Author + information
- Received April 7, 2000
- Revision received December 13, 2000
- Accepted December 28, 2000
- Published online April 1, 2001.
- Masao Daimon, MDa,
- Hiroyuki Watanabe, MDa,* (, )
- Hiroyuki Yamagishi, MDa,
- Takashi Muro, MDa,
- Kaname Akioka, MDa,
- Kumiko Hirata, MDa,
- Kazuhide Takeuchi, MDa and
- Junichi Yoshikawa, MD, FACCa
- ↵*Reprint requests and correspondence:
Dr. Hiroyuki Watanabe, Department of Internal Medicine and Cardiology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan
We evaluated the value of coronary flow reserve (CFR), as determined by transthoracic Doppler echocardiography (TTDE), for physiologic assessment of coronary artery stenosis severity, and we compared TTDE measurements with those obtained by exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT).
Coronary flow reserve measurements by TTDE have been reported to be useful for assessing angiographic left anterior descending coronary artery (LAD) stenosis. However, discrepancies exist between angiographic and physiologic estimates of coronary lesion severity.
We studied 36 patients suspected of having coronary artery disease. The flow velocity in the distal LAD was measured by TTDE both at rest and during intravenous infusion of adenosine. Coronary flow reserve was calculated as the ratio of hyperemic to basal peak (peak CFR) and mean (mean CFR) diastolic flow velocities. The CFR measurements by TTDE were compared with the results of Tl-201–SPECT.
Complete TTDE data were acquired for 33 of 36 study patients. Of these 33 patients, Tl-201–SPECT confirmed reversible perfusion defects in the LAD territories in 12 patients (group A). Twenty-one patients had normal perfusion in the LAD territories (group B). Peak CFR and mean CFR (mean value ± SD) were 1.5 ± 0.6 and 1.5 ± 0.7 in group A and 2.8 ± 0.8 and 2.7 ± 0.7 in group B, respectively. Both peak and mean CFR ≤2.0 predicted reversible perfusion defects, with a sensitivity and specificity of 92% and 90%, respectively.
Noninvasive measurement of CFR by TTDE provides data equivalent to those obtained by Tl-201–SPECT for physiologic estimation of the severity of LAD stenosis.
Coronary flow reserve (CFR), estimated as the ratio of maximal hyperemic to basal coronary flow velocity, has gained wide acceptance as a diagnostic index for assessment of the physiologic significance of coronary stenosis. It has been assessed mainly by an invasive intracoronary Doppler guide wire (1,2), semi-invasive transesophageal probe studies (3–5)or expensive positron emission tomographic studies (6), and their clinical use has a general restriction. Recently, technologic improvement in transthoracic Doppler echocardiography (TTDE) has permitted noninvasive CFR measurement in the distal left anterior descending coronary artery (LAD) (7–11). This method, which was confirmed to accurately reflect the results of invasive measurement by the Doppler guide wire (10), permits rapid, reproducible and totally noninvasive assessment of coronary blood flow, at a low cost.
The value of CFR, as determined by TTDE, was reported to be useful for noninvasive assessment of significant stenosis in the LAD, as compared with that value obtained by quantitative coronary angiography (11). However, discrepancies exist between angiographic and physiologic estimates of coronary lesion severity (12–14). Coronary flow reserve determined by TTDE, likewise, has not been evaluated sufficiently to determine its usefulness for physiologic assessment of the severity of coronary artery stenosis. The purpose of this study was to evaluate the value of CFR, as determined by TTDE, for physiologic assessment of the severity of coronary stenosis, as compared with that value obtained by exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT).
We selected for this study 36 patients (mean age 62 ± 9 years; 27 men and 9 women) who had been admitted to our hospital for assessment of coronary artery disease. Exclusion criteria were previous myocardial infarction, previous cardiac surgery, artificial pacemaker, nonsinus rhythm, significant valvular heart disease, angina at rest, chronic obstructive pulmonary disease and congestive heart failure. All patients continued taking anti-ischemic medications (nitrates, beta-blockers, calcium antagonists) and antiplatelet agents (aspirin, 81 mg) on the day of the echocardiographic study. On the two-dimensional echocardiogram, none had evidence of a left ventricular (LV) wall motion abnormality, LV hypertrophy (wall thickness at end-diastole >12 mm) or valvular heart disease. All patients underwent Tl-201–SPECT and coronary angiography within one week of having their CFR studied by TTDE. Patients were included after providing written, informed consent. The protocol was approved by our hospital’s Committee on Medical Ethics and Clinical Investigation.
