a University of Wales College of Medicine, Cardiff, UK
b University Hospital Benjamin Franklin, Berlin, Germany
c Hôpital Saint Antoine, Paris, France
d Hôpital Charles Nicolle, Rouen, France
e University Hospital Sart Tilman, Liège, Belgium
f University Hospital, Linköping, Sweden
g Huddinge University Hospital, Stockholm, Sweden
* Author for correspondence. Dr Alan G. Fraser, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, CardiffCF14 4XN, Wales, UK. Tel.: +44-2920-743489; fax: +44-2920-743500
E-mail address: fraiserag{at}cf.ac.uk
Received 10 October 2002; revised 2 December 2002; accepted 11 December 2002
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Abstract |
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Methods and results We acquired tissue Doppler digital data during dobutamine stress in 289 subjects, and measured myocardial responses by off-line analysis of 11 left ventricular segments. Diagnostic criteria developed by comparing 92 normal subjects with 48 patients with coronary disease were refined in a prospective series of 149 patients referred with chest pain. Optimal diagnostic accuracy was achieved by logistic regression models, using systolic velocities at maximal stress in 7 myocardial segments, adjusting for independent correlations directly with heart rate and inversely with age and female gender (all p<0.001). Best cut-points from receiver-operator curves diagnosed left anterior descending, circumflex and right coronary disease with sensitivities and specificities of 80% and 80%, 91% and 80%, and 93% and 82%, respectively. All models performed better than velocity cut-offs alone (p<0.001).
Conclusion Non-invasive diagnosis of coronary artery disease by quantitative stress echocardiography is best performed using diagnostic models based on segmental velocities at peak stress and adjusting for heart rate, and gender or age.
Key Words: Stress echocardiography Tissue Doppler Dobutamine
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1. Introduction |
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Regional myocardial function can be quantified by tissue Doppler echocardiography. In experiments, myocardial velocity falls progressively from 5s after the onset of ischaemia,4and so its measurement has been proposed as an objective marker of dysfunction during stress. Early clinical investigations were based on decoding the velocity of a segment from the colour flow map,5or on recording velocity in real-time using a pulsed Doppler technique.6Ischaemia has also been detected by measuring a reduced transmural myocardial velocity gradient.7
Tissue Doppler data can be stored as digital images of the left ventricle, which are then available for post-processing after a stress study has been completed.810We have demonstrated high feasibility and reproducibility for off-line measurements of myocardial systolic velocities obtained during dobutamine stress.11Other investigators used myocardial velocities with cut-points, and reported that these were as accurate in diagnosing coronary disease as wall motion scoring by an expert.12To date, however, there is no agreement on methods or diagnostic criteria. We tested the hypothesis that tissue Doppler diagnosis of coronary disease will be optimised by taking account of factors that influence myocardial responses in normal subjects.
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2. Patients and Methods |
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Regional myocardial velocity responses to dobutamine were compared firstly in two selected groups normal subjects (Group 1) and patients with known coronary artery disease (Group 2)to identify the best method of discriminating between normal and ischaemic responses. The criteria were tested in a third, unselected group of patients who were studied prospectively after referral for the diagnosis of chest pain (Group 3), in order to develop the final diagnostic models.
2.2. Patients
A total of 289 subjects aged >20 years were studied. Patients were included even if grey-scale images were suboptimal or incomplete. Exclusion criteria were atrial fibrillation, previous myocardial infarction (Q waves on the electrocardiogram, or akinetic segments on the resting echocardiographic images), previous revascularisation, unstable angina, complete bundle branch block, significant heart valve disease, contraindication to dobutamine or atropine, and possible pregnancy. Normal subjects were excluded if they had echocardiographic evidence of left ventricular hypertrophy, and patients were excluded if they had uncontrolled hypertension. The groups are described in Table 1.
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Group 2 (known coronary disease): 48 patients selected because recent coronary arteriography demonstrated significant epicardial coronary disease. Their ages ranged from 44 to 80 years, and 69% were men. There were 19 with single vessel, 15 with double vessel, and 14 with triple vessel disease. The totals with disease in each territory were: 38 left anterior descending artery (LAD), 31 left circumflex artery (Cx), and 22 rightcoronary artery (RCA). Patients in Group 2 were on average 12 years older than subjects in Group 1.
Group 3 (prospective study): 149 unselected patients referred with chest pain. All had exercise ECG and then dobutamine stress echocardiography, before elective coronary arteriography. The investigations were performed and interpreted by different observers, who were unaware of the results of the other tests. This group included 59 patients with normal coronary arteriography (i.e. no angiographic diameter stenosis >50%) and 90 with coronary disease (36 patients with single vessel, 27 with double vessel, and 27 with triple vessel disease). The totals with disease in each territory were 70 LAD, 53 Cx, and 48 RCA. Patients with and those without significant coronary disease had similar age distributions, but there was a higher proportion of women among the patients without significant disease.
