On-line quantitative assessment of left ventricular filling during dobutamine stress echocardiography: a useful addition to conventional wall motion scoring1

International Journal of Cardiology 59 (1997) 57–69

On-line quantitative assessment of left ventricular filling during dobutamine stress echocardiography: a useful addition to conventional wall motion scoring 1 Antonio Vitarelli*, Marco Ferro Luzzi, Maria Penco, Francesco Fedele, Armando Dagianti Cardiac Department, ‘ La Sapienza’ University, Rome, Italy Received 11 September 1996; revised 19 November 1996; accepted 19 November 1996

Abstract In order to determine whether the diastolic rate of ventricular volume change obtained on-line with an automatic border detection (ABD) system during dobutamine stress echocardiography (DSE) would provide an interpretation of the diastolic ventricular response to the drug in quantitative terms in the assessment of coronary artery disease, we studied, with ABD and DSE, 59 patients who underwent coronary arteriography within 2 months of the stress test. Eleven patients had normal coronary findings or non-significant coronary lesions. Significant ($70% diameter stenosis) coronary artery disease (CAD) was present in 48 patients (81%). Dobutamine stress echocardiography (DSE) to a maximal dose of 50 m g / kg per min was performed in all patients. ABD images were acquired at rest and at the peak of infusion along with conventional two-dimensional images. The following measurements were evaluated: left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), slope of rapid filling segment (RFS), peak filling rate (PFR), rapid filling phase fractional change (RFFC). Patients with non-significant coronary artery lesions exhibited a hyperdynamic response with an LVEF increment of at least 20% from baseline to peak drug infusion. In these patients the effect of dobutamine produced an increase of RFS from 35.565.6 to 86.5610.5 ml / s, an increase of PFR from 4.460.6 to 6.860.6 EDV/ s, and an increase of RFFC from 7468 to 9265% (P,0.001). Of the 48 patients with coronary artery disease, 27 had ,20% LVEF increase at peak dobutamine infusion. Four of 22 patients with single vessel disease and 23 of 26 patients with multivessel disease had an abnormal systolic response. After dobutamine infusion single vessel CAD patients showed a decrease of RFS from 33.465.3 to 26.765.9 ml / s, a decrease of PFR from 3.860.7 to 3.060.7 EDV/ s, and a decrease of RFFC from 7366 to 5964% (P,0.001). Multivessel CAD patients showed a decrease of RFS from 32.065.9 to 23.164.1 ml / s, a decrease of PFR form 3.860.6 to 2.860.6 EDV/ s, and a decrease of RFFC from 7165 to 5468% (P,0.001). The overall sensitivity of detecting CAD was 85% for conventional DSE and 90% for ABD-DSE (P5NS). The sensitivities of detecting patients with single vessel and multivessel CAD with conventional DSE were 68 and 92%, respectively, and with ABD-DSE were 91% (P,0.01) and 96% (P5NS), respectively. Our results show that an abnormal diastolic as well as systolic response during on-line quantitative assessment of dobutamine stress echocardiography is a sensitive marker of coronary artery disease and is predictive for the detection of extensive lesions. The described measurements can be utilized to improve the DSE sensitivity in identifying coronary artery disease. On-line quantitation of diastolic indexes with ABD can represent another step toward obtaining uniform results after stress echocardiography.  1997 Elsevier Science Ireland Ltd. Keywords: Dobutamine stress echocardiography; Automatic boundary detection; Left ventricular diastolic function

*Corresponding author, via Lima 35 00198 Rome, Italy. Tel: 139 6 85301427; Fax: 139 6 8841926; E-mail: [email protected]. 1 Presented in part at the American Federation of Clinical Research Meeting, New Orleans, February 1994.

1. Introduction Exercise and pharmacological stress echocardiography have been shown to be highly sensitive,

0167-5273 / 97 / $17.00  1997 Elsevier Science Ireland Ltd. All rights reserved PII S0167-5273( 96 )02895-1

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specific and accurate for the detection of coronary artery disease and have gained widespread acceptance with the development of acquisition and storage of images in digital format [1–5]. The interpretation of results have been based on a qualitative evaluation of segmental and global left ventricular function [6,7]. An approach for on-line quantification of ventricular size and function during pharmacological stress testing, based on a new echocardiographic automatic boundary detection (ABD) method that quantitates cardiac chamber areas and volumes with instantaneous graphic display of the data, has recently been reported [8]. Since it has been shown that abnormal diastolic response is a sensitive marker of significant coronary artery disease [9–11], a quantitative evaluation of diastolic left ventricular function during stress would also be desirable. This study was designed to determine whether the diastolic rate of ventricular volume change obtained on-line with the ABD system during dobutamine stress echocardiography (DSE) would provide an interpretation of the diastolic ventricular response to the drug in quantitative terms in the assessment of coronary artery disease.

