Dobutamine stress Doppler echocardiography: reproducibility and physiologic left ventricular filling patterns

International Journal of Cardiology 58 (1997) 293–303

Dobutamine stress Doppler echocardiography: reproducibility and physiologic left ventricular filling patterns a, a b a Uwe Nixdorff *, Stefan Wagner , Raimund Erbel , Susanne Mohr-Kahaly , a a a ¨ Peter Weitzel , Klaus Rieger , Jurgen Meyer a

b

II. Medical Clinic, Johannes Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany Centre of Internal Medicine, Department for Cardiology, University Essen, Hufelandstrasse 55, D-45122 Essen, Germany Received 24 September 1996; revised 24 October 1996; accepted 24 October 1996

Abstract Qualitatively, dobutamine stress echocardiography has become an established procedure. Quantitative results are in great demand but this is still difficult due to limited endo- and epicardial border definition. Transmitral Doppler variables are strictly quantitative and less subjective. Furthermore, ischemic alterations precede systolic ones (ischemic cascade). There are preliminary reports of the utility of dobutamine stress Doppler echocardiography, but proof of reproducibility and left ventricular filling patterns are still lacking. Fourteen healthy volunteers (10 men, 4 women, median age 25.9 years, range 21–32 years) were investigated according to the usual dobutamine stress echocardiographic protocol (5, 10, 15, 20, 30, 40 and 40 m g / kg / min10.5 mg atropine). At each titration step a standardized transmitral PW-Doppler recording with the sample volume positioned at the opened mitral leaflet tips was analyzed three times by two independent, experienced investigators. Of the early, late, and mean velocities (Vmax E, Vmax A, Vmean ), time integrals (VTI-E, VTI-A, VTI), their ratios (E /A, E /A VTI), and various time intervals (T acc , T dec , E- and A-duration, FillT), Vmax E (0.82 to 1.09 m / s; P,0.0001), VTI-E (16.17 to 17.19 cm; P,0.0001) and Vmean (0.29 to 0.82 m / s; P,0.0001) were found to have the greatest discriminatory power, commencing already at a dose of 10–15 m g / kg / min dobutamine. Vmax E and VTI-E demonstrated the smallest intra- and interobserver variation without any increase in variability during incremental dose titration. Assessment of the early diastolic filling pattern by Doppler echocardiography is a valuable quantitative and reproducible adjunct to conventional dobutamine stress echocardiography. Further controlled studies in coronary artery disease patients have to confirm, whether lower dobutamine doses could be used in the test and sensitivity increased due to better data acquisition in cases of limited echogenicity, less subjectivity, and earlier onset of ischemic alterations. Copyright  1997 Elsevier Science Ireland Ltd. Keywords: Dobutamine stress Doppler echocardiography; Left ventricular filling; Myocardial ischemia

1. Introduction *Corresponding author. Tel.: 06131 172829; fax: 06131 176617; e-mail: [email protected]; private tel.: 0611 9600197

Since the first report by Berthe et al. [1] dobutamine stress echocardiography has been used increasingly and has become a valuable diagnostic

0167-5273 / 97 / $17.00 Copyright  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0167-5273( 96 )02875-6

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tool in the evaluation of coronary artery disease [2,3]. The higher sensitivity of this technique in comparison to conventional exercise ECG testing [4] is explained by the fact that regional wall motion abnormalities can be detected by two-dimensional echocardiography before ischemia causes electrocardiographic alterations [5]. Furthermore, from the ischemic cascade it is also known that diastolic filling abnormalities precede wall motion abnormalities [5,6]. Since Doppler echocardiography is a non-invasive technique capable of providing information about left ventricular filling — which has been validated against invasive methods [7] — its application during dobutamine stress might further contribute to the diagnostic value of stress echocardiography. Indeed, abnormal Doppler indices of left ventricular filling due to ischemia have been already demonstrated for dynamic exercise [8], pacing [9] and dipyridamol stress testing [10]. During dobutamine stress testing it could even be shown that diastolic Doppler indices are more sensitive markers of single-vessel coronary disease than new wall motion abnormalities [11]. However, both intra- and intersubject and intra- and interobserver variability data as well as the physiologic response of left ventricular filling are still lacking. The purpose of this study, therefore, was to investigate the physiologic diastolic filling patterns during the usual titrating steps of dobutamine stress echocardiography in a population of healthy volunteers. In this context, reproducibility in terms of intra- and interobserver variation should be clarified.