2.3. Stress protocol
Cardiovascular drugs were stopped 48h before the study, apart from short-acting nitrates which patients could continue until the morning of the investigation. No patient was taking a beta-receptor antagonist at the time of the study.
Dobutamine was infused intravenously for 3-minute stages at 5, 10, 20, 30 and 40µg/kg/min. In patients who had not reached their target heart rate [>85% of (220age in years)] or another end-point, the last dose was continued while atropine 0.25mg was given by intravenous bolus every minute up to a total of 1mg. Heart rate and rhythm were monitored from a precordial modified lead I or II, and blood pressure and the 12-lead ECG were recorded every 3min. Symptoms were documented.
Pre-defined end-points were intolerable symptoms (such as chest pain), 2mm of horizontal or downsloping ST-segment depression on any ECG lead, persistent arrhythmias such as ventricular tachycardia or new atrial fibrillation, systemic hypotension (fall of systolic pressure >30mmHg), or bradycardia.
2.4. Echocardiographic acquisition
Patients were studied in the left lateral decubitus position, using a Vingmed System V (GE Vingmed Ultrasound, Horten, Norway) with a 1.52.5MHz transducer. After 10min of rest (baseline), and during the last 90s of each stage of the infusion, digital images were acquired during passively held end-expiration, from 4 standard imaging planes: parasternal long-axis (PLAX), parasternal short-axis, apical four-chamber (A4C), and apical two-chamber (A2C) views. In each view, a 2-beat loop was edited to start before one QRS complex and to end after the third QRS complex. This loop was reviewed to ensure that there was no significant translation of the heart on the image, and then transferred to a Macintosh computer for storage in the Echopac programme (GE Vingmed) and on magneto-optical disk.
Grey-scale studies were performed with harmonic imaging, but digital loops were acquired while displaying superimposedcolour tissue Doppler. To avoid aliasing during stress, the Nyquist limit was increased to 25cm/sec. Sector angles were adjusted with the aim to obtain frame rates for colour tissue Doppler of >100/s.
2.5. Off-line analysis
Investigators who performed echocardiographic studies and off-line analyses were unaware of the findings of coronary arteriography. The protocol for measuring myocardial velocities has been described in detail elsewhere.11Digital loops were retrieved and 11 segments were analysed at each stage, by one of three observers. Velocities of radial function were recorded in three segments, from the PLAX image: basal posterior (BP), mid posterior (MP), and mid-anterior septum (MAS). Velocities of longitudinal shortening were measured from the A4C and A2C, in four basal [basal septal (BS), basal anterior (BA), basal lateral (BL) and basal inferior (BI)] and four mid-ventricular [mid septal (MS), mid anterior (MA), mid lateral (ML) and mid inferior (MI)] segments. Five segments normally included in an analysis of wall motion14were not used (apical segments and basal anterior septum) because off-line velocities in these segments areunreliable.11
In parasternal views, the cursor was positioned in the posterior wall so that it did not encompass the pericardium at any time during the cardiac cycle. In apical views, each left ventricular "wall" was divided into thirds and the cursor was placed within the basal portion of each segment during systole; in the basal segments it never encompassed the mitral annulus. No angle corrections were used. Velocities were measured using customised software (Echopac TVI, GE Vingmed).
Inter-observer agreement in the MYDISE study has been reported.11Ten randomly selected studies were each analysed by nine observers. The most reproducible parameter was peak systolic velocity (PSV), defined as the maximal velocity (in cm/s) during ejection. Pooled standard deviations for its measurement in the four basal segments from apical windows at peak stress ranged from 1.4 to 2.1cm/s, giving coefficients of variation between 11% (BS) and 18% (BA); for mid-ventricular segments in the same views, coefficients of variation were between 17% (MI) and 26% (ML). In the PLAX view, the coefficient of variation for PSV at maximal stress in the BP segment was 16%. Although the coefficients of variation at peak stress ranged from 11 to 26%, most were closer to the lower boundary. The median and mean coefficients of variation for measurements of PSV in all segments, were 12% at rest and 16% at peak stress.