2. Methods

2.1. Patient population Fifty-nine patients (38 men, mean age 52 years, range 31–74) with technically good quality echocardiographic studies, who underwent coronary arteriography within 2 months of DSE, were included in the present investigation. Significant coronary artery stenosis was defined as $70% angiographic reduction in the luminal diameter of any of the three coronary arteries or their primary branches, or $50% reduction of the luminal diameter of the left main coronary artery. Indications for DSE examinations were chest pain evaluation (n548) and preoperative cardiac risk stratification before non-cardiac surgery (n511). All patients gave informed consent to undergo DSE. Exclusion criteria included NYHA functional class III or IV congestive heart failure symptoms, rest or unstable angina, acute myocardial infarction within the previous 3 weeks, uncontrolled hypertension (systolic blood pressure $200 or diastolic blood pressure $110 mmHg), or a history of

sustained ventricular arrhythmias. Six patients had hypertensive heart disease. All patients were in sinus rhythm and 89% of them were taking at least one cardiac medication. Beta-blocker therapy was discontinued 48 h before testing, whereas nitrates and calcium antagonists were continued.

2.2. Dobutamine infusion Dobutamine at a concentration of 1 mg / ml was prepared and infused intravenously at an initial dose of 5 m g / kg per min. After 3 min the dose was increased to 10 m g / kg per min and thereafter by incremental doses of 10 m g / kg per min every 3 min to a maximal dose of 50 m g / kg per min. Electrocardiographic monitoring and symptom notation were performed throughout testing, with blood pressure determined every 3 min. Echocardiograms were obtained with commercially available equipment (Hewlett-Packard Sonos 1500 or 2500, Andover, MA, USA). Images were recorded in standard parasternal long and short axis and apical four- and twochamber views. Segmental left ventricular wall motion was described as normal, hyperkinetic, hypokinetic, akinetic, or dyskinetic (hyperkinesia is a normal response to stress) according to a 16-segment model [12]. Positive test findings were defined as a new or worsening wall motion abnormality during infusion. Side-by-side analysis of baseline, initial, intermediate, and peak stress images were displayed in a quad-screen format for each of the four standard views, each in an eight-cell sequence (cine loop) synchronized to the R wave. End points for terminating the test were as follows: (1) a heart rate of $85% of predicted maximal heart rate, (2) a maximal dose of dobutamine of 50 m g / kg per min, (3) a new segmental wall abnormality, (4) progressive angina, (5) ST depression .2 mm, (6) serious cardiac arrhythmias, (7) severe hypertension (systolic .200 mg or diastolic .120 mmHg), (8) severe hypotension (systolic pressure ,90 mmHg and / or a drop of systolic pressure .30 mmHg).

2.3. On-line quantification After the highest quality possible conventional two-dimensional echocardiogram was recorded and digital quad screen resting images were obtained, quantitative integrated backscatter imaging was per-

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formed as developed at the Washington University [13,14] and as validated by others [15–20]. A set of automatic border detection images was obtained in the apical four-chamber view. The acoustic blood / tissue interface was displayed by a colored line that was superimposed on the two-dimensional echo image. All gain settings were adjusted as a compromise between cavity clutter induced by excessive gain, or wall dropout induced by insufficient gain. After the gain settings were optimized and the automated border detection system had displayed a border following the detected cavity wall interface, a region of interest was manually traced around the left ventricular cavity. Real time left ventricular volumes were obtained with the method of discs. The waveforms of volume change and the rate of volume change were displayed along with the electrocardiogram (Fig. 1) and the concurrent cross-sectional image. A stable and well-defined dV / dt tracing served as an indicator for a good-quality ABD imaging. Automatic border detected images were acquired at rest and at the peak of infusion of dobutamine along with conventional two-dimensional images. Off-line analysis was performed in all studies with the built-in calibration and measurement systems of the echocardiographic equipment. Measurements from the volume-time waveforms were obtained from three beats and averaged. The R wave on the electrocardiogram was considered to represent end-diastole, whereas the nadir of the curve was considered to mark end-systole. The following measurements were evaluated: left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), slope of rapid filling segment (RFS; the abrupt upslope of the curve considered to start at the opening of the mitral valve), rapid filling phase fractional change (RFFC; amount of total volume change that occurred at the end of the rapid filling period), atrial filling phase fractional change (AFFC; amount of the total volume change that occurred during atrial contraction), peak filling rate (PFR; first upward peak in diastole on the dV / dt waveform, normalized to end-diastolic volume).

