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European Journal of Echocardiography 2003 4(3):169-177; doi:10.1016/S1525-2167(02)00161-0
© 2003 by European Society of Cardiology
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Copyright © 2003, The European Society of Cardiology

Quantitative analysis of dobutamine–atropine stress echocardiography

S Carstensen*, U Høst, K Saunamäki and H Kelbæk

Department of Medicine B 2142, The Heart Centre at Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Received 4 July 2002; accepted after revision 9 October 2002.

* Address correspondence to: Steen Carstensen, MD., Department of Medicine B 2142, The Heart Centre at Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel: +45 354 52760; Fax: +45 354 52705. sc{at}dadlnet.dk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 
Aims: To investigate the usefulness of fractional area change of entire left ventricular areas obtained from apical views for quantitative analysis of dobutamine–atropine stress echocardiography in the presence of mild to moderately reduced left ventricular function and abnormal intra-thoracic heart motion after coronary artery bypass surgery.

Methods and Results: Stress echocardiograms from 38 echogenic patients before and 3 months after bypass surgery and from 44 echogenic healthy subjects were analysed. In successfully revascularized patients the fractional area change at peak stress was correlated to the baseline left ventricular ejection fraction (r=0.54, P<0.01), whereas the increase from baseline to peak stress was constant over a wide range of baseline ejection fractions. With respect to identifying the pre-revascularization examination as diseased, the area under the receiver operator characteristics curve based on {Delta} fractional area change from baseline to peak stress was 0.78 (95% CI 0.55–1.00) indicating moderate accuracy comparable with the results obtained with conventional analysis.

Conclusion: Fractional area change of entire left ventricular cavity areas is a useful parameter for quantitative analysis of dobutamine–atropine stress echocardiography. The diagnostic properties of the parameter are not offset by moderate reduction in left ventricular function or by surgery-induced abnormal intra-thoracic heart motion.

Keywords: drugs; echocardiography; ischaemia; stress


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 References
 
Dobutamine–atropine stress echocardiography is an accurate diagnostic test for coronary artery disease but the qualitative interpretation of the test is subject to considerable variation between expert institutions[1–3]. More reproducible analysis methods are desirable and the fractional area change of the entire left ventricular cavity area obtained from apical views reflects global and regional left ventricular function and may be useful in this respect[4,5]. While diverging results have been obtained with a segmental approach the method based on the entire cavity area of apical views appear to be accurate and more robust[4–7]. In patients with a normal left ventricular function a normal reference can be used, but this may not necessarily apply to patients with reduced left ventricular function because some of the inotropic potential may be permanently lost after myocardial infarction and because of the inherent characteristic of the method that dilatation of the left ventricle reduces fractional area change even at a constant stroke volume[4,6]. Furthermore, fractional areas change mainly reflects endocardial excursion and is sensitive to abnormal intra-thoracic motion of the heart induced by open heart surgery, a characteristic that might limit the use of this parameter in the evaluation of patients after surgical revascularization[8].

Because left ventricular dysfunction and prior coronary artery bypass surgery are common features of patients referred for non-invasive evaluation of coronary artery disease, the current study was undertaken in order to assess the usefulness of fractional area change of entire cavity areas in the quantitative evaluation of inducible ischaemia by dobutamine–atropine stress echocardiography in patients exhibiting these confounding factors.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 References
 
Study population
Thirty-eight consecutive, echogenic patients without significant valvular disease referred to coronary artery bypass grafting because of stable angina pectoris and angiographically documented coronary artery disease underwent dobutamine–atropine stress echocardiography for a median of 73 days (range 1–195 days) before and 101 days (range 69–221 days) after bypass surgery. Mean age was 61 years (39–79 years) and eight patients were women. No myocardial infarctions occurred in the period from dobutamine–atropine stress echocardiography to revascularization or in the follow-up period. Twenty-nine patients were angina free at follow-up while nine patients still suffered from stable angina pectoris. Before coronary artery bypass surgery 12, 29 and 25 patients received beta-blockers, calcium antagonists and long-acting nitrates but at follow-up medical therapy had been significantly reduced with only five, five and three patients receiving the respective drugs. There were no differences in medical therapy between patients with and patients without residual angina pectoris at follow-up.