Transthoracic Doppler echocardiography
Echocardiography was performed with an Acuson Sequoia 512 digital ultrasound system (Acuson, Mountainview, California), using a high frequency transducer (5 to 7 MHz). For color Doppler echocardiography, the velocity range was set in the range of 12 to 24 cm/s. Adequate filtering was used to minimize low frequency wall motion artifacts. Echocardiographic images were obtained from the acoustic window around the mid-clavicular line in the fourth and fifth intercostal spaces in the left lateral decubitus position. After the lower portion of the interventricular sulcus had been located in the long-axis cross section, the ultrasound beam was rotated laterally, visualizing the distal portion of the LAD under color flow mapping guidance (11). Color flow was visualized by a high frequency (3.5 MHz) color Doppler technique. Blood flow velocity was measured by pulsed wave Doppler echocardiography (frequency 3.5 MHz), using a sample volume (1.5 to 2.0 mm) placed on the color signal in the distal LAD. We tried to align the ultrasound beam direction with the distal LAD flow as parallel as possible. All studies were continuously recorded on 0.5-in. (1.27-cm) super-VHS videotape, and clips of the stopped frame were also stored digitally on magneto-optical disks (230 MB) for off-line analysis.
Echocardiographic contrast enhancement
In cases in which visualization of color signal in the LAD was unsuccessful or Doppler spectral tracing of velocity was not clear, an echocardiographic contrast agent (Levovist, Schering, Berlin, Germany) was used to improve visualization of the color Doppler signals and to obtain clear spectral Doppler signals (n = 8). On the basis of the results of a previous study (15), Levovist was administered at a concentration of 300 mg/ml by intravenous infusion of a volume of 7 ml at a rate of 1 ml/min, using an infusion pump. The infusion rate was adjusted in the range of 2.0 to 0.5 ml/min according to the quality and entity of the Doppler signal enhancement achieved.
Measurements of CFR by TTDE
Adenosine was administered by intravenous infusion (0.14 mg/kg per min) for 2 min to record spectral Doppler signals during hyperemia. The electrocardiogram and heart rates were monitored continuously during the patients’ examination. Blood pressure was recorded at baseline and every 1 min after intravenous adenosine was started.
We continuously recorded spectral Doppler signals in the LAD at baseline over three cycles and during hyperemia. The position of the transducer was not changed during administration of adenosine. An experienced operator, who had no knowledge of the results of Tl-201–SPECT and coronary angiography, assessed CFR. Measurements of blood flow velocity were performed off-line by contouring the spectral Doppler signals, using the integrated evaluation program in the ultrasound system. Both peak and mean diastolic flow velocities at baseline and peak hyperemia were measured as variables necessary for CFR assessment. Each variable was averaged over three consecutive cycles. Coronary flow reserve was calculated as the ratio of hyperemic to basal peak (peak CFR) and mean (mean CFR) diastolic flow velocities. Normal CFR was defined as >2.0, on the basis of the results of previous studies that evaluated flow velocities in the distal LAD (16,17).
Thallium-201 SPECT was performed within one week of the CFR studies by TTDE. All patients performed symptom-limited exercise on a bicycle ergometer in the sitting position. Nitrates, beta-blockers and calcium channel blockers were withheld on the morning of the test. Twelve-lead electrocardiograms and blood pressure measurements were obtained at baseline and every minute during exercise. The initial work load was 50 W, which was increased by 25 W every 2 min until an end point was reached. The end points included excessive fatigue, dyspnea, dizziness, angina, hypotension, diagnostic ST segment depression (>1.5 mm horizontal or downsloping or >2.0 mm upsloping) or significant arrhythmia. At peak exercise, a dose of 111 MBq of Tl-201 was injected intravenously. The initial images were obtained immediately after the termination of exercise, and delayed images were obtained 4 h later.
Single-photon emission computed tomography was performed using a single-head gamma scintillation camera equipped with a low energy, all-purpose, parallel-hole collimator. Thirty-two equidistant projections were acquired over 180° from the right anterior oblique to left posterior oblique view at 25 s/projection.