2.4. Statistical analysis Analysis of variance was used to determine

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whether any ABD echocardiographic changes occurred more frequently in any angiographic category. The least-squares procedure was used for linear regressions. Sensitivity, specificity, positive and negative predictive values, and accuracy were calculated in the standard manner. Data are reported as mean6S.D. Values of P#0.05 were considered significant.

2.5. Reproducibility of measurements To assess intra-observer variability one investigator reanalysed the videotaped studies in ten patients and re-calculated diastolic indexes on the volume waveform on preselected frames, at baseline and after dobutamine infusion. Ten randomly selected studies were assessed by a second investigator to obtain interobserver reproducibility of the same set of measurements. In addition, the reproducibility of ABD data dependent on the initial gain settings between individual operators was assessed in ten patients with normal coronary arteries by completely repeating the control adjustment, recording and measurement procedure of the study parameters. Results of intra- and interobserver variability were expressed as the mean difference between observations divided by their average measurement.

2.6. Validation with off-line planimetry In this study we further validated the ABD methodology to verify if values of left ventricular volumes measured on-line by automatic boundary detection exhibit a correlation with values measured off-line from videotaped images. Two sets of measurements were obtained in non-simultaneous beats at end-diastole and end-systole at both baseline and peak dobutamine infusion in 12 patients. The correlation coefficient and standard error of the estimate between the two measurements were determined.

3. Results

3.1. Angiographic findings Eleven patients had normal coronary findings or non-significant coronary lesions. None of these patients had hypertensive heart disease. Significant

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($70% diameter stenosis) CAD was present in 48 patients (81%). This included 22 patients with onevessel, 15 patients with two-vessel, and 11 patients with three-vessel CAD. Only 1 patient had left main coronary artery stenosis $50% and he had narrowing in more distal coronary territories as well. The presence of CAD was known in five patients on the basis of prior myocardial infarction or previous catheterization and was previously undocumented in the remainder. No patient with single vessel disease had a previous myocardial infarction.

New or worsening regional wall motion abnormalities (positive test) during dobutamine infusion developed in 41 of the 48 patients with coronary artery disease. Two of the 11 patients with normal coronary arteries had false-positive DSE findings. Thus, the sensitivity of the test for the detection of coronary artery disease was 85% and the specificity 82%. The positive predictive value was 95%, the negative predictive value was 56%, and the overall accuracy (number of tests with true-positive plus true-negative results divided by the total number of tests) was 85%. No wall motion abnormalities at rest were present in patients with normal coronary findings. In the CAD group baseline wall motion abnormalities were present in 28 of 41 patients (68%) with positive DSE studies and in 3 of 7 patients (43%) with negative studies. Two or three-vessel coronary artery disease occurred in 14 (45%) of the 31 patients with rest wall motion abnormalities and in 6 (35%) of the 17 patients with no wall motion abnormalities at rest (P5NS). Regional wall motion abnormalities in the distribution of more than one major coronary artery were seen in 7 of the 22 patients with single vessel CAD and 10 of the 26 patients with multivessel disease.