Forty-four echogenic healthy subjects with a likelihood of <5% of coronary artery disease underwent dobutamine–atropine stress echocardiography and constituted the normal reference[9]. Their mean age was 60 years (range 31–79 years) and 21 were women.

Coronary angiography
Coronary angiography was performed via the femoral artery and calculation of coronary artery stenoses was performed by visual analysis supplied with quantitative analysis when necessary considering a ≥70% diameter narrowing by visual estimation or a ≥50% diameter narrowing by quantitative measurement a significant stenosis. One-vessel disease was found in three patients (8%), two-vessel disease in 15 (39%) and three-vessel disease was found in 20 patients (20%). The diseased vessel was the left anterior descending artery in 32 (84%) patients, the left circumflex artery in 29 (76%) and the right coronary artery in 32 (84%) patients.

Coronary artery bypass surgery
Coronary artery bypass grafting was carried out via a medial sternotomi during cardioplegia and cardiopulmonary bypass. Post-operative monitoring including EKG and creatinin kinase (myocardial band) indicated one case of a clinically silent and EKG negative myocardial infarction based on elevated enzyme levels and one case of an ischaemic stroke in relation to post-operative atrial fibrillation; however, only minor deficits remained at follow-up.

Dobutamine–atropine stress echocardiography
Dobutamine–atropine stress echocardiography was performed according to a standard protocol as previously described (up to 40 µg/kg/min ± atropine)[9]. All digital echocardiographic recordings were obtained using fundamental two-dimensional imaging mode and analyses were performed using a Vingmed CFM 750® ultrasonic scanner connected to a Macintosh PowerPC 7100® computer equipped with the appropriate software EchoPAC® (GE Vingmed Ultrasound, N-3191 Horten, Norway). In conventional as well as quantitative analysis echocardiography was considered to predict the presence of significant coronary artery stenosis in case of an abnormal stress test response and the presence of coronary artery disease in case of an abnormal stress test response or an abnormal study at rest.

Conventional stress echocardiography analysis
An observer with extensive experience in the evaluation of stress echocardiograms performed conventional wall motion analysis on the 116 (36+36+44) stress echocardiography recordings in random order and blinded to clinical data, angiographic results and the results of quantitative analysis. Using a 16-segment model an abnormal test result was defined as either stress induced wall motion abnormalities in ≥1 segment with normokinesia at baseline or an initial improvement followed by deterioration at increasing stress levels in ≥1 segment with hypo- or akinesia at baseline[10].

Quantitative stress echocardiography analysis
In the 116 dobutamine–atropine stress echocardiography recordings endocardial tracings in the apical two- and four-chamber views at baseline and at peak dobutamine infusion were made in random order by an observer unaware of the results of wall motion analysis, clinical and angiographic data. Tracings were drawn in accordance with the recommendations of the American Society of Echocardiography[10]. Biplane left ventricular volumes and ejection fraction were calculated using the method of disks and fractional area change during systole was defined as: [(end-diastolic area) – (end-systolic area)]/(end-diastolic area).

Statistical analysis
Differences in continuous variables within and between groups of subjects were analysed with the Student's t-test for paired and unpaired data, respectively. Unpaired categorical data were analysed using the chi-square test or Fisher's exact test. In all patients fractional area change measurements were normalized to that of healthy subjects in the following way: normalized fractional area change = (actual fractional area change – mean fractional area change in the healthy population)/standard deviation of fractional area change in the healthy population. The resulting parameter gives the number of standard deviations that an individual measure deviates from the normal mean, allowing comparison of the diagnostic performance of measures obtained by different methods, and allowing the combination of several measures to form diagnostic criteria[11]. The area under the receiver operator characteristic curve was calculated by the Wilcoxon method and diagnostic accuracy of parameters and methods were described in terms of the area under the curve, and sensitivity and specificity at the optimal cutoff[12]. An area under the curve ≤0.50 indicate no diagnostic contribution of the diagnostic test in question, 0.50–0.70 a low accuracy, 0.70–0.90 a moderate accuracy and <0.90 a high accuracy[13]. Correlation were described using Pearsons r and all P-values represent two-sided test.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 References
 
