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Ann Thorac Surg 1998;65:397-402
© 1998 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Preoperative Assessment of Coronary Artery Disease in Aortic Stenosis: A Dipyridamole Echocardiographic Study

CNR Institute of Clinical Physiology, Pisa, Italy

Accepted for publication July 26, 1997.

Dr Maffei, Ospedale Pediatrico Apuano, Via Aurelia sud, Montignoso, 54100, Massa, Italy.

	Abstract

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Background. The aim of this study was to establish the feasibility, safety, and diagnostic accuracy of the dipyridamole echocardiography test in patients with severe aortic valve stenosis for noninvasive detection of coexisting coronary artery disease.

Methods. The high-dose dipyridamole echocardiography test was performed in 52 patients with severe aortic stenosis; all patients also underwent coronary angiography, independent of test results, before cardiac operation.

Results. The dipyridamole echocardiography test was completed without major complications. One patient had transient atrial fibrillation that was reversed by aminophylline. Thirty-one patients (60%) had a negative test result; all had normal coronary arteries. Ten of the 21 patients (48%) with a positive test result had coexisting coronary artery disease. The positive predictive value of the dipyridamole echocardiography test for detection of coronary disease in patients with severe aortic stenosis was 48%. The negative predictive value was 100%. The sensitivity was 100% and the specificity was 74%.

Conclusions. Dipyridamole echocardiography is a safe and feasible tool in patients with severe aortic stenosis eligible for a cardiac operation. A negative test result reliably rules out a significant stenosis, whereas a positive one is much less accurate in predicting coronary artery disease.

	Introduction

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Angina and myocardial ischemia are frequent in severe aortic stenosis and there are various, often overlapping, pathophysiologic mechanisms that can influence myocardial oxygen supply-demand relationship, namely, decreased capillary or myocyte density, prolonged ejection time, increased systolic and diastolic wall stress, myocardial fibrosis, and atherosclerotic coronary artery disease [1] [2].

The recognition of the latter mechanism has obvious diagnostic, therapeutic, and prognostic implications, but it remains an elusive task on the basis of clinical presentation and noninvasive testing with 12-lead electrocardiogram (ECG) or nuclear perfusion imaging, which are plagued by an unacceptably low specificity in patients with left ventricular hypertrophy [3] [4] [5]. Theoretically, pharmacologic stress echocardiography [6] is a particularly attractive option for the noninvasive detection of coronary artery disease in aortic stenosis. It has shown a consistently high specificity—definitively higher than ECG and perfusion imaging—also in patients with left ventricular hypertrophy [7] [8], female sex, or conduction abnormalities in resting ECG [7]. All these conditions may be found in patients with aortic stenosis and may contribute to obscure the relationship between coronary artery disease and stress-induced electrocardiographic alterations or perfusion abnormalities [9] [10].

Among the various types of pharmacologic stresses, the two most popular ones are dipyridamole and dobutamine [6]. We chose the former because of its recognized lower arrhythmogenic potential as well as its diagnostic accuracy similar to dobutamine in the diagnosis of coronary artery disease [11] [12] [13]. The aim of the present study was to assess the safety, feasibility, and diagnostic accuracy of dipyridamole echocardiography test for coronary artery disease detection in patients with severe aortic stenosis. Accordingly, we prospectively evaluated, with the dipyridamole echocardiography test, 52 patients with aortic stenosis referred to coronary angiography, which was performed independent of test results.

	Material and Methods

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Study Patients
After the approval by the local institutional human research committee in November 1988, 63 in-hospital patients with aortic stenosis referred to our Cardiovascular Department were initially considered for the dipyridamole echocardiography test. All patients had a complete physical examination, chest roentgenogram, and 12-lead ECG.