2. Materials and methods The study population consisted of 14 healthy volunteers, 10 men and 4 women. The median age was 25.9 years (range 21–32 years). There was no history of any illness, physical examination did not reveal any abnormalities and left ventricular dysfunction could be excluded by two-dimensional echocardiography [12]. All subjects were instructed extensively about the study and gave their informed consent. On the day of examination they did not take any drugs. For 4 h before, they did not eat. An intravenous line was fixed on the right arm (dobutamine infusion) and a cuff for non-invasive

blood pressure measurements (Siemens Sirecust, Erlangen, Germany) was fixed on the left arm. The electrodes of a 12-lead ECG recording system (Marquette Case 12, Milwaukee, WI, USA) were positioned in a modified fashion on the chest such that the transducer could be placed in an apical position. For safety reasons syringes of esmolol (Brevibloc, DuPont Pharma, Bad Homburg, Germany) were prepared and a resuscitation kit was available. After at least 5 min in a recumbent and quiet position, incremental doses of 5, 10, 15, 20, 30 and 40 m g / kg / min dobutamine were infused at 3min intervals (Perfusor, Braun, Melsungen, Germany). This was followed by another 3 min of additional 0.5 mg atropine administration. Besides the regular control of heart rate (HR) and blood pressure (BP) at each titration step, the volunteers were continuously monitored by ECG. PW-Doppler ultrasound scans were obtained with a phased-array sector scanner (Toshiba SSH 140, Toshiba Medical Co. Ltd., Tokyo, Japan) and a 3.5 MHz transducer. Each subject was examined in the left sided position during unforced end-expiration to provide a standard, including a stable signal unaffected by respiration. Mitral inflow velocity was recorded from the apical window (four-chamber view), where the cursor was positioned at the leaflet tips of the opened mitral valve. The greatest velocity of diastolic flow was obtained by visual and auditory guidance. Care was taken to obtain the smallest possible angle between the assumed blood flow direction and the cursor at the sampling space. This angle was estimated to be zero or less than 208 in each subject. All signals were recorded on videotape. Doppler recordings were analyzed by two independent, experienced investigators by tracing the velocity envelope of three cardiac cycles (Fig. 1). Peak transmitral flow velocities were measured in m / s at the darkest point of the spectral waveform (peak modal velocity). Both the peak velocity and flow velocity time integral of early left ventricular filling (Vmax E and VTI-E) and late (atrial) ventricular filling (Vmax A and VTI-A), respectively, were measured. The ratios of the peak velocities (E /A Vmax ) and flow velocity time integrals (E /A VTI) as well as the mean velocity (Vmean ) and integral (VTI) were derived from these measurements. Furthermore, the duration from onset to peak early diastolic velocity

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server variability was assessed by the F-ratio-test (Table 1). Variances between the two observers were also averaged and differences between representative dobutamine titration steps (15 and 40 m g / kg / min1 0.5 mg atropine) and baseline were approved by the F-ratio-test. The standard deviations and additionally their percentages (coefficient of variation) are given in Table 1 to demonstrate also their relation to the mean values of the parameters.

3. Results

Fig. 1. Schematic representation of the transmitral Doppler velocity profile with its temporal relationship to the ECG. E (Vmax E), early diastolic filling velocity; A (Vmax A), late (atrial) diastolic filling velocity; VTI-E / VTI-A, velocity time integral of early / late (atrial) filling. DE (T acc ), acceleration time; EF (T dec ), deceleration time; DG (FillT) diastolic filling time.

(acceleration time T acc 5DE, Fig. 1), the duration from peak early diastolic velocity to the time when flow velocity returned to baseline (deceleration time T dec 5EF, Fig. 1), the duration of early and late filling (E- and A-duration5DE1EF and FG, Fig. 1), and the diastolic filling time (FillT5DG, Fig. 1) were determined. If there was no well-defined diastasis between the early and late diastolic filling peaks, the onset of flow was defined as the first increase in flow velocity after the plateau or downslope of the E peak. Quantitative measurement and analysis were performed offline at a computer workstation (EchoCom, Individual Software, Fulda, Germany).

Technically, Doppler recordings were adequate in all subjects and could be quantitatively analyzed. However, the fusion of the E and A velocities at increased HR made it impossible to quantitatively differentiate the A-wave parameters at the last titration step. Mitral regurgitation was excluded pre and during dobutamine infusion by color Doppler echocardiography in all subjects.