Clinical response to stress echocardiography
Healthy subjects
In 42 of the 44 healthy subjects the reason for termination of drug infusion during dobutamine–atropine stress echocardiography was achievement of target heart rate. In one case the test was terminated because of maximal drug infusion and in another because of non-sustained ventricular tachycardia. The mean heart rate increased from baseline 63 bpm (95% CI 45–81 bpm) to 139 bpm (95% CI 118–161 bpm) at peak stress (P<0.05) and the mean systolic blood pressure increased from 127 mmHg (95% CI 90–163 mmHg) to 137 mmHg (95% CI 102 171 mmHg) during the test (P<0.05). No severe adverse events occurred.

Patients
In Table 1 the haemodynamic response during dobutamine–atropine stress echocardiography and the reasons for termination of the test before and after revascularization are listed for nine patients with and 29 patients without residual angina pectoris at follow-up. In both groups the maximal achieved heart rate increased after bypass surgery and the achievement of target heart rate was a more frequent reason for termination of the test at follow-up (90% vs 48%, P<0.05). Furthermore, the number of patients with ischaemic endpoints during dobutamine–atropine stress echocardiography (intolerable angina pectoris or obvious stress induced wall motion abnormalities) decreased from nine before to zero after surgical revascularization (P<0.05) and six of 38 patients developed angina pectoris during the stress test at follow-up compared to 29 of 38 patients prior to coronary surgery (P<0.05).


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  		Table 1 Haemodynamics and reasons for termination of dobutamine–atropine stress echocardiography before and after coronary artery bypass grafting in patients with and in patients without angina pectoris at follow-up.

 
Conventional stress echocardiography analysis
Thirty-four of the 38 patients had wall motion abnormalities at rest (28 patients) or during dobutamine–atropine stress echocardiography (25 patients) prior to coronary artery bypass grafting and the corresponding numbers for the 44 healthy subjects were a total of six cases, three at rest and three during stress yielding sensitivity and specificity of 89% (95% CI 80–99%) and 86% (95% CI 76–97%) for coronary artery disease and 66% (95% CI 51–81%) and 93% (95% CI 86–100%) for the presence of significant coronary stenosis by angiography in this selected population. At follow-up dobutamine–atropine stress echocardiography still induced wall motion abnormalities in eight of 25 patients with a positive pre-operative test, whereas in 17 patients new wall motion abnormalities could no longer be induced and 11 of 13 patients remained dobutamine–atropine stress echocardiography negative after revascularization and two patients were considered to develop stress-induced wall motion abnormalities only after bypass surgery (P<0.05). In the 29 patients without angina pectoris at follow-up, conventional analysis identified the pre-surgery (i.e. the diseased) stress echocardiography with a sensitivity of 72% (95% CI 56–89%) and a specificity of 72% (95% CI 56–89%). There were no differences between patients with and those without residual angina pectoris at follow-up with regard to the frequency of wall motion abnormalities at rest or during stress echocardiography prior to surgical revascularization.

Quantitative stress echocardiography analysis
Left ventricular ejection fraction at baseline and fractional area change of the two- and four-chamber views during dobutamine–atropine stress echocardiography in healthy subjects are listed in Table 2. In both views fractional area change increased from baseline to peak stress. No correlation between left ventricular ejection fraction at baseline and fractional area change at peak stress during dobutamine–atropine stress echocardiography was found.