The diagnosis of aortic stenosis was always confirmed by two-dimensional and Doppler echocardiography (Aloka SSD 870). A 2.5-MHz probe with continuous wave and pulsed wave Doppler or a nonimaging transducer was used. Aortic valve gradient was derived from peak aortic velocity recorded by continuous wave Doppler from the apical, suprasternal, or right parasternal windows. The highest velocity was used for analysis of peak pressure gradient and mean pressure gradient through the aortic valve. Left ventricular outflow tract velocity was measured from the apex by pulsed-wave Doppler echocardiography with the sample volume just proximal to the aortic valve. Left ventricular outflow tract diameter was measured by two-dimensional echocardiography. Aortic valve area was derived from the continuity equation. Measurements were done on the average of five cardiac cycles [14]. Left ventricular mass index was calculated according to the American Society of Echocardiography formula, corrected by Devereux and associates [15] and normalized for body surface: 0.8 {1.04 [IVS (interventricular septum) + LVED (left ventricular end-diastolic diameter) + PWT (posterior wall thickness)]³ LVED³} + 0.6 g/body surface. Predetermined exclusion criteria for dipyridamole echocardiography test were technically poor acoustic window (n = 5), severe global left ventricular dysfunction with ejection fraction less than 0.35 (n = 6), severe concomitant asthmatic disease requiring chronic theophylline therapy (n = 0), and refusal to enter the study (n = 0). A set of 52 patients (age, 65.2 ± 9.6 years; range, 19 to 78 years; 34 men and 18 women) finally entered the study.

Thirty-one (59%) patients had history of chest pain, 18 (35%) had syncope, and 26 (50%) had dyspnea. None had a clinically documented previous myocardial infarction. Approval by the institutional review board was obtained and all patients were informed about the methodology, finality, and risks inherent in the study. All patients gave their informed consent before entering the study.

Cardiac catheterization including coronary angiographic data was performed in all patients within a week of dipyridamole echocardiography test. Both angiographic and stress echocardiographic examinations were performed and interpreted by observers blind to the result of the other test.

Dipyridamole Echocardiography Test
Intravenous dipyridamole was infused at a dosage of 0.56 mg/kg in 4 minutes followed by 4 minutes of no dose and then 0.28 mg/kg in 2 minutes [11]. The patients were instructed to avoid coffee and tea for at least 3 hours before the test and to stop all medications for at least 24 hours. Baseline evaluation included 12-lead ECG, blood pressure evaluation, and all possible standard echocardiographic views.

During the procedure, blood pressure and 12-lead ECG were recorded every 2 minutes; two-dimensional echocardiograms were recorded continuously and up to 5 minutes after the end of dipyridamole infusion.

Aminophylline (up to 240 mg in 3 minutes) was then injected, as needed. Electrocardiographic tracings were considered diagnostic for myocardial ischemia when an ST-segment shift of at least 0.20 mV, 0.08 seconds after the J point, was recorded. Two-dimensional echocardiographic videotaped images, obtained by a commercially available scanner (Aloka SSD 870), were analyzed by two independent observers unaware of other data; in case of disagreement, a third observer reviewed the study and his or her judgement was binding. Off-line digital acquisition of videotaped images for side-by-side rest-stress comparison in a cine-loop format was performed by an array-processor-based computer for medical image processing (Mipron, Kontron, Germany).

Wall motion abnormalities were evaluated by dividing the left ventricle into 16 segments, according to the recommendations of the American Society of Echocardiography [16], and were graded (based on the subjective impression) as normal-hyperkinetic (score = 1), hypokinetic (score = 2), akinetic (score = 3), or dyskinetic (score = 4). The wall motion score index was derived by summation of individual segment scores divided by the number of interpreted segments. Inadequately visualized segments were not scored.

Positivity of the test was linked to the detection of a transient dissynergy, absent or of lesser degree during the basal examination. Any region already akinetic or dyskinetic in the baseline study was not considered for analysis. The test was stopped when new obvious wall motion abnormalities were detected. In positive tests, the dipyridamole time, ie, the period from the beginning of drug infusion to the development of the stress-induced dissynergy, was also evaluated.

Angiographic Study
Patients underwent ventriculography and selective right and left coronary arteriography using either the Judkins or Sones technique; multiple views of each vessel were obtained. Two independent observers blinded to dipyridamole echocardiography test analyzed the coronary angiograms. In the presence of a visually assessed, nonoccluded "significant" coronary lesion, a caliper-assisted analysis of the stenosis was performed. A vessel was considered to have significant obstruction if its quantitatively assessed diameter was narrowed by 50% or more, in comparison with the prestenotic tract.

Statistical Analysis
Continuous variables are expressed as mean ± standard deviation. Differences in continuous variables were evaluated by Student’s t test for paired values. Differences in dichotomous variables were evaluated by using the ² test; a Fisher’s exact test was used when appropriate. Sensitivity, specificity, accuracy, and predictive value of a positive dipyridamole echocardiography test in detecting angiographically assessed coronary artery disease were calculated according to the standard definitions. A p value <0.05 was the predetermined level of significance.

