colby et al., 1983] or (4) an ST segment elevation ³ 1 mm of the J point compared to the baseline electrocardiogram.

Figure 1. Two exercise systems are used, while the patient is walking on the treadmill of the one system.

The exercise electrocardiogram was considered negative concerning ST segment changes, if the patient achieved at least 85 percent of the maximal predicted heart rate in the absence of significant ischemic ST segment changes. Exercise electrocardiograms without ischemic ST segment changes, which were terminated at a heart rate < 85% of the predicted maximal heart rate, were considered inconclusive. The measurements of the exercise electrocardiograms were performed using magnifying lenses by two of the investigators who were unaware of the thallium-201 scintigraphy data. Interobserver disagreements were resolved by a third interpretation.

2.3. Thallium-201 Single Photon Emission Computed Tomography

At peak exercise, 2 mCi of thallium-201 were administered intravenously, and patients continued to exercise for an additional 45 to 60 seconds. Thallium images were then obtained with a high-sensitivity, low-energy, medium-resolution, parallel-hole collimator (General Electric 400 AC/T) centered on the 68-KeV photo peak with a 20 percent window. The camera was rotated in a 180-degree arch, in an elliptical orbit around the patient's thorax from a right-anterior oblique angle of 40 degrees to a left-posterior angle of 40 degrees, at 6-degree increments for 30 seconds each. Redistribution images were obtained three to four hours after exercise testing while the patients were resting. From the raw scintigraphic data, vertical short axis, and long-axis tomograms were reconstructed and four consecutive representative slices of each view were selected for interpretation. The reconstructed stress and redistribution images were then analyzed both qualitatively and quantitatively using standard techniques [Guidelines for…, 1995]. The interpretation was performed by two independent investigators without knowledge of the exercise and catheterization data.

Figure 2. The position of the usual 12 leads and the three additional right anterior chest leads (RV3, RV4 and RV5).

2.4. Coronary Arteriography and Left Ventriculography.

All patients underwent left ventriculography in the 30-degree right anterior oblique projection and selective coronary arteriography by the percutaneous (Judkins) technique. Significant coronary artery disease was diagnosed when there was a diameter narrowing of 70 percent or more in the lumen of left anterior descending or left circumflex or right coronary artery, or a diameter narrowing ³ 50 percent of left main coronary artery. Catheterization laboratory investigators were unaware of the results of exercise testing and thallium-201 scintigraphy.

2.5. Statistical Analysis

Values are expressed as mean±SD. Chi-square test for paired data was used in order to detect possible significant associations between different observations on the same persons (new technique versus usual exercise testing and new technique versus thallium-201 scintigraphy). The differences of quantitative parameters in the subgroups of the study population (patients with coronary artery disease and individuals with normal coronary arteries) were tested by two-way analysis of variance. All tests were considered to be significant at a 0.05 level of statistical significance. Statistical analyses were performed with SPSS statistical software (release 8.0).

3. Results

The baseline characteristics of the studied patients in relation to the findings of the coronary angiography and of the data of exercise-testing are presented in Table 1. There were no significant differences related to age, gender and left ventricular ejection fraction between the subjects of the studied groups.

Table 1.

Forty-nine of the studied individuals (52%) had normal coronary arteries, while 45 patients (48%) had significant (³70%) coronary artery lesions. Thirty-nine patients had exclusively right coronary artery disease, three had stenoses in both the right and the left circumflex coronary arteries, two in both the right and left anterior descending coronary arteries, and one patient had significant lesions in all the three major coronary arteries.

The sensitivities and specificities of exercise-testing with or without using the right chest leads are presented in Table 2. Out of the 49 patients who had reversible perfusion defects in the inferior wall according to thallium-201 scintigraphy and normal coronary arteries on coronarography, only one patient had abnormal electrocardiographic findings indicative of myocardial ischemia in the three right chest leads. Thus, the specificity of the right chest leads alone in the detection of coronary artery disease in this population was 98%. Furthermore, the usual 12-lead exercise-testing had a modest sensitivity (27%) to distinguish patients with coronary artery disease (12/45), which was significantly enhanced with the interpretation of the additional right chest leads, resulting to a sensitivity of 78% (35/45). The interpretation of the right precordial leads enabled us to identify 23 patients, who the standard 12-lead exercise ECG failed to diagnose. Furthermore, right chest leads showed excellent specificity in this cohort of patients with scintigraphic evidence of myocardial ischemia in the inferior myocardial wall since only one of the patients with normal coronary arteries on coronary angiography showed electrocardiographic evidence of ischemia in the right precordial leads.