2.6. Coronary arteriography
Patients underwent elective coronary arteriography using standard projections. Significant disease was coded if there was a diameter stenosis 50% in a vessel or its major branch (e.g. first diagonal of LAD or obtuse marginal of Cx). Left main stenosis was coded as both LAD and Cx disease. Segments judged to be supplied by the LAD were MAS, BA, MA, and MS. The Cx segments were BP and MP, and BL and ML. The BI, MI, and BS segments were supplied by the RCA when it was dominant, and the BS the by Cx when it was dominant.15Arteriograms were interpreted by observers blinded to the results of stress echocardiography, using quantitative coronary arteriography where available (in 12%) or visual analysis with calipers. The arteriograms of 63 patients were reported independently by two observers, who agreed on the presence or absence of significant coronary disease in 96% of arterial territories.
2.7. Statistical methods
Analyses were performed using commercially available software (SPSS Inc, Chicago, Illinois). Continuous variables were described by means and standard deviations and categorical data were described by percentages. In each subject, the peak response was taken at the maximal dose of dobutamine which was attained, or at the penultimate stage if the patient had developed hypotension or bradycardia.
Peak systolic velocity data from Groups 1 and 2 were first assessed by analysis of variance to determine the between-subject effects (group, age, and gender) and the within-subject effects (dobutamine dose and heart rate). To determine the best discriminators of normal status and disease, univariate and multiple stepwise logistic regressions were performed including factors for velocity data, age, gender and heart rate. The logistic regression models from the multivariate analysis gave an outcome y, which was used to generate a predicted probability of disease p, using the formula p=ey÷(1+ey). One model was developed for each coronary territory (Cx, RCA, LAD). There was insufficient evidence to suggest that the relationships between the continuous covariates (PSV measurements, age and heart rate) and the endpoint (disease status) were non-linear. A p-value <0.05 was considered significant.
Receiver-operator curves were used to determine a cut-point for p that gave optimal sensitivity and specificity, with the aim of maximising sensitivity without significantly compromising specificity. A minimum level of specificity of >80% was accepted, in order to optimise sensitivity, since the most important clinical objective was considered to be a high negative predictive value. A patient with a probability that was lower than the cut-point was classified as normal, and a patient with a probability that was higher was classified as diseased. In the models, male sex was coded as 1 and female sex was coded as 2.
A new variable (any disease) was calculated for each patient using the results of the three separate models. Subjects predicted to have coronary disease in any of the three territories were coded with 1, and subjects predicted to have no coronary disease at all were coded with 0. A receiver-operator curve was used to determine the diagnostic accuracy of the new variable.
The distribution of coronary disease in the selected subjects was bimodal, with patients either having no angiographic disease at all (Group 1) or flow limiting coronary disease (Group 2) whereas the unselected patients recruited prospectively (Group 3) demonstrated a more normal distribution of angiographic severity. The logistic formulae from Groups 1 and 2 were therefore refined using the data from Group 3.
Reproducibility of velocity data, as assessed by pooled standard deviations and coefficients of variation, has been reported elsewhere.11
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3. Results |
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3.2. Discrimination between normal and ischaemic responses (Groups 1 and 2)
At peak stress, patients with coronary disease reached a lower peak systolic velocity than did normal subjects. Representative traces are shown in Fig. 1.
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3.3. Diagnosis of coronary artery disease (Group 3)
3.3.1. Diagnostic models
Refined models developed to diagnose significant coronary disease in patients in Group 3 selected the same segments and factors as for the analysis of Groups 1 and 2, apart from one: for the diagnosis of LAD disease, the model selected one segment supplied by the LAD (basal anterior) but also one supplied by the Cx artery (mid lateral). There was high concordance between velocities in the ML and MA segments (r=0.6, P<0.001), which are contiguous, and the feasibility of obtaining data was higher in the ML segment (92% compared with 82% in the MA11).
The regression models were:
These models gave sensitivities and specificities of 80% and 80% for LAD disease (cut-point of probability score 0.53), 91% and 80% for Cx disease (cut-point 0.37), and 93% and 82% for RCA disease (cut-point 0.37). The areas under the receiver-operator curves were 0.84, 0.92, and 0.91 respectively (Fig. 2). The models gave high negative predictive values, especially for excluding Cx or RCA disease (91% and 94% respectively, Fig. 3). When the three models were combined to diagnose significant stenosis in any coronary territory, compared with no disease, the overall sensitivity was 87% and specificity 75%.
