Background
The aim of this study was to determine whether poststenotic diastolic-to-systolic velocity ratio (DSVR) assessed by transthoracic Doppler echocardiography could accurately identify significant stenoses in the left coronary artery.
Methods
A total of 108 patients scheduled for coronary angiography because of chest pain or acute coronary syndromes were studied.
Results
The success rates of peak DSVR (pDSVR) measurements in the distal to mid left anterior descending coronary artery and marginal branches of the left circumflex coronary artery were 85% and 32%, respectively. With peak coronary flow velocity reserve as a reference, pDSVR was significantly higher in arteries with normal coronary flow reserve (peak coronary flow velocity reserve ≥ 2.0) compared with arteries with reduced coronary flow reserve (peak coronary flow velocity reserve < 2.0) (1.86 ± 0.32 vs 1.53 ± 0.31, P < .0001). In comparison with quantitative coronary angiography, pDSVR was significantly higher in lesions with diameter stenosis < 50% compared with those with diameter stenosis of 50% to 75% (1.92 ± 0.32 vs 1.53 ± 0.18, P < .0001) or diameter stenosis of 76% to 100% (1.43 ± 0.13, P < .0001). Receiver operating characteristic curves showed pDSVR < 1.68 to be the optimal cutoff value for identifying both functionally significant stenoses and diameter stenoses ≥ 50%, with sensitivity of 86% and 90%, specificity of 74% and 84%, positive predictive value of 51% and 71%, and negative predictive value of 94% and 95%, respectively.
Conclusions
Transthoracic pDSVR measurements in the distal to mid left anterior descending coronary artery and marginal branches of the left circumflex coronary artery had high accuracy for excluding functionally significant stenoses in the left coronary artery, as well as for identifying angiographic significant stenoses.
Quantitative coronary angiography (QCA) has traditionally been the gold standard for assessing coronary artery disease, with a significant coronary stenosis generally defined as luminal diameter reduction ≥ 50%. However, it can be difficult to determine on angiography whether a stenosis causes ischemia or not. This distinction is important, because anatomically significant but functionally nonsignificant stenoses have a good prognosis without invasive treatment. Functionally nonsignificant stenoses are common in the borderline stenosis group (diameter stenosis, 50%–75%) and may as well be found among high-grade stenoses (diameter stenosis, 76%–100%), with a recent study showing that 65% of lesions with diameter stenosis of 50% to 70% and 20% of lesions with diameter stenosis of 71% to 90% were without functional significance. Other testing options are therefore important in the selection for coronary angiography and to distinguish functionally significant from nonsignificant coronary stenoses, with fractional flow reserve as a probable reference for the functional evaluation of a coronary stenosis. Coronary flow velocity reserve (CFVR) assessed using Doppler transthoracic echocardiography (TTE) has recently been shown to be a noninvasive surrogate of fractional flow reserve, especially in the detection of a functionally nonsignificant lesion. Normal coronary arteries display a predominant diastolic blood flow pattern, which is less marked in the distal right coronary artery (RCA), probably because of lower intramyocardial systolic contraction pressure in the right ventricle. Several studies have shown that in the presence of a significant coronary stenosis, the ratio between the diastolic and systolic coronary blood flow velocities, diastolic-to-systolic velocity ratio (DSVR), is significantly reduced when invasively measured distally to the stenosis. This reduction is postulated to be caused by a combined poststenotic decrease of diastolic flow and an increased systolic flow from an intramyocardial systolic contraction pump acting on the intramyocardial capacitance vessels. Modern high-end echocardiographic equipment permits excellent imaging of coronary artery blood flow, allowing measurements of coronary blood flow profiles. Recent reports have indicated that findings of reduced DSVR measured by TTE in the distal left anterior descending coronary artery (LAD) may be a simple, noninvasive method for the detection of high-grade coronary stenoses located more proximally in the LAD. This is demonstrated for patients with or without wall motion abnormalities of the left ventricle, and peak DSVR (pDSVR) values < 1.6 to 1.8 are proposed to represent high-grade LAD stenoses. However, there is a paucity of studies comparing LAD pDSVR obtained by TTE with various degrees of stenosis in the LAD and the left main coronary artery (LM) as defined by QCA, and pDSVR measurements in marginal branches of the left circumflex coronary artery (CxMb) might be used for evaluating coronary disease in the left circumflex coronary artery (Cx) and LM. Furthermore, the functional significance of pDSVR requires further validation, and this parameter could be useful in the evaluation of borderline coronary stenoses. Because the normal pDSVR in the distal RCA is low and probably close to pathologic values, the potential utility of distal pDSVR measurements seems primarily to be in the evaluation of possible upstream stenoses in the LAD and Cx.
