Background
The aim of this study was to evaluate the diagnostic potential of coronary flow velocity reserve (CFR) measurement by transthoracic Doppler echocardiography (TTDE) to detect restenosis in the 3 major coronary arteries: the left anterior descending coronary artery, right coronary artery, and left circumflex coronary artery.
Methods
The lesions of 175 patients who were scheduled for follow-up coronary angiography and TTDE 6 months after undergoing stents implantation were studied. CFR was assessed by TTDE in the targeted arteries into which stents had been implanted.
Results
Coronary stents were implanted in a total of 238 angiographic lesions in 175 patients. Doppler recordings of coronary flow in the 3 major arterial lesions were obtained in 211 of the 238 angiographic lesions (89% feasibility). CFR was significantly lower in lesions with restenosis than those without restenosis (1.70 ± 0.32 vs 2.65 ± 0.66, P < .01). A CFR value < 2.0 was 89% sensitive and 91% specific for detecting restenosis in the 3 major coronary arteries. Sensitivity and specificity were 86% and 91%, respectively, in the left anterior descending coronary artery (95% feasibility); 92% and 92%, respectively, in the right coronary artery (85% feasibility); and 91% and 92%, respectively, in the left circumflex coronary artery (81% feasibility).
Conclusion
CFR assessment by TTDE is an accurate method for monitoring restenosis, not only in the left anterior descending but also in the right and left circumflex coronary arteries in patients previously subjected to percutaneous coronary intervention.
Intimal hyperplasia after percutaneous coronary intervention (PCI) and the resultant restenosis remain problematic despite numerous improvements in stent technology. Although a recent randomized trial showed that use of drug-eluting coronary stents results in less restenosis, such use is associated with late stent thrombosis and still requires about 8% target legion revascularization. Therefore, careful surveillance is strongly recommended after stent implantation. Although angiography is commonly considered a reference for defining restenosis, its invasive nature makes it inadequate in repeated assessments of vessel anatomy. A previous study showed that both nuclear scintigraphy and stress echocardiography are accurate methods for diagnosing restenosis. However, the cost and radiation exposure of nuclear scintigraphy limits its widespread clinical application. In addition, nuclear scintigraphy and stress echocardiography may provide insufficient sensitivity and low predictive value for the detection of restenosis, especially for lesions in the right coronary artery (RCA) and left circumflex coronary artery (LCX). To mitigate these disadvantages, a noninvasive, quantitative, and accurate method for the diagnosis of restenosis, especially in RCA and LCX lesions, may be of great value.
Coronary flow velocity reserve (CFR) is a useful index for the quantitative assessment of coronary stenosis. CFR is impaired by significant coronary stenosis and recovers after successful PCI. A previous study showed that CFR measurement can be used to evaluate restenosis in the left anterior descending coronary artery (LAD) after PCI. Recently, advances in transthoracic Doppler echocardiography (TTDE) have allowed the estimation of CFR not only in the LAD but also in the RCA and LCX to accurately detect coronary stenosis. However, limitations such as insufficient feasibility and time requirements because of interpatient variability hinder its clinical usefulness. Therefore, prior knowledge of a patient’s coronary anatomy, which can be obtained after initial coronary angiography, for detecting coronary flow might solve these problems. Considering that no previous studies have shown the applicability of CFR measurements to detect restenosis in the RCA and LCX and that this method might be more easily applied for detecting restenosis than for detecting stenosis before angiography, our objective was to determine the usefulness of measuring CFR by TTDE to detect restenosis in all 3 major coronary arteries: the LAD, RCA, and LCX.
Methods
Study Group and Protocol
Between March 2007 and October 2009, a total of 175 patients (130 men, 45 women; mean age, 69 ± 13 years) were consecutively recruited from a patient population referred to Osaka City University School of Medicine and Higashisumiyoshi Morimoto Hospital for follow-up coronary angiography and TTDE after undergoing stent implantation for angina pectoris. Stent implantation was successfully performed, with residual diameter stenosis < 50% by quantitative coronary angiography 6 months before TTDE. The day before each of the angiographic studies was conducted, CFR was noninvasively assessed by TTDE of the targeted arteries in which stents had been implanted 6 months previously. We ascertained that the patients selected for this study did not have heart failure, acute myocardial infarctions or unstable angina, severe left ventricular hypertrophy, congenital or valvular heart disease, or nonsinus rhythm. Of these 175 patients, 48 had histories of myocardial infarction. Use of standard anti-ischemic medications was continued during this study. All patients submitted their written consent for the study. The study was approved by the Osaka City University and Morimoto Hospital ethics committee.