3.1. Heart rate and blood pressure In accordance with the well-known effects of a b 1-adrenergic drug such as dobutamine on the cardiovascular system, the HR (Fig. 2a) and systolic and diastolic BP (Fig. 2b) increased. This was achieved significantly for HR at 15 m g / kg / min; in particular, the parasympatholytic action of atropine supported positive chronotropy (Fig. 2a). Systolic and diastolic BP increased significantly at low and moderate doses (10–30 m g / kg / min), whereas the high doses including atropine were insufficient to contribute to this effect.

2.1. Statistical analysis Data are expressed as medians625% and 75% percentiles (quartiles). Differences between the values of each titration step to the baseline value as well as differences between values of one titration step to the next were assessed by the Wilcoxon test for paired data. A P-value of ,0.05 was considered as significant. Reproducibility was investigated in terms of intraand interobserver variation. Variances of three measurements in each volunteer and each titration step were averaged among all the volunteers. Interob-

3.2. Diastolic filling velocities and velocity time integrals Dobutamine induced a dose-dependent increase in Vmax E and VTI-E (Fig. 3a and e), which started at a dose of 15 m g / kg / min but was only maintained without any further effects at 20 m g / kg / min and above. The Vmax E variability was particularly reasonable. There were only minor increases in Vmax A with a considerable variability at high doses (Fig. 3b). VTI-A did not show any alterations or considerable dose-dependent increases in variability (Fig. 3f). The

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3.3. Diastolic filling time intervals T acc did not demonstrate a unidirectional change. A decrease at modest doses of 20 and 30 m g / kg / min stood in contrast to an increase due to the additional administration of atropine (Fig. 4a). T dec showed a tendential decrease (with an exception at 10 m g / kg / min) throughout the whole protocol; therefore significance was only reached at the last two and highest doses (Fig. 4b). E- (Fig. 4c) and A-duration (Fig. 4d) decreased at high doses; however, Aduration reached gradual and higher significance in this respect. FillT remained stable during low doses and demonstrated a highly significant incremental decrease from 20 m g / kg / min onwards (Fig. 4e). Variability decreased in parallel with the significant decrease.

3.4. Reproducibility data

Fig. 2. Time course of heart rate (a) and systolic and diastolic blood pressure (b) during dobutamine titration in medians and quartiles. A., atropine. Statistical significance: *P,0.05, **P, 0.01, ***P,0.001, ****P,0.0001. Stars (*) on the bottom line compare the particular values with baseline values, whereas stars on the graphs compare the particular values with those of the preceding titration steps.

ratios of filling velocities (E /A Vmax ) and velocity time integrals (E /A VTI) did not appear to represent discriminatory variables at all. There were no significant differences between the titration steps. In addition, the variation of values increased at high doses (Fig. 3c and g). In contrast, there was a dosedependent, incremental and highly significant increase in Vmean which commenced at the dose of 15 m g / kg / min (Fig. 3d), though the variability of this parameter remained in a reasonable range. The complete diastolic velocity time integral (VTI) showed a dose-dependent, bell-shaped curve (Fig. 3h). During administration of modest doses (10–30 m g / kg / min) an increase in values was noted, which was followed at 40 m g / kg / min and 40 m g / kg / min plus additional atropine by a decrease.

Reproducibility data in terms of intra- and interobserver variation are presented in Table 1. In general, variances and coefficients of variation appeared to be very reasonable without any significant differences between the results of two independent observers except Vmean , A-duration, and FillT. Variability in respect of incremental titration of the diagnostic drug compared to baseline did not reveal significant differences except in Vmean and VTI-E at the highest measurable doses (Table 1).

4. Discussion

4.1. Findings and clinical implications Dobutamine stress echocardiography is well established as a valuable diagnostic tool in the evaluation of coronary artery disease [1–4]. Usually the onset of regional wall motion abnormalities in an individual patient is interpreted as a sign of ischemia [1–4]. However, since its introduction into the clinical arena [1] the literature has expanded [1–4] without any considerable effort having been made to establish normal values. There are only single reports of investigations of the normal and physiologic reaction of global myocardial function in terms of

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Fig. 3. Diastolic filling velocities and diastolic velocity time integrals: time course of the medians and quartiles of early diastolic filling velocity (Vmax E) (a), late (atrial) diastolic filling velocity (Vmax A) (b), the ratio of Vmax E and Vmax A (E /A Vmax ) (c), mean diastolic filling velocity (Vmean ) (d), early diastolic velocity time integral (VTI-E) (e), late (atrial) diastolic velocity time integral (VTI-A) (f), the ratio of VTI-E and VTI-A (E /A VTI) (g) and whole diastolic velocity time integral (VTI) (h). A., atropine. Statistical significance: *P,0.05, **P,0.01, ***P,0.001, ****P,0.0001. Stars (*) on the bottom line compare the particular values with baseline values, whereas stars on the graphs compare the particular values with those of the preceding titration steps.