The aim of this study was to assess the feasibility and accuracy of pDSVR measurements on TTE as a simple method for diagnosing significant stenoses in the LM, LAD, and Cx, using QCA and CFVR measured by TTE as the anatomic and functional references, respectively.
Methods
Study Population
Patients were included in the study if they fulfilled the following criteria: (1) already scheduled for coronary angiography because of documented or suspected stable or unstable coronary disease, (2) age > 18 years, and (3) met no exclusion criteria. The exclusion criteria were (1) previous aortocoronary bypass surgery, (2) presumed insufficient acoustic windows because of severe emphysema or severe overweight, (3) significant valvular disease, (4) atrial fibrillation, and (5) administrative reasons.
The study protocol was approved by the Regional Committee for Medical and Health Research Ethics and the Norwegian Data Inspectorate. All participants gave written informed consent. This study is registered at ClinicalTrials.gov under identifier NTC00281346 .
A total of 108 patients were included in the study, and this patient cohort has been previously presented. Clinical characteristics of the patients are presented in Table 1 . All patients took their medications on the day of the echocardiographic study. Standard 12-lead electrocardiograms were recorded in all patients.
| Variable | Value |
|---|---|
| Age (y) | 63.1 ± 9.5 |
| Heart rate (beats/min) | 63 ± 7.4 |
| BMI (kg/m 2 ) | 26 ± 3.6 |
| Men | 79 (73%) |
| Total cholesterol (mmol/L) | 4.9 ± 1.1 |
| Blood pressure (mm Hg) | |
| Systolic | 142 ± 20 |
| Diastolic | 82 ± 12 |
| Medical history | |
| Hypertension (>140/90 mm Hg) | 61 (55%) |
| Current smoking | 29 (27%) |
| Diabetes | 11 (10%) |
| Previous CAD | 23 (21%) |
| ACS | 35 (32%) |
| Cardiac medication | |
| Aspirin | 97 (90%) |
| Thienopyridine | 38 (35%) |
| Low–molecular weight heparin | 30 (28%) |
| β-blockers | 85 (79%) |
| Statins | 87 (81%) |
| Calcium antagonists | 21 (19%) |
| ACE inhibitors/ARBs | 24 (22%) |
| Organic nitrates, daily maintenance | 13 (12%) |
Transthoracic Coronary Flow Measurements
Patients were examined using an Acuson Sequoia C512 (Siemens Medical Solutions USA, Inc., Mountain View, CA) ultrasound system connected to standard 4V1C and 7V3C transthoracic transducers. Contrast agent was not used. TTE with CFVR measurements was not performed earlier than the day after hospital admission and only after the patients were clinically stable. The coronary arteries were investigated using color Doppler mapping with the data postprocessing mix function, which makes the colors transparent, as described previously. The velocity scale of color Doppler was set to 0.24 m/sec but was actively changed to provide optimal images. With the patient in the left lateral decubitus position, the course of the mid and distal LAD could be seen from modified parasternal short-axis and long-axis views or from modified apical two-chamber and three-chamber views, focusing on the anterior interventricular sulcus ( Figure 1 A1). From modified left parasternal short-axis and long-axis views, the Cx could be imaged leaving the LM and further coursing caudally in the atrioventricular sulcus to the inferior margin of the sulcus. However, measurements of flow velocities in the main trunk of the Cx are difficult because of cyclic cardiac motion. Marginal branches of the Cx leave the artery at various levels, and from modified apical four-chamber views focusing on different levels of the lateral wall of the left ventricle, marginal branches could be visualized coursing in the distal direction on the epicardial surface toward the transducer ( Figure 1 B1). Measurements of coronary flow velocities in marginal branches are less influenced by cardiac cyclic motion. Whenever possible, the most inferior marginal branch viewed was used for measurements. Echocardiographic evaluation of regional left ventricular contractility was not part of the study protocol, but regional contractility was assessed in 30 of 35 patients (86%) with and in 32 of 73 patients (44%) without unstable coronary disease.