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All patients showed severe aortic valve stenosis. In all patients, a mild aortic regurgitation (<2+/4+) and a mild mitral regurgitation (1+/4+) were also detected. In all cases a degenerative cause of aortic valve disease was present (and in 1 case a bicuspid valve). Mean transvalvular aortic pressure gradient, evaluated by means of Doppler echocardiography, was 66 ± 15.2 mm Hg; the aortic area was 0.69 ± 0.12 cm².

Resting Echocardiography
Forty-four patients had normal and 4 had abnormal resting wall motion, with septal hypokinesia in 3. Diffuse hypokinesis was present in 4 patients. The resting wall motion score index was 1.07 ± 0.24. The left ventricular mass index was 206 ± 50 g/m².

Feasibility and Safety of Dipyridamole Echocardiography Test
Two-dimensional echocardiographic studies were adequate for analysis in all 52 patients. There were no serious cardiac complications related to dipyridamole infusion and the high-dose infusion was completed in all patients. Isolated, frequent premature ventricular contractions, followed by sustained atrial fibrillation, without hemodynamic instability, occurred in one patient immediately after the second dipyridamole dose. The results of this submaximal test were included in the analysis.

Hemodynamic Response to Dipyridamole
The hemodynamic response to high-dose dipyridamole echocardiography test is reported in Table 1. There was no significant change in diastolic blood pressure and only a mild increase in heart rate.

Coronary Angiographic Findings
Significant coronary artery disease was present in 10 patients and absent in 42. Of the 10 patients with coronary artery disease, 8 had one-, 1 had two-, and 1 had three-vessel disease.

Comparison of Dipyridamole Echocardiography Test and Coronary Angiographic Results
Of the 10 patients with significant coronary artery disease, all had a new or worsening wall motion abnormality whereas 11 of 42 patients without significant coronary artery disease had a positive dipyridamole echocardiography test result. Considering the occurrence of transient regional dissynergy to be the only positivity criterion, the overall sensitivity of the test was 100%, its specificity 74%, predictive value of a positive test 48%, and diagnostic accuracy 81% (Fig 1).

View larger version (31K): [in this window] [in a new window]   Test sensitivities and specificities (Ecg = electrocardiogram.)

In the subset with angiographically normal coronary arteries, patients with dipyridamole-induced dissynergy tended to have higher values of left ventricular hypertrophy and had higher prevalence of chest pain and ischemiclike ECG changes during dipyridamole echocardiography test when compared with patients without stress-induced dissynergy (Table 2).

	Comment

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High-dose dypiridamole is able to induce transient myocardial ischemia by inhibiting the uptake of adenosine, bringing coronary arteriolar vasodilation to a maximum without significantly affecting systemic hemodynamics. Maximal coronary vasodilation leads to a phenomenon of vertical steal lowering subendocardial perfusion and, in the presence of narrowing of epicardial coronary arteries, elicits a horizontal steal. The high-dose dipyridamole echocardiography test was found to be a safe, very well tolerated, and reasonably accurate tool for the noninvasive diagnosis of coronary artery disease in patients with aortic stenosis. A negative dipyridamole echocardiography test result is especially useful for excluding angiographically assessed coronary artery disease.

Comparison With Previous Studies
Our data are consistent with those reported in the literature regarding the feasibility and safety of the dipyridamole echocardiography test, which have been conclusively demonstrated in large patient series, encompassing a wide spectrum of disease [11]. To our knowledge, however, only limited data with either standard (0.56 mg/kg for 4 minutes) [17] or high-dose (0.7 mg/kg) [9] dipyridamole combined with imaging techniques such as technetium 99m sestamibi or thallium scan are available in patients with aortic stenosis. According to our experience, the test—even with aggressive dosing—appears to be safe also in these patients. No major complication occurred in our series, and the feasibility was only slightly lower than the 99% level observed in a series of more than 10,000 tests performed in 9,000 patients with known or suspected coronary artery disease [11]. The 74% specificity and 100% sensitivity we found in our patients might appear in disagreement with the literature, which is in line with the 92% specificity and 74% sensitivity obtained in a consecutive series of 429 patients with normal resting function reported by Severi and associates [18]. However, the higher sensitivity and lower specificity we observed might reasonably be reconciled with the published evidence by taking into account the very peculiar pathophysiologic condition of patients with aortic stenosis. Extreme forms of left ventricular hypertrophy can reduce coronary flow reserve [19] and provoke subendocardial underperfusion—and therefore regional dysfunction—during stress, even in the absence of coronary artery stenosis, as shown by experimental [20] and clinical [21] studies, and this may account for the false-positive results lowering the specificity to 74%. Consistent with this hypothesis, in our series patients with false-positive dipyridamole echocardiography test results tended to have a higher left ventricular mass index in comparison with patients with true negative studies (Table 2). On the other hand no statistically significant differences were detected in terms of aortic pressure gradient, LVEDP, and preexisting wall motion abnormalities.