TTDE
Echocardiography was performed with an Acuson Sequoia 512 (Siemens Medical Solutions USA, Inc, Mountain View, CA) with a high-frequency transducer (7V3c; Doppler frequency, 5 MHz) in the LAD and a low-frequency transducer (3V2c; Doppler frequency, 2 MHz) in the RCA and LCX, or with a Vivid 7 (GE Vingmed Ultrasound AS, Horten, Norway) with a broadband transducer in the LAD (M4S; Doppler frequency, 3.0 MHz) and in the RCA and LCX (M4S; Doppler frequency, 2.4 MHz). For color Doppler flow mapping, the velocity ranged from ±12 to ±25 cm/s. The color gain was adjusted to provide optimal images. In cases in which visualization of the color signal of the coronary flow was unsuccessful, an echocardiographic contrast agent (Levovist; Schering AG, Berlin, Germany) was used to improve signal visualization. On the basis of the results of a previous study, 7 mL of Levovist (300 mg/mL) was infused intravenously at a rate of 1 mL/min with an infusion pump. Before searching for coronary flows, we first studied the patient’s coronary anatomy by watching the coronary angiogram that was obtained 6 months previously.
To measure LAD flow, we located an acoustic window in the midclavicular line in the fourth or fifth intercostal space in the left lateral decubitus position. After the lower portion of the interventricular sulcus had been located in a long-axis cross-section, the ultrasound beam was inclined laterally. Next, coronary blood flow in the LAD (middle to distal) was measured using color Doppler flow mapping ( Video 1 ; 
view video clip online). After a sample volume (length, 1.5 mm) was positioned on the color signal in the LAD, coronary flow velocity was recorded by fast Fourier transformation analysis ( Figure 1 A). We tried to make the ultrasound beam as parallel to the LAD flow as possible.
To measure RCA flow, we selected the posterior descending coronary artery for color Doppler identification and flow velocity measurement. After an optimal two-dimensional image had been obtained in the apical 4-chamber view, the transducer was rotated in a counterclockwise manner until the posterior interventricular sulcus was clearly visualized. Next, the linear color signal, which persisted throughout the diastole, was searched carefully in the posterior interventricular sulcus under the guidance of Doppler color flow mapping ( Video 2 ; 
view video online). A sample volume (1.5-2.0 mm) was positioned on the color signal in the posterior descending coronary artery, after which point the coronary flow velocity was recorded by pulsed-wave Doppler echocardiography ( Figure 1 B).
To measure LCX flow, we searched Doppler flow signals in the LCX as the linear color signal persisted during diastole at the basal to the mid portion of the left ventricular lateral region in the apical 4-chamber view, avoiding the far apical portion, where a signal recorded could belong to a diagonal artery coming from the LAD ( Video 3 ; view video clip online). The reference structure was the lateral wall itself, where obtuse marginal arteries (distal LCX) run. Next, Doppler spectral tracings of the circumflex flow velocities were recorded with a sample volume positioned on the visualized color signal ( Figure 1 C). First, we recorded the baseline spectral Doppler signals in >5 cardiac cycles at end-expiration by TTDE. Then, we intravenously administered adenosine triphosphate (0.14 mg/kg body weight/min) for 2 minutes to record spectral Doppler signals. This allowed us to obtain the peak flow response induced by coronary microvessel dilation. Heart rate was monitored, and electrocardiography was performed continuously in all patients. Blood pressure was recorded at the baseline and every minute during adenosine triphosphate infusion. An experienced investigator who was blinded to all other data used the ultrasonographic system’s computer to obtain measurements offline by tracing the contour of the spectral Doppler signal. Mean diastolic velocities were measured at the baseline and at the peak flow response. Measurements were averaged over 5 cardiac cycles. CFR was defined as the ratio of mean diastolic velocity at the peak flow response to mean diastolic velocity at the baseline.
Follow-Up Coronary Angiography
Coronary angiography was performed in all patients 6 months after PCI using the Judkins technique within 24 hours after the CFR measurement. The severity of coronary artery stenosis at the previous intervention site was determined by quantitative coronary angiography (QCA-CMS 6.0; Medis Medical Imaging Systems, Leiden, The Netherlands) and expressed as the percentage of diameter stenosis. Restenosis was considered significant if a luminal narrowing of >50% was measured angiographically at the previous PCI site at the time of the 6-month follow-up examination.
Reproducibility of Data
Interobserver and intraobserver variability in CFR measurements were determined in 15 randomly selected vessels by repeated coronary flow recordings. Interobserver variability was calculated as the standard deviation of the differences between the measurements made by two independent observers who were unaware of the other patient data and was expressed as a percentage of the average value. Intraobserver variability was calculated as the standard deviation of the differences between the first and second measurements (2-week interval) for a single observer and was expressed as a percentage of the average value.
The mean absolute differences in CFR measurements were 4.0 ± 3.8% (interobserver) and 4.2 ± 3.9% (intraobserver), which were similar to the results of previous studies.
Statistical Analysis
Continuous variables are expressed as mean ± SD. Differences between groups were assessed using χ 2 tests or Fisher’s exact tests for categorical variables or unpaired Student’s t tests for continuous variables. Echocardiographic and hemodynamic variables during adenosine triphosphate infusion in each group were evaluated by two-way repeated-measures analysis of variance, testing for group effect, adenosine triphosphate effect, and interaction with post hoc Scheffé’s comparison. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated in the traditional manner to predict >50% luminal diameter narrowing in the previous PCI site by the 6-month follow-up examination. Diagnostic accuracy and a CFR cutoff value to predict restenosis in each of the 3 major coronary arteries were derived by receiver operating characteristic curve analysis. Differences were considered significant when the P value was <.05.