On the SPECT images, anteroseptal and apical segments were considered to be in the LAD territory. The SPECT images were analyzed individually by two experienced nuclear physicians who had no knowledge of the angiographic or echocardiographic data. Disagreements in interpretation were resolved by consensus of the two physicians. The patients were considered to have myocardial ischemia when Tl-201–SPECT revealed perfusion defects with redistribution on delayed imaging.
Coronary angiography was performed in all patients by using standard techniques within one week of the CFR studies by TTDE. Angiographic data were subsequently analyzed by an experienced investigator who had no knowledge of the echocardiographic or Tl-201–SPECT results. The severity of coronary stenosis was visually determined and expressed as the percent lumen diameter. Stenosis was considered significant if there was >50% diameter stenosis in at least one projection. Electrical calipers were used when necessary.
On the basis of the Tl-201–SPECT data for the LAD territories, the study patients were classified into group A (abnormal perfusion) and group B (normal perfusion). Parametric data are presented as the mean value ± SD. Categorical variables were compared using the Fisher exact test. Echocardiographic and hemodynamic variables during adenosine infusion between groups A and B were evaluated by two-way repeated measures analysis of variance (ANOVA), testing for group effect, adenosine effect and interaction. The Fisher’s protected least-significant difference test was used for post hoc testing. Mean and peak CFR values for groups A and B were compared by the unpaired ttest. For all analysis, p < 0.05 was considered significant. The sensitivity, specificity, positive predictive value and negative predictive value were calculated in the traditional manner for CFR, as a predictor of abnormal perfusion on the Tl-201–SPECT image.
Of the 36 study patients, adequate spectral Doppler recordings of coronary flow in the distal LAD were obtained for 33 (92%), including 4 patients given an echocardiographic contrast agent to improve spectral Doppler signals. Therefore, these 33 patients comprised the study group in which we compared echocardiographic data with Tl-201–SPECT results; 3 patients were excluded from the study. No significant difference in age or gender was found between groups A and B (Table 1). The results of the two-way repeated measures ANOVA for group and adenosine effect are summarized in Table 2.
All patients in this study performed exercise tests until the end points were reached. Twelve of the 33 patients qualitatively exhibited abnormal perfusion in the LAD territories on Tl-201–SPECT and were classified as group A. The remainder of the patients (n = 21) had normal perfusion (n = 13) or abnormal perfusion in other territories (n = 8) and were classified as group B . The peak heart rate and rate–pressure product were similar in groups A and B for all exercise tests.
No patient developed serious adverse effects, such as angina, atrioventricular block, nausea, flushing or palpitations, during the administration of adenosine. Two-way ANOVA showed no significant differences or interaction in terms of heart rate, systolic blood pressure and diastolic blood pressure between groups A and B during administration of adenosine (Tables 1 and 2).
Coronary angiography demonstrated significant coronary stenosis in the proximal LAD in all of the 12 patients of group A and in 5 patients of group B. Of the three patients who could not undergo Doppler recording, one had total occlusion in the proximal LAD, with good collateral flow from the right coronary artery.
Coronary flow reserve measured by TTDE versus Tl-201–SPECT
An increase in coronary flow velocity was observed in all patients within 1 min of the start of adenosine infusion. The contour of flow velocity remained stable throughout the infusion period and returned to baseline rapidly after adenosine infusion was stopped. There were no significant differences in coronary flow velocity measurements at baseline between groups A and B (Table 3). However, two-way ANOVA showed a significant group effect and interaction in both peak and mean diastolic flow velocities during adenosine infusion (Table 2). Both peak and mean diastolic flow velocities during adenosine infusion in group B increased significantly, as compared with those in group A (p < 0.005 and p < 0.0001, respectively) (Fig. 1). Thus, the echocardiographic study demonstrated significant differences in both peak and mean CFR between groups A and B (peak CFR 1.5 ± 0.6 vs. 2.8 ± 0.8; mean CFR 1.5 ± 0.7 vs. 2.7 ± 0.7, respectively; p < 0.0001). Only one patient of group A had peak and mean CFR >2.0, whereas two patients of group B had peak and mean CFR <2.0 (Fig. 2). Both peak and mean CFR ≤2.0 predicted a reversible perfusion defect in the LAD territory, with a sensitivity of 92%, a specificity of 90%, a positive predictive value of 85% and a negative predictive value of 95%.