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  		Table 2 Quantitative measures of left ventricular function during dobutamine–atropine stress echocardiography in 44 healthy subjects.

 
Table 3 gives the mean values of parameters of left ventricular geometry and function during dobutamine–atropine stress echocardiography in patients before and after surgical revascularization. Left ventricular ejection fraction and fractional area change at rest decreased from baseline to follow-up in both patient groups. In patients with residual angina pectoris after revascularization this was due to an increase in both end-diastolic (P<0.06) and end-systolic volumes, whereas in the angina free the end-diastolic volume decreased with no change in the end-systolic volume. During dobutamine infusion the fractional area change at peak stress and the change in fractional area change from baseline to peak stress were unchanged in patients with residual angina after revascularization whereas in patients without angina pectoris these parameters increased. In this subgroup left ventricular ejection fraction at baseline was correlated to fractional area change at peak stress both before and after bypass surgery and the effect of revascularization appeared to be an upward and leftward translation of the regression line (Fig. 1). No correlation between left ventricular ejection fraction and change in fractional area change from baseline to peak stress was observed in any of the echocardiographic views. When abnormality was defined as a value below the lower 10% percentile of the normal population for single parameters and below the lower 5% percentile when the two echocardiographic views were combined (in both cases aiming at a specificity of approximately 90%), an abnormal left ventricular ejection fraction at rest (18 patients) or an abnormal change in fractional area change from baseline to peak stress of the combined two- and four-chamber view (29 patients) identified 34 of 38 (89%, 95% CI 80–99%) patients with coronary artery disease and 29 of 38 patients (76%, 95% CI 63–90%) with significant coronary artery stenosis by angiography before revascularization.


Figure 1
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  		Figure 1 Scatterplot and regression lines for left ventricular ejection fraction vs fractional area change at peak stress (FACpk) of the four- and the two-chamber views during dobutamine–atropine stress echocardiography before and after coronary artery bypass grafting (CABG) in 29 patients without angina pectoris after revascularization.

 


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  		Table 3 Quantitative measures of left ventricular function during dobutamine-atropine stress echocardiography before and after coronary artery bypass grafting in patients with and in patients without angina pectoris at follow-up.

 
At follow-up the change in fractional area change from baseline to peak stress of the combined two- and four-chamber view was still abnormal in 10 of 29 patients with a positive pre-operative dobutamine–atropine stress echocardiography whereas it was normalized after revascularization in 19 patients, in six of nine patients with a normal pre-operative value it remained normal at follow-up whereas it turned abnormal after revascularization in the remaining three patients (P<0.05).

Receiver operator characteristics curve analysis of the normalized fractional area change data from the 29 patients that were angina free after surgical revascularization showed that the change in fractional area change from baseline to peak stress of the two- and four-chamber views and their combination, in contrast to fractional area change at peak stress, could distinguish between dobutamine–atropine stress echocardiography studies obtained before and after clinically successful revascularization with an area under the curve indicating moderate accuracy (Fig. 2). At the optimal cutoff sensitivity and specificity for detecting a pre-revascularization study using the change in fractional area change from baseline to peak stress of the combined two- and four-chamber views were 76% (95% CI 60–91%) and 76% (95% CI 60–91%), respectively.


Figure 2
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  		Figure 2 Receiver operator characteristics curves describing the ability of normalized fractional area change at peak stress (FACpk) and change in fractional area change from baseline to peak stress ({Delta}FAC) to distinguish between the pre- and post-revascularization dobutamine–atropine stress echocardiography in 29 patients without angina pectoris after coronary artery bypass surgery. (AUC, area under the curve.)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 References
 