Results
Patient Characteristics
The clinical characteristics of the patients are presented in Table 1 . Coronary stents had been implanted in 238 angiographic lesions (106 in the LAD, 74 in the RCA, and 58 in the LCX) in 175 patients 6 months before this study. Multiple stents were implanted in 57 patients. All 175 patients underwent TTDE and coronary angiography at the scheduled time. Adequate spectral Doppler recordings of coronary flow were obtained in the case of 211 of the 238 angiographic lesions (89% feasibility). There was no between-study platform difference for obtaining adequate spectral Doppler recordings of coronary flow: feasibility was 86% for the Acuson Sequoia 512 and 90% for the Vivid 7. Adequate Doppler signals were obtained in 101 of 106 LAD lesions (95% feasibility), 63 of 74 RCA lesions (85% feasibility), and 47 of 58 LCX lesions (81% feasibility). A contrast agent was used for 38 angiographic lesions to improve Doppler signal visualization. Of 211 angiographic lesions, 37 lesions (14 in the LAD, 12 in the RCA, and 11 in the LCX) showed significant restenosis (>50%) and were classified into group A. The remaining 174 angiographic lesions (87 in the LAD, 51 in the RCA, and 36 in the LCX) showed no restenosis and were classified into group B ( Table 2 ). Lesion severity in group A increased from 19.2 ± 5.1% to 80.3 ± 8.5% over 6 months; this was significantly greater than the increase in lesion severity for group B (20.1 ± 5.3% to 31.2 ± 6.1%). One lesion in group A and 3 lesions in group B had new stenotic lesions proximal to the site where the stent was located before PCI.
| Variable | Value |
|---|---|
| Mean age (y) | 69 ± 13 |
| Men | 130 (74%) |
| Body mass index (kg/m 2 ) | 23.6 ± 3.4 |
| Multivessel disease | 63 (36%) |
| History of myocardial infarction | 48 (27%) |
| Diabetes mellitus | 85 (49%) |
| Hypertension | 129 (74%) |
| Hyperlipidemia | 124 (71%) |
| Smoking | 134 (77%) |
| Chest pain after initial PCI | 26 (15%) |
| Variable | Group A (n = 37) | Group B (n = 174) |
|---|---|---|
| Heart rate (beats/min) | ||
| Baseline | 63 ± 11 | 62 ± 11 |
| ATP infusion | 65 ± 11 | 63 ± 10 |
| Systolic blood pressure (mm Hg) | ||
| Baseline | 131 ± 20 | 127 ± 14 |
| ATP infusion | 129 ± 21 | 124 ± 15 |
| Diastolic blood pressure (mm Hg) | ||
| Baseline | 77 ± 11 | 73 ± 10 |
| ATP infusion | 75 ± 12 | 70 ± 12 |
| Mean diastolic velocity (m/s) | ||
| Baseline | 0.23 ± 0.06 | 0.20 ± 0.07 |
| ATP infusion | 0.40 ± 0.10 ∗ | 0.53 ± 0.21 |
| CFR | 1.70 ± 0.32 † | 2.65 ± 0.66 |
Hemodynamics and Coronary Flow Velocity Measurements at Rest and During Adenosine Triphosphate Infusion
None of the patients experienced serious adverse effects during the adenosine triphosphate infusion. All CFR measurements in each targeted coronary artery were completed within 20 minutes (average measuring time, 10.1 minutes). In each artery, the average time was 8.75 minutes in the LAD, 10.75 minutes in the RCA, and 11.75 minutes in the LCX. Two-factor repeated-measures analysis of variance showed no significant differences or interactions between heart rate, systolic blood pressure, and diastolic blood pressure between groups A and B during adenosine triphosphate infusion. Moreover, mean diastolic velocity at the baseline was not significantly different between groups A and B. However, there was a significant group effect and interaction effect with regard to the mean diastolic velocity between the two groups during adenosine triphosphate infusion ( P < .05; Table 2 ). In addition, a greater increase in mean diastolic velocity during adenosine triphosphate infusion was observed in group B than in group A ( P = .001; Table 2 ). Consequently, CFR was greater in group B than in group A ( P < .001; Table 2 , Figure 2 ). Twenty-five of the lesions in group A belonged to patients with chest pain. CFR was significantly lower in these lesions than in the lesions of patients without chest pain (1.60 ± 0.28 vs 1.91 ± 0.32). In each of the coronary arteries, CFR was greater in patients without restenosis than in patients with restenosis in all 3 arteries (2.72 ± 0.72 vs 1.67 ± 0.33 in the LAD, 2.54 ± 0.55 vs 1.74 ± 0.30 in the RCA, and 2.62 ± 0.67 vs 1.70 ± 0.36 in the LCX).