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4. Discussion |
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4.1. Limitations of standard stress echocardiography
An objective method of quantifying myocardial function during stress echocardiography is needed because the reproducibility of conventional methods is disappointing. Agreement is increased by applying protocols for interpretation,16but recognition of wall motion abnormalities on grey-scale images remains difficult particularly in patients with single vessel disease, and uncertain when images are incomplete.2Overall, sensitivities and specificities are not more than 8085%,3and accuracy is less when the test is performed by inexperienced observers.17
Image quality and inter-observer agreement in the interpretation of wall motion are improved by using harmonic imaging and by injecting echocardiographic contrast agents that cross the pulmonary circulation and outline the endocardial border of the left ventricle,18,19but interpretation remains subjective. Colour kinesis displays endocardial motion objectively,20but its resolution is relatively low. Our objectives therefore were to develop new methods for quantifying dobutamine stress echocardiography and diagnosing coronary disease that would be feasible in most subjects, highly reproducible, accurate, and easily applied by inexperienced as well as expert observers.
It would be useful to determine the incremental diagnostic value in the same population of using tissue Doppler quantification, compared with grey-scale wall motion abnormalities. This could not be tested in the current study because digital data could only be collected with colour Doppler superimposed on the grey-scale images, which therefore were not optimised.
4.2. Tissue Doppler echocardiography in ischaemia
Tissue Doppler echocardiography (also called Doppler myocardial imaging)21has major advantages for quantifying regional function during stress. Data are acquired digitally at high frame rates, so function can be measured after the test with good temporal resolution in each segment. Changes that have been documented during ischaemia include reduced and delayed peak systolic velocities,4reduced myocardial velocity gradients,7and impaired diastolic relaxation.22We studied systolic velocity because it is the most reproducible tissue Doppler parameter,11and because it is very sensitive to ischaemia. We measured the velocities of longitudinal shortening of the left ventricle, in basal myocardial segments studied from apical windows, because these reflect subendocardial function and this is linearly related to myocardial perfusion.23
Myocardial functional reserve has been studied by tissue Doppler during pharmacological stress5,24and dynamic exercise.25An early limiting factor was the impracticality of recording spectral pulsed Doppler from each segment every 3min, but this was overcome by storing images digitally.8,9The feasibility of measuring velocities off-line was confirmed for dynamic stress on a semi-supine bicycle,10and we reported feasibilities of at least 90% when it is applied to dobutamine stress.11
4.3. Study design
The MYDISE study was designed in two stages. Firstly, since it was not known what factors might discriminate between populations, we selected two groups that would be as different from each other as possible: Group 1 subjects were healthy volunteers or else patients with no disease (normal coronary arteriography), whereas Group 2 consisted of patients with angiographically proven severe disease. These groups gave good power for the identification of criteria that could distinguish normal from diseased responses, but differences between the groups were exaggerated by the selection criteria. The regression analysis of stress responses in Groups 1 and 2 identified that peak systolic velocity was the most useful parameter for discriminating between normal subjects and patients with severe coronary artery disease, and it also demonstrated that heart rate and gender were significant covariates. Comparison of these groups also selected age as an important factor that influences the peak myocardial response to dobutamine, irrespective of the presence of coronary artery disease, but this is not surprising since the groups had not been matched for age: subjects in Group 1 were aged 2080 years, whereas most patients in Group 2 were aged 5070 years.
Having first identified the variables that differentiated between normal subjects and patients with coronary disease, we then studied prospectively a group of unselected patients (Group 3) who had been referred for the diagnosis of chest pain. These results are presented in greatest detail because this group most accurately reflects the distribution of normal or insignificant disease (<50% stenosis) and severe coronary artery disease (>50%) that is present in a population referred for stress echocardiography in clinical practice. Regression analysis in this group confirmed the findings of the study of Groups 1 and 2, namely that peak systolic velocity, heart rate and gender, best predict the presence of coronary artery disease. In Group 3, age was not a discriminating variable in the model, since patients with and those without significant coronary disease had similar mean ages.
When implementing quantitative stress echocardiography in clinical practice, whether to diagnose myocardial ischaemia or to detect reduced regional functional reserve from any other cause, peak responses will need to be compared to those of age-matched controls, or else adjustments for age will need to be made in a diagnostic model.
4.4. Tissue Doppler stress echocardiography
The most important new finding of the MYDISE study is that tissue Doppler diagnosis of coronary artery disease is much more accurate using logistic regression models rather than myocardial velocities alone. The accuracy achieved exceeds that which can be obtained by conventional analysis of wall motion abnormalities.3
Cain and colleagues used systolic velocities without any adjustment, and reported that these gave diagnostic accuracy equivalent to expert interpretation of regional wall motion.12They selected the lower 20th centiles of the distributions of velocities at peak stress in a normal population as their cut-off values, whereas we selected cut-points from receiver-operator curves. Applied to the MYDISE groups, their velocity cut-points give poor overall diagnostic performance (with specificities of about 95% but sensitivities of less than 25%). These differences may be explained at least in part by varying selection criteria and methods. Cain and colleagues defined controls by the presence of normal wall motion at peak stress,12but given the suboptimal sensitivity of conventional stress echocardiography to diagnose single vessel disease3they may have included some diseased subjects among their controls. They did not exclude patients receiving beta blockers which lower velocities.26There may also have been differences in the proportions of patients with left ventricular hypertrophy27or chronic volume overload,28both of which are associated with reduced longitudinal velocities perhaps as a non-specific effect of subendocardial fibrosis. In apical views they measured velocities in the middle of each segment, which would give lower values than we obtained in the basal parts of each segment, since there is a gradient of velocity from base to apex.