Diagnostic parameter
In a previous study we found that fractional area change of the entire left ventricular area of the apical views is a useful diagnostic parameter in dobutamine stress echocardiography, provided the baseline left ventricular function is normal[4]. The results of the current study extends these findings to patients undergoing dobutamine–atropine stress testing under less favourable conditions provided the baseline left ventricular function is taken into account. These findings are not trivial because it is the general assumption that fractional area change of entire cavity areas are insensitive to the subtle changes in left ventricular function that may be the only sign of induced ischaemia during stress echocardiography[14]. Secondly, the favourable performance of this quantitative parameter, even in the presence of confounding factors known to reduce the accuracy and reproducibility of conventional analysis is important. Finally, these results were obtained using manual tracing of the left ventricular cavity, a method characterized by significant intra- and inter-observer variation[6] and therefore fractional area change of the entire left ventricular area obtained from apical views appear to be a robust and promising parameter for quantitative analysis of dobutamine–atropine stress echocardiography.

The results of the current study are supported by reports from other institutions. Perez et al. reported a reduced increase in fractional area change during dobutamine–atropine stress echocardiography in patients developing new wall motion abnormalities during the test[5] and using the same parameter and a segmental approach Kock et al. were able to accurately identify patients with significant coronary lesions[7]. In addition the latter group were able to correctly predict the location of coronary lesions with their segmental approach, a finding we were unable to reproduce in a recent study in patients with normal left ventricular function at rest[4], and because we had no reason to believe that the segmental approach would perform better in our hands under the far less favourable conditions of the present study (resting wall motion abnormalities, surgery-induced changes in intra-thoracic motion of the heart) we did not perform segmental analysis.

Conventional wall motion analysis was highly specific but only moderately sensitive with regard to predicting significant coronary artery stenosis in this echogenic population of healthy subjects and patients with predominantly multivessel disease. A higher sensitivity might be expected based on pooled data from previous studies[1], however, two multicentre studies solely incorporating interpreters with extensive experience in dobutamine–atropine stress echocardiography have reported sensitivities in the 40s and 60s, figures in the absolute low end of published sensitivities indicating significant publication bias in the literature[2,3]. Therefore, the diagnostic value of our conventional dobutamine–atropine stress echocardiography analysis is within the range covered by expert dobutamine–atropine stress echocardiography interpreters both with regard to the diagnosis of coronary artery disease and to predict the presence of significant coronary artery stenosis.

Effect of left ventricular function at baseline
Because the increase in fractional area change during dobutamine–atropine stress was not correlated to left ventricular ejection fraction at baseline after successful revascularization, no signs of a clinically relevant reduction in inotropic reserve was observed in these patients with mildly to moderately reduced left ventricular function. This is a surprising finding because myocardium have been permanently lost in the majority of these patients with prior myocardial infarctions and because left ventricular dilatation in dysfunctioning hearts tends to decrease fractional area change because of the increased end-diastolic area[6]. It appears that the pre- and afterload reducing properties of dobutamine may have outweighed any reduction in inotropic reserve in these patients[15] and with regard to the methodological component it appears that the left ventricular dilatation in these patients was too small to exhibit any effect on the results. However, in patients with more severe left ventricular dysfunction and cavity dilatation these problems may be significant[6]. While the inotropic reserve appeared intact, the maximal achievable left ventricular function during the test in terms of fractional area change was reduced parallel to the reduction in baseline ejection fraction. This finding was in accordance with our expectations for the same reasons as those mentioned above and explain the failure of fractional area change at peak stress (compared with normal values) to identify the effects of successful revascularization.

Effects of open heart surgery
Open heart surgery induces changes in the intra-thoracic motion of the heart in the majority of patients, changes that may persist at least for 3 months and can be quantitated by measuring fractional area change with a segmental approach[6,8]. We used fractional area change of the entire left ventricle that may be less sensitive to changes in intra-thoracic motion of the heart than the segmental method. However, altered translation of the heart in and out of the scanning plane, surgery-induced changes in fractional area change (and stroke volume) and differences in the effect of surgery on endocardial excursion at baseline and during stress may reduce the diagnostic accuracy of even this parameter. In addition, medical therapy is usually reduced after coronary artery bypass surgery potentially affecting the quantitative evaluation of left ventricular function. None of these confounding factors can, however, explain the near normalization in dobutamine-induced increase in fractional area change at follow-up that can only be attributed to improved myocardial perfusion after revascularization, and that the change in fractional area change from baseline to peak stress correctly identified the pre-revascularization stress studies as the diseased shows that the accuracy of this parameter was not offset by these confounding factors and underscores the rationale for use of this parameter in stress echocardiography where intra-thoracic motion of the heart during stress may occur frequently[16].