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Fig. 4. Diastolic time intervals: time course of the medians and quartiles of acceleration time (T acc ) (a), deceleration time (T dec ) (b), E- (c) and A-duration (d), diastolic filling time (FillT) (e). Statistical significance: *P,0.05, **P,0.01, ***P,0.001, ****P,0.0001. Stars (*) on the bottom line compare the particular values with baseline values, whereas stars on the graphs compare the particular values with those of the preceding titration steps.

quantitative volumetry (ESV↓ and EF↑) as an epiphenomenon of positive b 1-adrenergic-mediated, positive inotropy [12] and quantitative regional wall motion analysis (ventricular circumferential hypercontractility with certain spatial heterogenicity [12]). The reason for this deficit can be found in the analytical approach. In spite of tremendous technical developments resulting in improved image resolution and sophisticated digitalization techniques [13], the exact definition of the endocardial borders is still a

limitation and matter of concern, especially when a patient is being subjected to stress [14]. Newer methods such as automatic border detection [15] or contrast echocardiography [16] during stress are encouraging but have not yet resolved the problem. In contrast, Doppler echocardiography of transmitral blood flow patterns is a quantitative measure of diastolic function which can be easily performed during almost any examination (also in those with limited echogenicity) without being time consuming

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Table 1 Reproducibility in terms of intra- and interobserver variation Variable

15 m g / kg / min Do

Baseline s2

40 m g / kg / min Do1A

CV

s2

CV

s2

CV

Intraobserver variation: Observer 1 Vmax E 0.001069 Vmax A 0.001638 E /A Vmax 0.076493 Vmean 0.000555* VTI-E 0.374048 VTI-A 0.166190 E /A VTI 0.398860 VTI 0.311667 T acc 0.000212 T dec 0.000517 E-duration 0.000507 A-duration 0.001871* FillT 0.002207*

3.14 7.27 8.01 5.72 3.84 10.64 12.13 2.71 14.63 10.41 6.18 10.29 5.39

0.002233 0.001140 0.051910 0.000705 0.545000 0.226429 0.381081 0.721905 0.000164 0.000331 0.000548 0.001427 0.001740

4.05 6.62 7.93 6.10 4.71 9.97 11.60 4.27 16.28 10.58 8.52 8.71 6.14

0.001610

3.47

0.002495

5.28

0.587143 0.000083

3.77 9.34

0.000362

6.60

Intraobserver variation: Observer 2 Vmax E 0.000700 Vmax A 0.000626 E /A Vmax 0.025598 Vmean 0.000129* VTI-E 0.344048 VTI-A 0.109048 E /A VTI 0.915400 VTI 0.449286 T acc 0.000114 T dec 0.000329 E-duration 0.000314 A-duration 0.002207 FillT 0.000126*

2.56 5.42 5.35 3.00 4.02 9.27 9.95 3.69 11.40 9.69 5.88 5.39 1.37

0.002117 0.000795 0.054874 0.000140 2.428333 0.144048 0.239129 0.850476 0.000093 0.000248 0.000157 0.001740 0.000255

3.56 5.59 6.52 2.68 6.84 8.33 10.72 4.04 10.67 8.82 4.13 6.14 2.26

0.001833

3.15

0.007155

9.85

2.368810 0.000107

7.02 8.96

0.000212

5.48

Interobserver variation Vmax E 0.000885 Vmax A 0.001132 E /A Vmax 0.050995 Vmean 0.000342 VTI-E 0.359048 VTI-A 0.137619 E /A VTI 0.657130 VTI 0.380476 T acc 0.000163 T dec 0.000423 E-duration 0.000411 A-duration 0.001126 FillT 0.001167

2.85 6.34 6.68 4.36 3.93 9.95 11.04 3.20 13.02 10.05 6.03 7.60 3.38

0.002175 0.000968 0.053392 0.000423 1.486667 0.185238 0.310105 0.786190 0.000129 0.000289 0.000352 0.000840 0.000998

