Acceleration Time of Systolic Coronary Flow Velocity to Diagnose Coronary Stenosis in Patients with Microvascular Dysfunction Kazushi Takemoto, BSc, Kumiko Hirata, MD, PhD, Nozomi Wada, MD, Yasutsugu Shiono, MD, Kenichi Komukai, MD, PhD, Takashi Tanimoto, MD, PhD, Yasushi Ino, MD, PhD, Hironori Kitabata, MD, PhD, Shigeho Takarada, MD, PhD, Nobuo Nakamura, MD, PhD, Takashi Kubo, MD, PhD, Atsushi Tanaka, MD, PhD, Toshio Imanishi, MD, PhD, and Takashi Akasaka, MD, PhD, Wakayama, Japan

Background: The aim of this study was to test whether acceleration time of systolic coronary flow velocity could contribute to the diagnosis of coronary stenosis in patients with microvascular dysfunction, on the basis of the hypothesis that systolic coronary flow is less influenced by microvascular function because of compressed myocardium. Methods: Coronary flow velocity was assessed in the left anterior descending coronary artery during hyperemia with intravenous adenosine by echocardiography in 502 patients who were scheduled for coronary angiography because of coronary artery disease and significant valvular disease. Coronary flow velocity reserve (CFVR) and the percentage acceleration time (%AT), as the percentage of the time from the beginning to the peak of systolic coronary flow over systolic time during hyperemia, were calculated. The diagnostic ability of CFVR and %AT for angiographic coronary artery stenosis was then analyzed. As invasive substudies, fractional flow reserve and %AT by a dual-sensor (pressure and Doppler velocity) guidewire were measured simultaneously with %AT on transthoracic echocardiography (n = 14). Results: Patients with coronary stenosis had significantly lower CFVR (1.7 6 0.4) and greater %AT (65 6 9%) compared with those without stenosis (2.6 6 0.6 and 50 6 13%, respectively). Percentage acceleration time by Doppler echocardiography was in good agreement with %AT (r = 0.98) and fractional flow reserve (r = 0.74) invasively measured by dual-sensor guidewire. Cutoff values of CFVR and %AT were determined as 2.0 and 60% in receiver operating characteristic curve analysis. The sensitivity, specificity, and accuracy of CFVR to detect coronary stenosis were 71.1%, 77.3%, and 75.4%, while those of %AT were 83.4%, 71.8%, and 75.4%, respectively. In addition, %AT provided high accuracy to detect coronary stenosis, especially in patients with previous myocardial infarctions, valvular disease, and left ventricular hypertrophy (81.1%, 84.1%, and 73.4%, respectively). Conclusions: The %AT of systolic coronary flow velocity is a promising marker to diagnose coronary stenosis in patients with microvascular dysfunction. (J Am Soc Echocardiogr 2014;27:200-7.) Keywords: Echocardiography, Coronary flow

Coronary flow velocity reserve (CFVR) by transthoracic echocardiography has been considered a useful diagnostic index for functional and physiologic assessment of coronary circulation.1-4 Clinical application of CFVR is limited to patients without microvascular dysfunction because it is altered either by the presence of epicardial coronary artery stenosis or an abnormality of the coronary microcirculation.5-8 In the clinical setting, patients with epicardial coronary stenosis commonly have one or more additional factors affecting the From the Department of Medicine, Wakayama Medical University, Wakayama, Japan. Reprint requests: Kumiko Hirata, MD, Division of Cardiology, Department of Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Japan 6418509 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2013.10.013

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microvasculature. Therefore, a noninvasive and physiologic method allowing the assessment of coronary stenosis in patients with microvascular dysfunction is needed. Previous studies have demonstrated that the acceleration time of systolic flow velocity is proportional to the severity of stenosis in peripheral arteries.9-11 However, the relationship between systolic acceleration time and the severity of coronary stenosis has not been investigated. Unlike peripheral arteries, flow velocity in the coronary arteries could be influenced by coronary microvasculature; moreover, microvascular resistance is increased with an increase in the severity of coronary stenosis in patients without collateral flow.12 In view of the fact that the myocardium thickens in systole, compressed intramyocardial microvessels thus lead to significantly diminished microvascular blood flow.13 Therefore, epicardial systolic coronary flow would be less influenced by microvascular circulation. We sought to investigate whether systolic acceleration time of coronary flow velocity could be useful to diagnose coronary artery