defined normal systolic response. The increment in LVEF was achieved at the expense of an approximate 15% reduction in end-diastolic volumes and 30% reduction in end-systolic volumes (Table 1). In these patients the effect of dobutamine on ABD indices of diastolic function produced an increase of RFS from 35.565.6 to 86.5610.5 ml / s, an increase of PFR from 4.460.6 to 6.860.6 EDV/ s, and an increase of RFFC from 7468 to 9265% (P,0.001). Heart rate increased (Table 2) from 73613 to 126619 beats / min (P,0.01) and systolic blood pressure rose from 132617 to 169632 mmHg (P,0.01). Of the 48 patients with coronary artery disease, 27 had ,20% increase in ejection fraction at peak dobutamine infusion (abnormal systolic response). Four of the 22 patients with single vessel disease and 23 of the 26 patients with two- or three-vessel coronary artery disease had an abnormal systolic response (Fig. 2 Fig. 3). After dobutamine infusion single vessel CAD patients showed a decrease of RFS from 33.465.3 to 26.765.9 ml / s, a decrease of PFR from 3.860.7 to 3.060.7 EDV/ s, and a decrease of RFFC from 7366 to 5964% (P,0.001). Multivessel CAD patients showed a decrease of RFS from 32.065.9 to 23.164.1 ml / s, a decrease of PFR from 3.860.6 to 2.860.6 EDV/ s, and a decrease of RFFC from 7165 to 5468% (P,0.001). An at least 10% decrease of all diastolic indexes was defined abnormal diastolic response. In CAD patients heart rate increased from 69614 to 113621 beats / min (P, 0.01) and systolic blood pressure rose from 139616 mmHg to 172630 mmHg (P,0.01). A decrease of all ABD filling parameters was seen in 20 of the 22 patients with single vessel disease and in 25 of the 26 patients with multivessel disease. Therefore, in these patients an abnormal left ventricular filling response to dobutamine had a sensitivity of 91% in identifying single vessel coronary artery disease (Table 3) and a sensitivity of 96% for multivessel disease.

3.3. ABD systo-diastolic changes

3.4. Feasibility and reproducibility

Patients with non-significant coronary artery lesions exhibited a hyperdynamic response with an increment in the left ventricular ejection fraction (LVEF) of at least 20% from baseline to peak drug infusion (Fig. 1). The 20% LVEF increment was

Among 71 consecutive patients who underwent DSE, ABD was feasible in the 4C view in the 59 patients (83%) who were included in the study. Good reproducibility was found for all diastolic measurements, both at baseline and after dobutamine infu-

3.2. DSE findings

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Fig. 1. Apical four-chamber automatic boundary detection images and corresponding instantaneous display of the measured cavity volume in a patient with a normal response to dobutamine. At baseline (upper panel) the end-diastolic left ventricular volume was 116 ml and the end-systolic volume 55 ml. At peak dobutamine infusion (bottom panel) a reduction in end-diastolic (87 ml) and end-systolic volumes (15 ml) is shown with a prominent increase (.20%) of ejection fraction. There is a parallel significant rise in diastolic indexes (rapid filling slope—49.9 vs. 67.8 ml / s, peak filling rate—2.9 vs. 5.0 EDV/ s, rapid filling fractional change—73 vs. 82%). The asterisks mark the slope of rapid filling segment and the arrowhead marks the atrial filling component on the volume change waveform. R: peak rapid filling rate (PFR); A: peak atrial filling rate.

sion: RFS (at rest: r50.95, mean error53%; after stress: r50.92, mean error54%); PFR (at rest: r5 0.89, mean error54%; after stress: r50.83, mean

error54%), RFFC (at rest: r50.81, mean error55%; after stress: r50.74, mean error57%). The percent variability was less then 7% in diastolic parameters

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Table 1 Systolic and diastolic indexes measured on-line prior to and after dobutamine infusion EF (%)

No CAD 1VD MVD

RFS (ml / s)

Basal

Peak

5766 5268 4966

7765 * 68611 * 5469 †

PFR (EDV/ s)

Basal

Peak

35.565.6 33.465.3 32.065.9

86.5610.5 * 26.765.9 * 23.164.1 *

RFFC (%)

Basal

Peak

Basal

Peak

4.460.6 3.860.7 3.860.6

6.860.6 * 3.060.7 * 2.860.6 *

7468 7366 7165

9265 * 5964 * 5468 *

CAD, coronary artery disease; EF, ejection fraction; MVD, multivessel disease; PFR, peak filling rate; RFFC, rapid filling fractional change; RFS, rapid filling slope; VD, vessel coronary artery disease. * P,0.001, † P5NS (compared to baseline).

derived from the waveform and 10% or less in those measured from the time derivative.

3.5. Validation with off-line planimetry A close correlation was observed between on-line measured left ventricular volumes and those measured off-line by planimetry at either end-diastole or end-systole (Fig. 4). The correlation between the two measurements had an ‘r’ value of 0.88 for enddiastolic and 0.71 for end-systolic volumes.