The alternative approach adopted in the MYDISE study was designed to control for any factors that influence myocardial velocities in normal subjects independently of the effects of coronary disease. Patients should be compared with age-matched controls (as occurred in Group 3) or else an adjustment for age is required (as the models for Groups 1 and 2 demonstrated). The difference between men and women at peak stress was related to height, suggesting that it may be a consequence of increased systolic augmentation of central arterial pressure in subjects with shorter aortas and earlier wave reflections. The independent association of maximal velocity with heart rate needs to be considered, as subjects can reach very different heartrates at their maximal tolerated dose of dobutamine. Ignoring these factors reduces both sensitivity and specificity.
A notable feature of the MYDISE study is that the results were achieved using only velocities in sevensegments at peak stress, and without considering wall motion. The high negative predictive values suggest that no other investigation is required to rule out coronary disease with considerable confidence. The selected segments make intuitive sense since they are supplied by the relevant coronary artery, with the exception of the mid-lateral segment in the model of LAD disease in Group 3. This is probably due to the reduced feasibility of obtaining velocities from the anterior wall and to tethering effects in adjacent segments, and it may account for the overall accuracy of the models when applied together to diagnose any coronary disease.
We measured velocities in basal segments but changes there can reflect ischaemia at the apex,29because ischaemia within any segment in the same wall on a longitudinal image will reduce the amplitude and velocity of motion of the basal segment. Once a diagnosis of ischaemia within a myocardial wall has been made, the site of ischaemia can be determined more precisely by studying apical grey-scale images if they are of good quality, or by assessing regional strain rate.30Another approach could be to use a composite mean velocity derived from measurements of both radial and longitudinal function,31but it would first be necessary to demonstrate that myocardial ischaemia affects radial and longitudinal function similarly.
4.5. Limitations of the study
The current results may be biased due to over-fitting, and they should be confirmed on new prospective series. Ideally, data are needed from very large populations to generate definitive normal values, and robust models. Our models may not perform equally well in populations of patients with different distributions of disease. We used coronary arteriography as the criterion standard for diagnosing coronary disease, but performed quantitative analysis (QCA) in a minority of patients. Inter-observer reproducibility of visual grading of stenoses was good, however, and QCA is unreliable because disease in reference segments in usually underestimated.32Tissue Doppler echocardiography may be a better test than angiography for assessing if there is significant ischaemia, since it is an objective test of function rather than anatomy.
The results of this study cannot be extrapolated directly to myocardial velocities measured by pulsed tissue Doppler during stress, since such velocities are about 20% higher than off-line measurements.33Velocities are reduced in patients with impaired resting left ventricular function34or left ventricular hypertrophy,27and after myocardial infarction,25and so separate studies are needed in such patients. Finally, our results were obtained in patients in sinus rhythm, and they will need to be tested separately in patients with atrial fibrillation. Other tissue Doppler methods may be needed in patients who have a significant resting conduction defect such as complete bundle branch block.
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Appendix A MYDISE study investigators: |
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University Hospital, Linköping: Professor George R. Sutherland, Professor Bengt Wranne, Dr Birgitta Janerot-Sjøberg, Dr Inna Sandblom, Dr Jan Engvall, Mrs Margareta Nordvall
Huddinge University Hospital, Stockholm: ProfessorLars-ke Brodin, Ms Britta Lind
Hôpital Saint Antoine, Paris: Professor Ariel Cohen, Dr Nathalie Lamisse
University Hospital Benjamin Franklin, Berlin: Dr Ursula Wilkenshoff, Dr Bettina Kürsten, Frau Ellen Tessun
University Hospital Sart Tilman, Liège: Professor Luc A. Piérard, Dr Patrizio Lancellotti, Dr Frédéric Lebrun, Dr Evdokia Petropoulou
Hôpital Charles Nicolle, Rouen: Professor Geneviève A. Derumeaux
Vienna University Medical School: Professor Helmut Baumgartner, Dr Michael Wütte, Dr Karl Berger, Dr Raphael Rosenhek
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Acknowledgments |
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References |
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