Heart rate at rest increased whereas ejection fraction and fractional area change decreased following surgical revascularization in both patient groups. In patients with residual angina pectoris both end-diastolic and end-systolic volumes was increased following surgery indicating further ischaemic damage to the myocardium. In contrast, patients relieved from angina pectoris after surgery exhibited a reduction in left ventricular end-diastolic volume whereas end-systolic volume was unchanged and inotropic potential during dobutamine infusion was regained. In these patients the apparent reduction in left ventricular function following cardiac surgery cannot be explained by ischaemia or myocardial damage and it is not likely to be the consequence of withdrawal of medical therapy. It could be caused by restrictive left and right ventricular filling as a result of the same mechanisms that alter the intra-thoracic heart motion following open heart surgery; however, these mechanisms are not fully understood rendering such an explanation speculative[17]. Although most previous studies report of improvement in left ventricular function following coronary artery bypass grafting our results are consistent, not only with the study of Wranne et al.[17] but also with recent studies from our own institution on different patient populations using different imaging modalities[18,19].

Study limitations
In symptomatic patients with ischaemic heart disease the relief of symptoms after revascularization is a strong indicator of true successful revascularization whereas persisting typical symptoms indicates the opposite. We used the clinical outcome of coronary artery bypass surgery as reference in appreciation of the fact that relief of symptoms after bypass surgery does not rule out silent ischaemia and that persisting symptoms does not rule out angiographically successful revascularization. In both cases, however, inaccuracies in classification of patients would tend to reduce the differences between the two groups, and a more accurate grouping would only increase the differences observed and the accuracy of the test.

Patients undergoing coronary artery bypass grafting have a high prevalence of multivessel disease and this may facilitate the differentiation between the pre- and post-revascularization stress echocardiography by fractional area change of entire left ventricular cavity areas. We have previously found high diagnostic accuracy of these parameters in patients with less severe coronary artery disease[4] but this may not necessarily hold true in patients undergoing stress echocardiography early after coronary artery bypass surgery.

Manual tracing of the left ventricular cavity is time consuming and the reproducibility of fractional area change based on manual tracings is not ideal[6]. Therefore, we performed pooled blinded analysis of dobutamine–atropine stress echocardiography recordings from patients and the control group in random order and, because the within-observer variation is lower than that between observers, we used a single observer set-up. Computerized detection and tracing of endocardial borders is achievable in an increasing number of patients[20] and development of new echocardiographic imaging modalities[21] and transpulmonary echo-contrast agents[22] may eventually enable reproducible endocardial tracings in the vast majority of patients undergoing dobutamine–atropine stress echocardiography. So, although manual tracing may not be suited for daily clinical practice, our results may form the basis for the rational use of these automatic border detection systems.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
References
 
Fractional area change of entire left ventricular areas obtained from apical views during dobutamine–atropine stress echocardiography appears to be a promising quantitative marker of coronary artery disease. Previous studies have shown that it can accurately identify diseased patients when the left ventricular function is normal, and the current study extends these results to patients with mildly to moderately reduced left ventricular function provided the baseline left ventricular function is taken into account. Furthermore, the diagnostic properties of this parameter were not offset by surgery-induced abnormal intra-thoracic motion of the heart.


   Acknowledgements
 
We appreciate the financial support of: The Danish Heart Foundation, Copenhagen, Denmark, Eli Lilly Denmark A/S, Copenhagen, Denmark and GE Vingmed Ultrasound, Horten, Norway.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 References
 

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