4. Discussion Despite extensive clinical experience on dobutamine as a pharmacological stress testing agent, at present only few reports [8,21] have dealt with quantitation of the normal and ischemic responses induced by the drug on ventricular dynamics. Our results show that an abnormal diastolic as well as systolic response during on-line quantitative assessment of dobutamine stress echocardiography is a sensitive marker of coronary artery disease and is predictive for the detection of extensive lesions. Table 2 Peak physiologic responses to dobutamine stress echocardiography No CAD

HR (beats / min) SBP (mmHg) DBP (mmHg) SBP3HR / 10 3

CAD

Basal

Peak

Basal

Peak

73613 132617 84614 9.962.5

126619 * 169632 * 73612 * 22.164.2 *

69614 139616 86615 9.762.8

113621 * 172630 * 7069 * 21.863.7 *

Data are mean6S.D. DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. * P,0.01 compared to baseline.

4.1. Left ventricular dimensional responses to dobutamine A reduction in left ventricular cavity size is an expected epiphenomenon of the significant inotropic effect and reduction in afterload induced by dobutamine when employed for diagnostic purposes. It has been shown [8] that patients with a normal response to dobutamine stress develop modest reduction in left ventricular diastolic areas, but marked reduction in systolic areas that result in marked increases in fractional area change, whereas ischemic patients have a more modest improvement or even blunted response in fractional change. When considering hemodynamic monitoring and radionuclide-determined left ventricular volumes [22], patients with more extensive coronary artery disease showed early increases in left ventricular end-diastolic pressure and less of a decrease in end-diastolic volume during pacing-induced ischemia. Similar failure of end-diastolic volume to decrease in patients with quantitatively more extensive coronary disease, presumably due to an early increase in end diastolic pressure, has been recently reported [21]. We observed similar findings in the behaviour of left ventricular ejection fraction during dobutamine stress test in patients with non-significant (.20% LVEF increase) or significant coronary artery disease (,20% LVEF increase in patients with multivessel disease). Previously published studies [23] suggest that two-dimensional echocardiography, radionuclide angiography and contrast cineangiography are equally acceptable methods of assessing left ventricular ejection fraction. Our results are in keeping with previous reports [21] that emphasize the value of determining left ventricular volume changes during dobutamine stress echocardiography. Furthermore, we observed a close correlation between on-line measured left ventricular vol-

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Fig. 2. Representative images and graphics from a patient with an abnormal response to dobutamine. At baseline (upper panel) the end-diastolic left ventricular volume was 56 ml and the end-systolic volume 25 ml. The bottom panel illustrates a blunted response of ejection fraction after stress (,20% increase) with a parallel significant decrease of diastolic indexes (rapid filling slope—44.1 vs. 26.5 ml / s, peak filling rate—3.2 vs. 2.8 EDV/ s, rapid filling fraction change—67 vs. 49%). R: peak rapid filling rate (PFR); A: peak atrial filling rate. Asterisks and arrowhead mark the slope of the rapid filling segment and the atrial filling component, respectively.

umes and those volumes measured off-line by planimetry from video-taped images at baseline and after dobutamine infusion (Fig. 4). Provided that an adequate centering of the region of interest on the left ventricle is maintained during the stress phase record-

ing, ABD echocardiography has a great potential role in automatic on-line monitoring of the left ventricle during maneuvers or conditions that acutely change left ventricular dimensions and function [14–16]. Because the patient remains in the supine position

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Fig. 3. Bar graph of systolic and diastolic indexes at baseline (open bars) and at peak dobutamine infusion (closed bars) in patients with no significant coronary artery disease (no CAD), single vessel disease (1 VD) and multivessel disease (MVD). After dobutamine, a blunted response of systolic ejection fraction is shown in patients with multivessel disease and a significant decrease of diastolic indexes in both groups of patients with coronary artery disease. *P,0.001, † P5NS.

throughout the study, body position can be optimized at each incremental level of stress.