3.80 6.11 7.23 4.39 5.78 9.15 11.16 4.16 13.48 9.70 6.32 6.20 4.20

0.001721

3.31

0.004825**

7.56

1.477976 0.000095

5.39 9.15

0.000287**

6.04

s2, mean value of variance (three measurements in each volunteer at each titration step); CV, mean value of coefficient of variation in % (three measurements in each volunteer at each titration step); 15 m g / kg / min Do, titration step of 15 m g / kg / min dobutamine; 40 m g / kg / min Do1A, titration step of 40 m g / kg / min dobutamine in addition to 0.5 mg atropine; Vmax E /Vmax A /Vmean , early / late (atrial) / mean diastolic filling velocity; E /A Vmax , ratio of Vmax E and Vmax A; VTI-E / VTI-A / VTI, velocity time integral of early / late (atrial) / complete diastolic filling; E /A VTI, ratio of VTI-E and VTI-A; T acc /T dec , acceleration / deceleration time; E- and A-duration, time interval of early and late (atrial) diastolic filling; FillT, entire diastolic filling time (E-plus A-duration). *P,0.01 F-ratio-test (comparison of the two observer variances); **P,0.01 F-ratio-test vs. baseline (comparison of interobserver variances between baseline and following titration steps).

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[17]. It is well established that diastolic abnormalities precede systolic ones in ischemia [6]. Recent reports have already demonstrated the utility of this method during various stress modalities [8–10]. In this respect, dobutamine Doppler stress testing seems to be even more sensitive than the conventional dobutamine stress test, which is restricted to twodimensional echocardiography [11]. In the current study the entire variety of Doppler indices was investigated and Vmax E, VTI-E and Vmean were found to be the most discriminatory variables (P-values, 0.0001) with the lowest intra- and interobserver variabilities. For Vmax E this is in accordance with other authors [18,19]. Nakamura et al. reported that early diastolic filling did not increase during exercise in patients who had normal systolic function but significant coronary artery disease [20]. Others found that in normal subjects dobutamine causes marked increases in peak filling velocity (as in our series) and decreases in patients [11]. The finding of a lack of b -adrenergic effects on the ratios of early and late diastolic filling (E /A Vmax and E /A VTI), which has been confirmed by others at least up to a maximal dose of 10 m g / kg / min [19], is clinically important, because the ischemic response is known to consist in a significant drop in filling ratios [11]. In dynamic ¨ Doppler stress echocardiography Voller et al. reported a decrease of E /A Vmax in normal subjects [21]. Besides the more difficult placing of the sample volume in the moving patients [22], it might be more difficult to distinguish Doppler variables between healthy and pathologic individuals than in pharmacologic testing. In comparison to how the results of dobutamine stress echocardiography are interpreted today, which is, in terms of the wall motion score index, qualitative, highly subjective and investigator dependent, Doppler parameters are strictly quantitative and less subjective. Our data and the method in general are strengthened by a very low intra- and interobserver variability (Table 1), which has been confirmed by others [18]. To our knowledge the physiologic values presented in this paper are the first to have been established systematically considering the complete titration protocol. However, for reference purposes in respect of interpreting potentially abnormal tests further studies on other aged populations are necessary as age is known to influence transmitral Doppler parameters [23].

4.2. Physiologic background The mechanisms of the finding that b -adrenergic stimulation results in augmented diastolic filling may involve several factors. Rather than being a simple, passive process, diastolic function involves dynamic elements that are closely interrelated with systolic function [24]. Most importantly, there is evidence of an increase in the atrio-ventricular pressure gradient in early diastole generated by acceleration in myocardial relaxation. This might be secondary to a b 1-mediated increase in intracellular cyclic adenosine 39,59-monophosphate, which accelerates the rate of calcium reuptake by the sarcoplasmatic reticulum and thus stimulates the myocardial deactivation process [25], thereby speeding the detachment of crossbridges [26]. This mechanism has to be considered an intrinsic effect of adrenergic stimulation, because CaCl 2 does not alter relaxation [27]. The increase of Vmax A may be due to an increase in the atrial contractile force, since an inotropic response to b -adrenergic stimulation has been demonstrated in atrial tissue [28]. However, in comparison to the mechanisms mentioned above, atrial effects may be only of minor relevance. The changes were only discrete and the variability relatively high. As systolic parameters in the same population were also altered, as published recently [12], commencing augmentation of systolic shortening was indicated, which might have enhanced diastolic filling by mechanical suction [29,30]. Current experimental evidence supports the concept of diastolic suction, in which the ventricles fill themselves by sucking blood from the atrial reservoir, an action caused either by an elastic recoil or by inertial properties of the myocardium [31]. Left ventricular relaxation during adrenergic stimulation is enhanced by an increase in sympathetic tone but also by an increase in HR [32]. As for our data, this might apply in particular to FillT and Vmean . However, early filling changes are not known to be decisively influenced by HR. A study by Harrison et al. [33] demonstrated unchanged Vmax E values during incremental right atrial pacing. Udelson et al. [34] compared isoprenaline infusion with atrial pacing: at similar HR only b -adrenergic stimulation with isoprenaline favourably modified measures of diastolic performance associated with im-