The coronary flow velocity waveform appears as a complex of a small wave in systole and a large trapezoid wave in diastole ( Figures 1 A2 and 1 B2). Blood flow velocities in the distal LAD and CxMb were measured using pulsed-wave Doppler at frequencies of 1.75 to 3.5 MHz in a sample volume of 1.5 to 5 mm, with the sample volume positioned on the laminar color flow Doppler signal. The sample volume was positioned distally to any visualized turbulent color flow Doppler signal, because turbulent color flow Doppler signals might represent stenosis. The level of the left ventricular papillary muscles marked the division between the mid and distal segments of the LAD, and the distal portion of the mid segment of the LAD was used for DSVR measurements if the distal LAD could not be visualized. We tried to find at least three consecutive cardiac cycles for measurements of diastolic and systolic peak flow velocities. Angle correction was used during velocity measurements to keep the angle between coronary blood flow and the Doppler beam as small as possible. The ratio between the peak diastolic and peak systolic velocities was measured in each cardiac cycle ( Figures 1 A2 and 1 B2), and the average of these peak velocity ratios measured in the consecutive cycles was the pDSVR.
For each segment (distal to mid LAD, CxMb), four different outcomes were defined: (1) the coronary segment was defined with retrograde flow; (2) the coronary segment was not visualized; (3) the coronary artery was defined with antegrade flow, with pDSVR impossible to measure; or (4) pDSVR was satisfactorily measured. Stop-motion frames and clips were digitally recorded for offline analysis.
CFVR was measured in the distal to mid LAD and in the CxMb, as described previously. In brief, blood flow velocities were measured using pulsed-wave Doppler, with measurements both at baseline and during the intravenous infusion of adenosine (0.14 mg/kg/min over 2 min). CFVR was calculated as the ratio of hyperemic to basal peak (pCFVR) diastolic flow velocities. A predefined pCFVR value < 2.0 was used as a cutoff value for functionally significant stenosis, in accordance with earlier studies. Peak CFVR findings were categorized in one of two groups: (1) pCFVR ≥ 2.0, indicating no functionally significant stenosis, or (2) pCFVR < 2.0, indicating functionally significant stenosis. The same CxMb were used for pDSVR and CFVR measurements. If retrograde coronary artery flow was found, we concluded that the artery was occluded more proximally, and pDSVR and CFVR measurements were not performed.
Coronary Angiography
Coronary angiography was performed using standard techniques. All angiographic studies were digitally stored for later offline reviewing and measurements, blinded to the findings on TTE. Disagreements in interpretation were resolved by consensus between the two cardiologists responsible for the angiographic readings. The angiograms were analyzed using a 16-segment model of the coronary arteries. All angiograms were classified according to left or right dominance. The severity of coronary stenoses in the LM, LAD, and Cx was determined by QCA, with each segment categorized in one of three groups: (1) diameter stenosis of 0% to 49%, (2) diameter stenosis of 50% to 75%, or (3) diameter stenosis of 76% to 100%. Collateral flow to the occluded LAD and Cx was graded according to the Rentrop classification.
Reproducibility
To assess interobserver measurement variability, two experienced observers (E.H. and J.V.) evaluated data from 13 random cases in a blinded manner. Intraobserver variability was similarly tested by one experienced observer (E.H.) 2 weeks apart, blinded to previous results. For the reproducibility studies, four separate coronary flow velocity waveform recordings were selected for measurements in each patient. Interobserver and intraobserver measurement variability was expressed as the mean difference as a percentage and the coefficient of variation of the differences between the measurements for each parameter.
Statistical Analysis
Continuous variables are presented as mean ± SD and categorical variables as fractions and percentages. Comparisons of mean values were performed using Student’s t tests for normally distributed parameters. Logistic regression analyses were used to explore relationships between the success rate for pDSVR measurements and demographic and clinical variables. Linear regression analyses were used to explore the relationships between coronary flow measurements (systolic and diastolic peak flow velocities and pDSVR) and baseline characteristics. Receiver operating characteristic (ROC) curve analysis was used to assess the optimal cutoff value of pDSVR. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to detect significant coronary disease defined as diameter stenosis ≥ 50% or pCFVR < 2.0 in the presence of the optimal pDSVR cutoff value were assessed using standard formulas. P values < .05 were considered statistically significant. All analyses were performed with SPSS for Windows version 15.0 (SPSS, Inc., Chicago, IL).