Factors other than the ventricular hypertrophy can lead to inadequate tissue oxygenation in severe aortic stenosis, even in the absence of coronary artery disease. The increased systolic pressure and prolongation of ejection elevate myocardial oxygen consumption and the abnormally elevated pressure compressing the coronary arteries exceeds the coronary perfusion pressure, thereby interfering with coronary blood flow. Myocardial perfusion is also impaired by the elevation of left ventricular end-diastolic pressure, which lowers the aortic–left ventricular pressure gradient in diastole, ie, the coronary perfusion pressure gradient [1] [2]. Therefore pathophysiologic evidence demonstrates that the subendocardium in severe aortic stenosis is susceptible to ischemia. In keeping with our findings, metabolic evidence of myocardial ischemia, ie, lactate production, can also be demonstrated during stress, such as exercise or isoproterenol, in patients with aortic stenosis in the absence of coronary arterial narrowing.

On the other side, left ventricular hypertrophy and hemodynamic factors can enhance and magnify the physiologic effects of an epicardial coronary artery stenosis, accounting for the excellent sensitivity obtained even in a population of patients mostly with single-vessel disease. In general, our data are consistent with those reported by other groups on patients with aortic stenosis evaluated by pharmacologic perfusion imaging. Kettunen and colleagues [9] reported 86% sensitivity and 81% specificity for detection of coronary artery disease with technetium 99m isonitrile tomography. Kupari and associates [10] reported an extremely high sensitivity (100%) and a poor specificity (57%) with exercise thallium 201 tomography and aortic stenosis.

Only preliminary data are available with stress echocardiography. Varin and coworkers [22] reported, in 50 patients with aortic stenosis, 69% sensitivity and 97% specificity for dipyridamole stress echocardiography; however, they used the standard dose (0.56 mg/kg) for the test. By using only the low-dose positivity criterion, we would have found a sensitivity of 40% versus the 100% obtained with the high dose and a specificity of 95% versus the 74% obtained with the high dose.

Study Limitations
The gold standard used for comparison of dipyridamole echocardiography test results was angiographically assessed coronary artery disease. It is known that angiographic stenosis is not necessarily related to the degree of impairment in regional flow reserve—and, therefore to dipyridamole echocardiography test results—especially in a condition, like aortic stenosis, in which the myocardial component can impair coronary reserve regardless of epicardial coronary artery stenosis [19]. In addition, we quantitatively measured percent diameter reduction, without a more complex, more technically exacting, but also more accurate, evaluation of minimum cross-sectional area [23].

Although an estimate of percent stenosis does not provide accurate insight into the hemodynamic impact of a lesion, the simplicity of the percent stenosis estimate and the force of tradition favor its continued use; in most cardiology centers, the assessment of percent coronary stenosis remains the final gold standard [23].

Another limitation is related to the use of conventional high-dose regimens of dipyridamole. This infusion protocol cannot be considered actually to be updated, as very recently it has been shown that atropine addition (up to 1 mg for 4 minutes) further increases the test sensitivity without decreasing its specificity [24]. However, our study started several years ago, and therefore the high-dose regimen was adopted; furthermore, we could find a very high sensitivity even without atropine addition.

The interpretation of stress echocardiographic data was qualitative and subjective. Although this is the true state-of-the-art method for regional wall motion analysis, and the intraobserver and interobserver reproducibility of test results is very high between experienced observers [25], it is also true that wall motion assessment may pose special problems in patients with distorted left ventricular geometry and pronounced left ventricular hypertrophy, as frequently occurs in patients with severe aortic stenosis.

Finally, in our population the subset of patients with significant coronary artery disease was relatively small. A large population of patients with coronary artery disease, possibly collected on a multicenter basis, should be evaluated before clinical implementation of this test in patients with severe aortic stenosis can be proposed.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We greatly appreciate Mrs Roberta Bertolini, Miss Gianna Eufrate, Miss Katia Galligani, and Miss Samira Volpi for their help in preparing the manuscript and Mr Claudio Michelassi for providing statistical analysis. This work was partially supported by a grant from the National Research Council (CNR) of Italy.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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