Table 3 Sensitivity calculations of conventional (DSE) and quantitative (ABDDSE) dobutamine stress echocardiography

Sens Spec PPV NPV Ac Sens-1VD Sens-2VD Sens-3VD Sens-MVD

DSE (%)

ABD-DSE (%)

41 / 48 (85) 9 / 11 (82) 41 / 43 (95) 9 / 16 (56) 50 / 59 (85) 15 / 22 (68)* 14 / 15 (93) 10 / 11 (91) 24 / 26 (92)

43 / 48 10 / 11 43 / 44 10 / 15 53 / 59 20 / 22 14 / 15 11 / 11 25 / 26

(90) (91) (98) (67) (90) (91)* (93) (100) (96)

Ac, accuracy; MVD, multivessel coronary artery disease; NPV, negative predictive value; PPV, positive predictive value; Sens, sensitivity; Spec, specificity; VD, vessel coronary artery disease. * P,0.01.

4.2. Diastolic response during stress as indicator of ischemia During myocardial ischaemia, left ventricular relaxation and compliance are impaired and isovolumic relaxation time is prolonged [24–29]. These changes are associated with detection of segmental abnormalities of relaxation, implying a close relation between asynchronized relaxation and global diastolic dysfunction in patients with ischemic heart disease. Heterogeneity of regional diastolic function has been considered to be one of the important determinants of global left ventricular diastolic dysfunction both in animals and in humans [29]. Abnormal asynchrony may be a more important determinant of isovolumic

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Fig. 4. Scatterplot and regression line of relation between on-line measured left ventricular cavity volumes (ordinate) and those volumes measured off-line by planimetry (abscissa) from videotaped images in 12 patients at either end-diastole (upper panel) or end-systole (bottom panel), at baseline and after dobutamine infusion.

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relaxation time in patients without systolic wall motion abnormalities than in those with systolic wall motion abnormalities. It has been shown [10] that, at the beginning of stress, alterations in relaxation are substantiated by the Doppler transmitral flow pattern, i.e. decrease in the E /A ratio and prolongation in deceleration time. In contrast, during prolonged marked ischemia, the left ventricle becomes very stiff, filling pressures rise and transmitral flow pattern becomes more restrictive (higher E /A, shorter deceleration time). Similar alterations in left ventricular filling during acute ischemia induced by different methods [30–32] have been previously reported. Thus, myocardial ischemia can be a possible mechanism influencing diastolic filling pattern in response to high dose dobutamine. In a normal heart increases in heart rate, cardiac contractility, arterial pressure, and oxygen consumption induced by dobutamine are associated with an increase in the speed of left ventricular relaxation, which augments filling. Demand ischemia provoked by inotropic stimulation would result in no change or a decrease in the speed of left ventricular relaxation. The pattern of left ventricular diastolic filling is influenced by a number of factors including left ventricular relaxation and compliance, left atrial pressure, left ventricular systolic function, age and heart rate [33]. Since it has been shown that dobutamine-induced ischemia results in a decrease in stroke volume with no change in pulmonary wedge pressure [34] and, consequently, it is not expected that left atrial pressure will increase during dobutamine administration, it is conceivable that reduction in early filling indexes observed in our patients can be attributed to worsened myocardial relaxation that precedes impairment of systolic function of the left ventricle and ST segment depression.

4.3. On-line quantification of left ventricular filling during stress Studies in patients undergoing dobutamine stress echocardiography [8] have demonstrated the feasibility of acquiring on-line geometric and functional information of left ventricular systolic function in a sequential manner in order to provide uniformity in the interpretation of the ventricular response to the

drug in quantitative terms. We have previously shown [20] that quantitative indexes of the left ventricular diastolic filling obtained with the automatic border detection (ABD) system were consistent in distinguishing normal from abnormal diastolic performance, with a strong relation with radionuclide angiographic indexes. This study shows that in patients with coronary artery disease and in response to dobutamine, left ventricular filling was significantly altered as evidenced by the marked decrease of the slope of rapid filling segment (RFS) as well as decrease of PFR and RFFC (Fig. 2). Nearly 90% of the patients with positive findings on the dobutamine stress echocardiogram and an abnormal systolic response to dobutamine stress had multivessel disease compared to only 18% with abnormal systolic response and single vessel disease. In patients with single vessel CAD a decrease of all ABD indexes of left ventricular filling was observed (Table 1) compared to normal patients. The sensitivity for detection of single vessel coronary artery disease was 68% for conventional dobutamine stress echocardiography and 91% for dobutamine stress ABD echocardiography (Table 3). Thus, it appears from our results that abnormal diastolic response is a more sensitive marker of significant CAD than wall motion abnormalities. Our data suggest that, in patients with single vessel CAD, regional left ventricular impairment was not severe enough to alter global systolic function, presumably due to compensatory hyperkinesia in normal segments, but severe enough to alter global diastolic filling. These findings are in agreement with those of El-Said et al. [9] who observed an increase of pulsed Doppler aortic velocity and acceleration after dobutamine infusion in patients with single vessel coronary artery disease and a decrease in peak mitral early filling velocity. Since an ischemia-related event, if small, may not necessarily impair global left ventricular diastolic function, ABD echocardiography offers advantages over Doppler by virtue of its potential capability to increase cardiac cross-sections to detect segmental diastolic wall motion abnormalities. Although not specifically quantified in this study, ABD diastolic parameters can be more accurately determined by obtaining multiple images in as many planes as possible (apical four chamber, apical two chamber, and apical long axis) and averaging the resultant indexes obtained in each of these views.