Results
QCA
There were 35 patients with and 73 patients without unstable coronary disease ( Table 1 ). For stable patients, the mean time from echocardiographic examination to angiography was 24.7 ± 31.7 days. In the group with unstable coronary disease, the mean time from echocardiographic examination to coronary angiography was 9.5 ± 23.1 days. However, two patients in this group had longer delays for coronary angiography because of intercurrent disease, and the mean time from echocardiographic examination to angiography was 4.3 ± 3.4 days for the remaining 33 patients. Table 2 lists findings on QCA for stenoses in the LM, LAD, and Cx (segments 5–8, 11, 13, and 16 in the American Heart Association’s 16-segment model ) in groups 2 and 3.
| Segment | Stenosis group 2 (DS, 50%–75%) | Stenosis group 3 (DS, 76%–100%) |
|---|---|---|
| LM | 4 | 0 |
| Proximal LAD | 21 | 12 |
| Mid LAD | 15 | 5 |
| Distal LAD | 4 | 2 |
| Proximal Cx | 6 | 4 |
| Mid Cx | 5 | 5 |
| Distal Cx | 3 | 2 |
Feasibility of pDSVR Measurements
For patients with unstable coronary disease, the mean time from symptom onset to pDSVR measurements was 3.9 ± 3.0 days. Table 3 presents the artery-based study protocol and results. Retrograde flow was identified by TTE in the distal to mid LAD in two patients and in the CxMb in one patient. Coronary angiography confirmed the findings of retrograde flow, with Rentrop grade ≥ 2 collateral circulation in all patients. Peak DSVR was satisfactorily measured in the distal to mid LAD and CxMb in 90 (85%) and 34 (32%) patients, respectively, with numbers in parentheses denoting the percentages of patients with pDSVR measurements among patients without retrograde flow in the relevant coronary artery segment. Peak DSVR was satisfactorily measured in both coronary territories in 28 patients (26%). The only baseline variables ( Table 1 ) related to the success rate of pDSVR measurements were age (positive relation to LAD measurements) and current smoking (inverse relation to CxMb measurements). The mean angle corrections used for pDSVR measurements in the distal to mid LAD and CxMb were 26 ± 11° and 19 ± 12°, respectively.
| Segment | Outcome 1 ∗ | Outcome 2 † | Outcome 3 ‡ | Outcome 4 § | Total |
|---|---|---|---|---|---|
| Distal to mid LAD | 2 | 1 | 15 | 90 | 108 |
| CxMb | 1 | 39 | 34 | 34 | 108 |
∗ The coronary segment was defined with retrograde flow.
† The coronary segment was not visualized.
‡ The coronary artery was defined with antegrade flow, with pDSVR impossible to measure.
Peak DSVR Compared with Angiography
On QCA, each main coronary artery could have more than one stenosis, with the most tight stenosis defining the degree of stenosis. Peak DSVR in the distal to mid LAD evaluates both the LAD and the LM because of the functional unity of the LAD and the LM, and findings for these two vessels were therefore analyzed together. Distal branches from the Cx were more difficult to visualize by TTE than the more proximal branches, thus implying that the CxMB pDSVR measurements primarily evaluated stenoses in the proximal and mid segments of the Cx and less often stenoses in the distal segment of the Cx. Hence, stenoses in the distal segment of the Cx (segment 15 in the American Heart Association’s 16-segment model ) were excluded from pDSVR CxMb analyses, with the proximal and mid segments of the Cx and the LM analyzed together because of functional unity.
Among coronary arteries with pDSVR measurements, 26 arteries (23 LADs and LMs and three proximal and mid segments of the Cx and LM) had stenoses in group 2, and 13 arteries (11 LADs and LMs and two proximal and mid segments of the Cx and LM) had stenoses in group 3. Systolic and diastolic peak flow velocities are listed in Table 4 , with corresponding pDSVR measurements. Because of the small number of CxMb measurements, the results are presented for both arteries together. No statistical differences were found between peak diastolic flow velocities (PDVs) in groups 1 (0.36 ± 0.12 m/sec), 2 (0.36 ± 0.10 m/sec), and 3 (0.34 ± 0.11 m/sec). Peak systolic flow velocity (PSV) was significantly lower in group 1 compared with group 2 (0.19 ± 0.06 vs 0.23 ± 0.06 m/sec, P = .002) and group 3 (0.24 ± 0.08 m/sec, P = .008), with no statistical difference between groups 2 and 3 ( P = .75). Peak DSVR was 1.92 ± 0.32 in group 1, significantly higher than in groups 2 (1.53 ± 0.18) and 3 (1.43 ± 0.13) ( P < .0001 for both). The difference between groups 2 and 3 did not reach statistical difference ( P = 0.077). The ROC curve for pDSVR for the detection of diameter stenosis ≥ 50% (groups 2 and 3 combined) is shown in Figure 2 .