Interobserver and intraobserver variabilities for measurement of Doppler velocity recording were 5.0% and 3.9%, respectively.
This preliminary study has evaluated the value of CFR, as determined by TTDE, for physiologic assessment of the severity of LAD stenosis and prediction of myocardial ischemia, as compared with that value obtained by exercise myocardial perfusion imaging results. The results demonstrated that CFR measurement by TTDE permits noninvasive and physiologic assessment of the severity of LAD stenosis.
Measurement of CFR by TTDE
Measurement of CFR has been considered as a useful diagnostic index for functional and physiologic assessment of significant coronary stenosis. However, conventional methods are invasive (Doppler guide wire) (1,2), semi-invasive (transesophageal probe) (3–5)or expensive (positron emission tomography) (6). Accordingly, clinical use of CFR has generally been restricted, despite such a great usefulness.
Recent studies have reported that TTDE successfully permits visualization and measurements of coronary flow velocity in the distal LAD (7–11). Furthermore, contrast-enhanced Doppler recording was recently reported to improve blood flow detection in the LAD and to increase the rate of success in obtaining spectral Doppler signals (18). In the present study, we measured CFR in the distal LAD with a high rate of success (92%), sufficiently applicable for clinical practice, using these color flow mapping and contrast-enhanced Doppler recording.
Physiologic assessment of coronary stenosis by TTDE
Coronary flow reserve, as measured by TTDE, was reported to be clinically useful for noninvasive assessment of significant stenosis in the LAD, as compared with CFR obtained by quantitative coronary angiography (11). However, coronary angiography, even with quantitative methods, has limited reliability in predicting the physiologic significance of coronary artery stenosis (12–14).
Many studies have demonstrated that there is a good correlation between the results of myocardial perfusion scintigraphy and intracoronary Doppler flow velocity variables, and CFR determined by the Doppler guide wire is a reliable marker of the physiologic significance of coronary artery stenosis and predicts the presence of myocardial ischemia (16,17,19–21). Miller et al. (16)found a strong correlation between CFR (≤2.0) measured by the Doppler guide wire and technetium-99m sestamibi myocardial perfusion imaging results (89%), and that concordance between these measurements was higher than that between the severity of stenosis (>50% diameter stenosis by quantitative coronary angiography) and CFR (74%), as well as that between the severity of stenosis by quantitative coronary angiography and technetium-99m sestamibi myocardial perfusion imaging results (89%). Likewise, Tron et al. (20)also found that CFR ≤2.0, as measured by the Doppler guide wire, was a stronger predictor of abnormal myocardial perfusion (89%) than angiographic variables, such as percent lumen stenosis and minimal lumen diameter. Thus, CFR measurement by TTDE should correlate more strongly with the results of myocardial perfusion imaging than with angiographic results.
In contrast, no previous study has demonstrated the clinical usefulness of CFR measured by TTDE for physiologic assessment of coronary lesion severity. The present study demonstrated, for the first time, to our knowledge, that CFR measured by TTDE enables accurate physiologic assessment of the severity of LAD stenosis and predicts the results of nucleotide stress tests (92% sensitivity, 90% specificity). This higher accuracy may reflect its value as a physiologic index of LAD stenosis severity, as compared with the findings of the previous study that each peak and mean CFR <2.0, as determined by TTDE, had sensitivities of 92% and 92% and specificities of 82% and 86%, respectively, for the presence of significant angiographic stenosis (11).
First, the number of subjects in the present study was small (n = 33). It will be necessary to increase the number of subjects for further investigation of the present method.