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4.4. Limitations of the study Some methodologic limitations are inherent in the acoustic quantification technology. The threshold for the automated border determination is directly influenced by operator-defined gain settings. The region of interest had to be drawn as close as possible to the end-diastolic border on the conventional image to minimize overestimation of cavity area by excluding low-density ultrasound signals that may appear within the lateral myocardium and falsely be included as blood area [19]. Also assumptions regarding left ventricular geometry may produce some inaccuracy in the volume estimates since a single tomographic plane was used to reflect global LV volume. Furthermore, a potential limitation is the need for an echocardiographic image with adequate endocardial definition, a problem that is similar to reported transthoracic quantitative echocardiographic studies [35] and not unique to this automated border detection system. Additional limitation is the reduced temporal sensitivity of ABD techniques compared with Doppler, as ABD data acquisition is dependant on frame rate. Finally, the distortion of individual waveforms by noise often results in some beat-to-beat variability that could be improved by averaging multiple volume waveforms [36]. Other limitations are represented by the fact that indexes of left ventricular filling are influenced by several well known factors. Changes in heart rate have been shown to significantly alter the diastolic profile, predominantly by increasing atrial contribution to filling. However, our observations were not based exclusively on the evaluation of changes of RFFC /AFFC ratio. Moreover, it is known that dobutamine induces more of an increase in cardiac contractility and output than it does in heart rate. Early filling indexes obtained by ABD echocardiography also decrease progressively with age as Doppler indexes [37], a factor that may have contributed in part to some of the observed abnormalities in ABD response in our patients. However, only eight patients in our study were older than 65 years and had mild baseline abnormalities of diastolic function. In addition, factors causing abnormal interventricular septal motion (bundle branch block, post cardiac surgery, pre-excitation) may influence ABD accuracy in detection of diastolic dysfunction, although no such

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patient was included in the present study. Finally, in patients with hypertensive heart disease, reduced coronary flow reserve may result in stress-induced myocardial ischemia (and hence systolic and diastolic regional dysfunction) even in the absence of epicardial coronary artery disease. However, no patient among those with normal coronary arteries and only six of 48 CAD patients had hypertensive heart disease. Other potential limitations of the study could be that angiography does not provide a physiologic assessment of the severity of coronary artery disease and that the sensitivity of the test would be even greater in patients not receiving cardiac therapy. However, previous studies using echocardiography with dobutamine [4,38] have noted no decrease in sensitivity in patients taking anti-anginal medications including b blockers.

4.5. Conclusions Despite the limitations in ABD methodology and the difficulties in assessing diastolic function, the present study provides a basis for quantitative standardization of the response of left ventricular filling indexes to dobutamine stress. Future studies need to address reference values for a normal age-matched population. On-line quantitation of diastolic indexes with automatic boundary detection could represent another step toward obtaining uniform results after stress echocardiography. Our measurements may be utilized to increase the predictive value of positive or negative stress findings in identifying high risk or low risk patients and improve the sensitivity of dobutamine stress echocardiography in detecting coronary artery disease. We believe that refinements in the technique with a comprehensive on-line assessment of global as well as regional diastolic function after stress may further help to achieve this goal.

References [1] Cohen JL, Greene TO, Ottenweller J, Binenbaum SZ, Wilchfont SD, Kim CS. Dobutamine digital echocardiography for detecting coronary artery disease. Am J Cardiol 1991;67:1311–1318. [2] Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. J Am Coll Cardiol 1992;19:1203–1211.

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