Study Population

We enrolled 502 patients who were scheduled for diagnostic coronary angiography from January 1, 2008, to February 28, 2011. They were admitted to our hospital for the assessment of heart disease, including significant valvular disease and coronary artery disease. Comprehensive echocardiographic examinations and coronary flow assessments were performed in all patients <48 hours before coronary angiography. Coronary flow studies by transthoracic echocardiography only were also performed in 10 healthy volunteers with no obvious ischemia as determined by exercise echocardiography (mean age, 35 ± 9 years; seven men). Exclusion criteria were acute coronary syndromes, congestive heart failure or nonsinus rhythm, and contraindication to adenosine (asthma, high-degree atrioventricular block). Prior myocardial infarction (MI) was defined as a history of MI (>1 month). The study protocol was approved by the local ethics committee, and written informed consent was obtained. All patients continued their medications on the day of echocardiographic examination and coronary angiography.

Echocardiography

Left ventricular (LV) diameters were measured on two-dimensional images. LV ejection fraction (LVEF) and left atrial volume were calculated using the biplane modified Simpson’s rule using apical four-chamber and two-chamber views. LV mass was calculated using the Devereux formula indexed to body surface area (LV mass index). Diastolic parameters using transmitral flow patterns and mitral annular velocities were also determined. Patients were considered to have ventricular hypertrophy when LV mass index was >150 g/m ² in men and >120 g/m ² in women.

Measurement of Coronary Flow Velocity

Coronary flow velocity was recorded using a Vivid 7 system (GE Healthcare, Milwaukee, WI) along with a 4-MHz transducer after an overnight fast and abstention from any beverages containing significant amount of flavonoids for 48 hours to avoid the effects of flavonoids on improving coronary endothelial function. First, we assessed blood flow in the left anterior descending coronary artery (LAD), which appears as a red color signal in the anterior interventricular sulcus during diastole, using Doppler color flow mapping. Second, we positioned the sample volume on the color signal in the distal LAD and measured coronary flow velocities by pulsed-wave Doppler echocardiography.

Doppler flow velocity recording in the LAD was performed at baseline and during hyperemia, which was induced by intravenous adenosine triphosphate administration (0.14 mg/kg/min). Heart rate and blood pressure were monitored continuously during the examination. Coronary flow velocities were measured offline by tracing the spectral Doppler signals (EchoPAC version 6.1; GE Vingmed Ultrasound AS, Horten, Norway). Mean diastolic flow velocities at baseline and hyperemia were averaged over three consecutive cycles. CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocities. Systolic coronary flow velocities during hyperemia were assessed offline as well. Acceleration time was determined as the time from the beginning to the peak systolic flow and percentage acceleration time (%AT) was defined as (acceleration time/systolic time) × 100 ( Figure 1 A ).

(A) Acceleration time (AT) was determined as time from the beginning to the peak systolic flow (A), and %AT was defined as AT/systolic time (B) × 100. (B) Examples of coronary flow velocity recordings by dual-sensor guidewire in the distal LAD during hyperemia before ( left ) and after ( right ) coronary intervention. Percentage AT of the systolic flow velocity decreased after coronary intervention. PCI , Percutaneous coronary intervention.

Coronary Angiography

All patients received an intravenous bolus injection of heparin 3,000 IU and intracoronary isosorbide dinitrate 2 mg before angiography. Quantitative coronary angiographic analysis was performed offline in multiple projections using a guiding catheter to calibrate magnification, as previously described. The analyses were performed by 2 independent observers who were completely blinded to any patient information. Significant coronary stenosis was defined as ≥50% luminal diameter narrowing on the angiogram.

As invasive substudies, %AT was measured using a Doppler flow guidewire (FloWire; Volcano, San Diego, CA) positioned in the distal LAD and compared with simultaneously determined %AT by transthoracic echocardiography in 14 patients ( Figure 1 B). In addition, to assess the effect of adenosine on %AT, we made a comparison of %AT values at rest and during hyperemia using the dual-sensor guidewire recordings.

Fractional flow reserve (FFR) and %AT using a 0.014-inch dual-sensor (pressure and Doppler velocity) guidewire (ComboWire; Volcano Therapeutics, Rancho Cordova, CA) were measured simultaneously with %AT by transthoracic echocardiography. FFR was calculated as dividing the mean distal coronary pressure measured with the dual-sensor guidewire by the mean aortic pressure measured through the guide catheter.

Reproducibility

Interobserver and intraobserver variability in coronary flow velocity measurements were determined in 40 randomly selected patients. Interobserver variability was calculated as the standard deviation of the absolute differences between the measurements made by two independent observers who were blinded to patient information. Intraobserver variability was also calculated as the standard deviation of the absolute differences between the first and second measurements (2-week interval) for a single observer. Variability is expressed as a percentage of the average value. The mean absolute differences in %AT and CFVR were 5.1 ± 4.7% and 4.2 ± 3.9% (interobserver) and 4.9 ± 4.7% and 4.0 ± 3.8% (intraobserver), respectively.