TABLE 2. Sensitivity and specificity of exercise-testing
for the detection of coronary artery disease in the study population.

	Standard 12 leads only	Right chest leads only
Sensitivity	12/45 (27%)	35/45 (78%)
Specificity	39/49 (80%)	48/49 (98%)

*For the comparison of the sensitivities of the
"Standard 12 leads" versus " Right chest leads", P<0.01.

4. Discussion

The principal finding of this ongoing study is that the use of right chest leads in exercise-testing could be useful for the detection of thallium-201 scintigraphy false positive results in the inferior myocardial wall. In addition, electrocardiographic data on ST-segment changes derived from right chest leads remarkably increased the sensitivity of exercise-testing to detect patients with coronary artery disease in this study population with increased prevalence of right coronary artery stenosis.
The ability of myocardial perfusion imaging techniques to image efficiently the regional myocardial blood flow distribution has reformed the management of ischemic heart disease in the last decades. The evolving achievements of nuclear cardiology, enforced by the development of new techniques and novel tracers, resulted in highly sensitive methods [Verani et al., 1978; Okada et al., 1980], not only for the detection of myocardial ischemia but also for the estimation of myocardial viability. Although the most sophisticated and accurate techniques, like positron emission tomography, have not been widely accepted in everyday clinical practice due to their high cost and limited availability, the implementation of thallium-201 single photon emission computed tomography (SPECT) provided us with a large accumulated experience in perfusion imaging.

Although thallium-201 SPECT is preferable to planar imaging [Zaret et al., 1992] and its performance has been further improved by quantitative analysis, its diagnostic accuracy and in particular its specificity is imperfect, especially in patients with one vessel disease. Mahmarian and Verani in a review of studies [Mahmarian and Verani, 1991] using quantitative analysis of exercise thallium-201 SPECT have shown an overall sensitivity of 90% and a specificity of 70%. According to Bayes' theorem the diagnostic accuracy of perfusion imaging techniques can be modest in individuals with very low pretest probability for clinically important coronary artery disease, and false positive results are substantially increased when thallium-201 scintigraphy is performed for routine diagnostic purposes in subjects with low pretest likelihood. Apart from socioeconomic reasons, this is the main rationale for not suggesting the routine use of thallium-201 scintigraphy in an important proportion of the patients, who are seen in general cardiologic practice [Guidelines for…, 1995]. Given that patients with abnormal thallium-201 SPECT results, are preferentially referred for cardiac catheterization, the detection of those who do not need to undergo coronary angiography would be of obvious clinical importance.

Taking care of patients with abnormal scintigraphic findings exclusively in the inferior myocardial wall, especially if they have low or intermediate pretest likelihood for ischemic heart disease, can be a clinical dilemma. From this study, it can be assumed that exercise-testing with the use of three additional right chest leads can be useful in the distinction of false scintigraphic findings in the inferior wall and thus, could negate this clinical dilemma. Based on previous reports [Michaelides et al., 1999], it would be of obvious interest to challenge the use of right chest leads in exercise-testing in patients with increased possibility of single vessel and in particular, right coronary artery disease. Indeed, the sensitivity of exercise-testing in the studied patients was substantially increased compared to the standard 12 lead exercise electrocardiogram. Nonetheless, these preliminary retrospective data could not support a policy for the patients with positive exercise-testing in this study population. Besides, these patients' physicians had already chosen thallium-201 scintigraphy as the most appropriate diagnostic method for a variety of reasons, whose rationale is beyond the scope of this study.

However, in agreement with our hypothesis, it is clearly postulated from our results that the patients with the aforementioned abnormal scintigraphic findings and no electrocardiographic evidence of myocardial ischemia in the three right chest leads are not likely to suffer from coronary artery disease and thus, further evaluation with coronary angiography could be avoided, with prevalent implications in hazards and costs. Although such a policy needs to be validated by specifically designed prospective studies in order to be accepted in clinical practice, this approach, being widely available, safe and cost-effective, truly merits further investigation.

References