Journal of the American Society of Echocardiography Volume 27 Number 2

Abbreviations

AS = Aortic stenosis AUC = Area under the curve CFVR = Coronary flow velocity reserve FFR = Fractional flow reserve LV = Left ventricular

stenosis in patients with microvascular dysfunction. In the present study, systolic acceleration time was measured during hyperemia to improve the resolution of the spectral tracing. METHODS

Study Population We enrolled 502 patients who ejection fraction were scheduled for diagnostic corLVH = Left ventricular onary angiography from January hypertrophy 1, 2008, to February 28, 2011. MI = Myocardial infarction They were admitted to our hospital for the assessment of heart dis%AT = Percentage ease, including significant valvular acceleration time disease and coronary artery dis%DS = Percentage diameter ease. Comprehensive echocardiostenosis graphic examinations and coronary flow assessments were ROC = Receiver operating performed in all patients 1 month).14 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. LVEF = Left ventricular

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).15 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/m2 in men and >120 g/m2 in women.16 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.17,18 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

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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 1A). 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.19 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 1B). 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 dualsensor (pressure and Doppler velocity) guidewire (ComboWire; Volcano Therapeutics, Rancho Cordova, CA) were measured simultaneously with %AT by transthoracic echocardiography.20 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 %ATand CFVR were 5.1 6 4.7% and 4.2 6 3.9% (interobserver) and 4.9 6 4.7% and 4.0 6 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 6 SD and were compared across groups using analysis of variance with Scheffe’s post hoc comparison. Categorical data are presented as absolute values and percentages, and they were compared using c2 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

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Journal of the American Society of Echocardiography February 2014

Figure 1 (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.

Figure 2 Patient flow diagram. Among the 502 patients who were scheduled for coronary angiography, 36 were excluded. The remaining 466 patients completed the entire protocol. As invasive substudies (dotted frame), we additionally performed simultaneous %AT measurement by echocardiography and %AT and FFR measurement by dual-sensor guidewire (n = 14). 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. RESULTS A total of 466 of 502 enrolled patients (93%) underwent the study (Figure 2). Twenty-five patients were excluded because of

low resolution of systolic flow profile recordings. An additional six were excluded because of retrograde LAD flow, along with five with no coronary signal in anterior interventricular sulcus, of which total LAD occlusion by coronary angiography was found in the former six and two in the latter case. In 466 patients, 212 with previous MIs, 75 with valvular disease (41 with aortic stenosis [AS], seven with aortic regurgitation, 24 with mitral regurgitation, and three with mitral stenosis) and 66 with LV hypertrophy (LVH) were included. With regard to previous MI, culprit vessels were the LAD in 103 patients and the right coronary artery or circumflex branches in 109.

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Table 1 Baseline characteristics and quantitative coronary angiographic analysis of the LAD Variable

Age (y) Men Diabetes mellitus Hypertension Dyslipidemia Smoking NYHA class II Comorbidities MI Valvular disease LVH Coronary angiography %DS (%) Reference diameter (mm) Minimum lumen diameter (mm) Lesion length (mm) Multiple lesions Echocardiographic data LVDd (mm) LVDs (mm) IVSWT (mm) PWT (mm) LVEDV (mL) LVESV (mL) LVEF (%) LVMI (g/m2) LAVI (mL/m2)

%DS $ 50% (n = 147)

%DS < 50% (n = 319)

69 6 9 110 (75%) 57 (39%) 99 (67%) 75 (51%) 56 (38%) 13 (11%)

67 6 12 220 (70%) 85 (27%) 188 (59%) 138 (44%) 82 (26%) 50 (15%)

.800 .196 .008 .177 .119 .317 .074

63 (43%) 10 (7%) 16 (11%)

149 (48%) 65 (20%) 50 (16%)

.437 .001 .208

26 6 13 3.0 6 0.6 2.2 6 0.7