Second, we evaluated the physiologic significance of only coronary artery stenosis, which was associated with abnormal myocardial perfusion. Coronary flow reserve must be assessed with strict attention to many factors that alter myocardial reserve capacity, such as microvascular disease (22,23), LV hypertrophy (24), age (25), hemodynamic conditions, even in the absence of angiographic coronary stenosis. In the present study, three discordant patients were found. One patient with normal CFR in group A was found to have multiple stenoses in three major vessels on coronary angiography. Of two patients with abnormal CFR in group B, one was found to have diffuse 50% diameter stenosis in the LAD and the left main coronary artery on coronary angiography, and the other was found to have 50% stenosis in the proximal LAD and 70% stenosis in the distal LAD. Other stenotic lesions, except for the proximal LAD, possibly affected CFR assessment. Further careful investigation of the usefulness of CFR, as measured by TTDE, in the physiologic assessment of the coronary circulation is needed.
Third, determination of CFR by TTDE was performed depending on changes in blood flow velocity measured by pulsed wave Doppler echocardiography, using a sample volume placed in the distal portion of the LAD. The angle between Doppler beam and the direction of the coronary blood flow may result in underestimation of the true flow velocity. However, CFR is unaffected if the position of the transducer is changed either before or during administration of adenosine.
In addition, our method of physiologic assessment of coronary artery stenosis with TTDE is currently restricted to the LAD, for anatomic reasons. However, one randomized trial showed that coronary artery bypass graft surgery improved survival of those with significant stenosis of the proximal portion of the LAD in two- or three-vessel coronary artery disease (26). Accordingly, physiologic assessment of the severity of LAD stenosis has a substantial clinical impact on the prognosis of patients with coronary artery disease.
The fact that our method is totally noninvasive, relatively inexpensive and generally available, as compared with conventional methods, is considered as an important advantage. Furthermore, our method permits quantitative assessment of the severity of physiologic stenosis. Although the use of stress echocardiography for the diagnosis of coronary artery disease has gained increasing popularity and its results are reproducible, no highly quantifiable method exists to evaluate wall motion or systolic thickening in the clinical setting.
Measurement of CFR by TTDE may provide physicians with additional information for making clinical decisions regarding physiologic severity of coronary stenosis. It may also be useful in cases in which exercise stress testing cannot be performed.
Measurement of CFR by TTDE provides physiologic information on the severity of LAD stenosis equivalent to that obtained with Tl-201–SPECT. This method is totally noninvasive and useful for the clinical evaluation of myocardial ischemia.
We thank Dr. Fukui Mitsuru for his considerable assistance with the statistical analysis.
- analysis of variance
- coronary flow reserve
- left anterior descending coronary artery
- left ventricular/left ventricle
- single-photon emission computed tomography
- transthoracic Doppler echocardiography
- Received April 7, 2000.
- Revision received December 13, 2000.
- Accepted December 28, 2000.
- American College of Cardiology
- Doucette J.W.,
- Corl P.D.,
- Payne H.M.,
- et al.
- Segal J.,
- Kern M.J.,
- Scott N.A.,
- et al.
- Iliceto S.,
- Marangelli V.,
- Memmola C.,
- Rizzon P.
- Redberg R.F.,
- Sobol Y.,
- Chou T.M.,
- et al.
- Demer L.L.,
- Gould K.L.,
- Goldstein R.A.,
- et al.
- Fusejima K.
- Ross J.J. Jr.
- Hozumi T.,
- Yoshida K.,
- Akasaka T.,
- et al.
- Hozumi T.,
- Yosida K.,
- Ogata Y.,
- et al.
- Vogel R.A.
- ↵Caiati C, Montaldo C, Zedda N, et al. Validation of a new noninvasive method (contrast-enhanced transthoracic second harmonic echo Doppler) for the evaluation of coronary flow reserve: comparison with intracoronary Doppler flow wire. J Am Coll Cardiol 1999;34:1993–200.
- Miller D.D.,
- Donohue T.J.,
- Younis L.T.,
- et al.
- Voudris V.,
- Manginas A.,
- Vassilikos V.,
- Koutelou M.,
- Kantzis J.,
- Cokkinos D.V.
- Caitai C.,
- Zedda N.,
- Montaldo C.,
- Montisci R.,
- Iliceto S.
- Joye J.D.,
- Schulman D.S.,
- Lasorda D.,
- Farah T.,
- Donohue B.C.,
- Reichek N.
- Chauhan A.,
- Mullins P.,
- Petch M.,
- Schofield P.
- Reis S.E.,
- Holubkov R.,
- Lee J.S.,
- et al.
- Senneff M.,
- Geltman E.,
- Bergman S.,
- Hartman J.