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proved diastolic distensibility, i.e. an increase in peak negative dP/ dt as well as a decrease of the time constant T 1 / 2 and time to peak negative dP/ dt.

4.3. Limitations Diastolic filling is a complex phenomenon that is influenced by many factors. Our study was limited to measures of transmitral filling velocities, velocity time integrals and filling time intervals. These noninvasive variables are ‘pattern recognition’ indices that cannot be precisely related to invasively derived measurements [35]. No intracardiac pressures, not even left atrial pressure by transseptal puncture, were measured in the current study, because we found it unacceptable to perform such invasive procedures in a healthy study group. However, our data consist of adrenergically mediated, dose-dependent differences in values in relation to short-term baseline values which makes them relatively independent of hemodynamically derived indices. In terms of measurement reproducibility, Doppler indices of diastolic function appeared to be excellent, which already has been shown by others [36]. Further, we could exclude decisive increases in variabilities due to increasing inotropic and chronotropic stimulation. The exception of significant variability for Vmean and FillT for both interobserver and titration step variation might be due to an error, especially in stimulated parameters, linked to the less smooth Doppler signal envelope. The Doppler indices utilized to assess late diastolic filling showed larger intersubject and intra- and interobserver variabilities (interobserver variation of A-duration being even significant) than those assessing early diastole. As there is considerably less transmitral flow in the normal heart during atrial systole than in early diastole, the direction of the Doppler ultrasound beam may more easily diverge from the direction of the atrial jet than from the path of the early diastolic jet. The higher variability and heterogeneous changes in acceleration and deceleration parameters reported by others [36] could be confirmed by the lower significances of changes and higher variations in our data. A margin of error can also be introduced by the uncertainty in selecting the exact onset and termination of the Doppler spectral tracing. However, variability could be overcome by analyzing and averag-

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ing multiple cardiac cycles and requiring multiple indices for the definition of left ventricular diastolic performance [18]. Our study group consisted of relatively more men than women, but a previous report did not find more frequent or more accurate registrations due to gender influences on Doppler filling velocities [37]. Postural changes were avoided 5 min before and during the whole investigation, as Suzuki et al. demonstrated significant decreases in peak filling rates, when normal subjects simply moved from the supine to the upright position [38]. There is no consensus as to what recording site is correct [39]. Some studies have used Doppler recordings at the annulus level [9], whereas others have recorded at the leaflet tips [17]. Selecting a standardized sampling site either at the annulus levels or at the tips of the leaflets is important to compare data in the same individual, from patient to patient, or from study to study. Therefore we used a constant location at the leaflet tips without any major angle to blood flow direction. Tachycardia at the highest titration step made differential analyses of Doppler profiles almost impossible because of a fusion of the E and A waves. Myocardial ischemia might be masked [40]; however, filling velocities are already maximally influenced at 20 m g / kg / min without any further incremental increase at higher doses. We do not think that sensitivities would be further increased at high doses.

5. Conclusions Evaluation of diastolic filling patterns by Doppler echocardiography is a valuable quantitative and reproducible adjunct to conventional dobutamine stress echocardiography. Early filling velocities (Vmax E and VTI-E) are the most advantageous discriminatory variables with the lowest intersubject and intra- and interobserver variabilities. Early filling is already maximally influenced at a dose of 20 m g / kg / min dobutamine. Further trials in patients with coronary artery disease should evaluate if highdose dobutamine stress test and atropine administration could be partially avoided in regard of these parameters, which might enhance applicability and

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safety of the test in spite of reasonable sensitivities. Physiologically, ratios of early and late filling velocities (E /A Vmax and E /A VTI) do not change, which is in contrast to the already known decline inducible by ischemia. Other Doppler variables provide less informations because of heterogeneous dose-dependent patterns, influences only at high doses, and higher variabilities and might be therefore disregarded. In particular, early filling velocity should be registered in all patients with limited echogenicity in whom endocardial borders are poorly defined and wall motion analysis aggravated.

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