Statistical Analysis

All analyses were conducted using SPSS for Windows version 13.0 (SPSS, Inc, Chicago, IL). Continuous data are expressed as mean ± SD and were compared across groups using analysis of variance with Scheffé’s post hoc comparison. Categorical data are presented as absolute values and percentages, and they were compared using χ ² tests. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive performance of CFVR and %AT to coronary stenosis in sequential patients enrolled from January 1 to December 31, 2008 (a derivation cohort). The diagnostic accuracy of CFVR and %AT for coronary artery stenosis was analyzed using the determined cutoff value by ROC curve analysis in sequential patients from January 1, 2009, to February 28, 2011 (a test cohort). P values < .05 were considered statistically significant.

Baseline Characteristics and Echocardiographic Data

Table 1 presents general baseline characteristics and echocardiographic data of the patients with percentage diameter stenosis (%DS) ≥50% and <50%. Patients with %DS ≥ 50% were more likely to have hypertension than those with %DS < 50%. Regarding New York Heart Association classification, there was no patients in class III or IV and no difference in the frequency of class II between two groups. All echocardiographic measurements were similar in the two groups.

Coronary Angiographic Findings

Coronary angiography revealed significant stenosis of the LAD in 147 of 466 patients (32%). The lesion lengths of the group with %DS ≥ 50% were longer than those in the group with %DS < 50% ( Table 1 ). Multiple lesions were found more frequently in the group with %DS ≥ 50% than the group with %DS < 50%. In addition, to assess the effect of lesion characteristics on CFVR and %AT, we compared data of multiple lesions with those of focal lesions in 142 of 466 patients with intermediate stenosis (%DS, 40% to 70%). We found impaired CFVR (2.0 ± 0.5) and %AT (68 ± 10%) in 66 patients with multiple lesions in comparison with 76 patients with focal lesions (2.5 ± 0.8 and 59 ± 10%, P = .02 and P = .004, respectively), while %DS was similar in both groups (multiple vs focal, 59 ± 10% vs 57 ± 9%).

To determine the reliability of transthoracic echocardiography in %AT measurements, we additionally performed intracoronary flow studies in 14 patients with various levels of severity of coronary stenosis. The results revealed that %AT measured by transthoracic echocardiography is indeed consistent with invasively measured %AT ( r = 0.98, P < .0001; Figure 3 A ). The systolic flow velocity analysis using dual-sensor guidewire recordings revealed that resting %AT (57 ± 10%) did not change significantly during hyperemia (56 ± 11%), while systolic peak velocity changed from 13 ± 9 to 27 ± 14 cm/sec.

Relationship between invasive (by dual-sensor guidewire) %AT and noninvasive %AT (by echocardiography) (A) and relationship between invasive %AT and FFR (B) .

In addition, %AT decreased in inverse proportion to FFR ( r = 0.74, P = .014; Figure 3 B). Consequently, we assessed the feasibility of %AT by transthoracic echocardiography to diagnose coronary stenosis in the clinical settings.

Coronary Flow Velocity Measurements

Analysis of coronary flow velocity measurements in 466 patients revealed severely reduced CFVR (1.7 ± 0.4) and prolonged %AT (65 ± 9%) in patients with %DS ≥ 50%. Patients with %DS < 50% had higher CFVR (2.6 ± 0.6) and shorter %AT (50 ± 13%) compared with those with %DS < 50% ( Figure 4 ). Percentage acceleration time was proportional to %DS as well ( Figure 5 ).

Coronary flow velocity recordings by transthoracic Doppler echocardiography in patients without coronary stenosis (A) , with stenosis (B) , and with AS and no coronary stenosis (C) . Acceleration time of systolic flow is prolonged in the patient with stenosis (B) but is not prolonged in those without stenosis (A) and with AS and no stenosis (C) . The yellow arrow indicates peak systolic flow.

Relationship between %DS and %AT. Percentage acceleration time is directly proportional to %DS.

Moreover, although healthy subjects showed higher CFVR (3.3 ± 0.7) than those with %DS < 50%, there was no significant difference in %AT (in healthy subjects, 48 ± 10%). There were no significant differences in blood pressure and heart rate at baseline and during hyperemia ( Table 2 ). To assess the effect of LV systolic function on %AT, we divided the 466 patients into two groups: 246 with LVEFs > 55% and 220 with LVEFs ≤ 55%. These two groups had similar %DS (39.6 ± 23.4% and 38.1 ± 21.9%, respectively, P = .48). However, the patients with LVEFs ≤ 55% had lower CFVR (2.3 ± 0.8) than those with LVEFs > 55% (2.5 ± 0.8, P = .005), whereas no difference in %AT (LVEF > 55% vs ≤ 55%, 54 ± 13% vs 53 ± 14%; P = .51).

Table 2

Hemodynamics and coronary flow velocity measurements

Variable	%DS ≥ 50%		%DS < 50%
	Baseline	Hyperemia	Baseline	Hyperemia
Heart rate (beats/min)	65 ± 11	66 ± 12	69 ± 14	69 ± 13
Systolic BP (mm Hg)	117 ± 19	114 ± 19	116 ± 19	111 ± 20
Diastolic BP (mm Hg)	59 ± 11	56 ± 13	61 ± 13	58 ± 12
MDV (cm/sec)	25 ± 14	41 ± 22	22 ± 8	57 ± 19
CFVR	1.7 ± 0.4 ∗		2.6 ± 0.6
%AT	65 ± 9 ∗		50 ± 13

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