Assessment of Coronary Flow Reserve by Transesophageal Echocardiography in Cardiac Transplant Recipients

Assessment of Coronary Flow Reserve by Transesophageal Echocardiography in Cardiac Transplant Recipients Philippe Unger, MD, Nicolas Preumont, MD, Jean-Luc Vachie´ry, MD, Marc Bougard, MD, Philippe Damhaut, PhD, Serge Goldman, MD, and Guy Berkenboom, MD, Brussels, Belgium

This study investigated the feasibility of dipyridamole Doppler transesophageal echocardiography to assess coronary flow reserve in 26 patients with orthotopic heart transplantation and compared it with positron emission tomography. We found an 85% success rate in obtaining Doppler flow signals in the proximal left anterior descending coronary artery. Our data also showed that the correlation between transesophageal echocardiography

Evaluation of coronary flow reserve (CFR) is increasingly used for functional assessment of various cardiac diseases. Current methods of measurement, involving either catheter techniques or positron emission tomography (PET), are invasive or require extensive and costly laboratory equipment. Transesophageal Doppler echocardiography (TEE) has emerged as an alternative method to evaluate blood flow velocities and CFR in the left coronary system. The procedure involves the use of pharmacologic agents such as dipyridamole or adenosine as coronary vasodilators.1,2 Measurements of resting and maximal blood flow velocities are performed in the proximal left anterior descending coronary artery or in the coronary sinus.1,2 Cardiac allograft vasculopathy is a major problem after heart transplantation.3 It is therefore important to assess this form of coronary artery disease by a less invasive method, ensuring a safe follow-up. The aims of this study were (1) to establish the feasibility of TEE to assess CFR in orthotopic cardiac transplantation recipients and (2) to compare TEEderived CFR to measurements of myocardial perfusion reserve corresponding to the territory supplied

and dipyridamole N-13 ammonia positron emission tomography increases when respective resting rate-pressure products are taken into account. However, comparison between the two methods should be made with caution because coronary flow reserve derived from transesophageal echocardiography tends to be higher than that obtained with positron emission tomography. (J Am Soc Echocardiogr 1998;11:612-9.)

by the left anterior descending artery derived from N-13 ammonia PET.

METHODS Study Patients Twenty-six patients (22 men and 4 women) undergoing routine coronary angiography 44 6 39 months (range 12 to 129) after orthotopic heart transplantation were studied. The mean age was 53.5 6 11.6 years (range 22 to 69). The mean left ventricular ejection fraction was 57% 6 10% (range 35% to 78%). TEE and PET studies were performed within 8 weeks of angiography, and the mean time interval elapsed between TEE and PET studies was 11 6 16 days. At the time of angiography, no patient had biopsy-documented signs of rejection (grade ,2, International Society for Heart and Lung Transplantation grading system).4 All patients were in stable condition within the study period. All drugs (except for immunosuppressive therapy) were discontinued 12 hours before TEE and PET studies. Patients were asked not to drink coffee, tea, or caffeinecontaining beverages during the 12 hours preceding both examinations. The protocol was approved by our institutional ethics committee, and informed consent was obtained from all patients. Transesophageal Echocardiography

From the Department of Cardiology and the PET/Biomedical Cyclotron Unit, Erasme Hospital. Supported by research grants from “Fondation Erasme” and “Fonds de la Recherche Scientifique Me´dicale 3.451692.” Reprint requests: Philippe Unger, MD, Cardiology Department, Erasme Hospital, 808, route de Lennik, B-1070 Brussels, Belgium. Copyright © 1998 by the American Society of Echocardiography. 0894-7317/98 $5.00 1 0 27/1/89945

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TEE was performed by using a 5 MHZ probe, single plane (8 patients) or multiplane (18 patients) probe connected to a Sonos HP-1000 or 2500 Hewlett-Packard echocardiographic system (Palo Alto, Calif.), with the patient under mild sedation when required (midazolam up to 3 mg). The left anterior descending coronary artery was imaged in the horizontal short axis (single-plane probe) or in a plane between 0 and 30 degrees (multiplane probe) by using color flow Doppler,

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Figure 1 Example of left anterior descending coronary artery biphasic flow velocity pattern obtained before (left) and after (right) dipyridamole (DIP) infusion. A 2.5-fold increase of maximal diastolic velocity is observed.

allowing adequate positioning of the pulsed Doppler sample in the proximal portion of the artery. Spectral profiles were recorded 2 minutes after probe insertion (baseline), and from that moment, the utmost caution was used to record velocities at the same site during the entire procedure. A biphasic coronary flow velocity pattern was recorded with two anterograde components; the diastolic component was greater than the systolic, as previously described in normal subjects.1 The flows were recorded on a 100 mm/sec paper speed, and the off-line analysis included the evaluation of maximal and mean diastolic velocities. Dipyridamole infusion was then started (0.60 mg/kg intravenously over 4 minutes at a constant rate of 10 ml/min, by means of a calibrated infusion pump).5 A 12-lead electrocardiogram was recorded every 2 minutes, and blood pressure was measured with a sphygmomanometer. The measurements of maximal and mean diastolic velocities were made at baseline and during 8 minutes after completion of dipyridamole infusion (Figure 1). Three measurements of the highest flow velocities were performed and averaged, both at baseline and after dipyridamole administration. The ratios of dipyridamole to rest maximal and mean diastolic flow velocity (TEE-CFR and TEEmean-CFR, respectively) were calculated and considered as indexes of CFR. To take into account the resting hemodynamic conditions, the obtained ratio was normalized to a standard cardiac workload: the corrected CFR (TEEc-CFR and TEEmeanc-CFR, respectively) was calculated by multiplying TEE-CFR and TEEmean-CFR by the baseline rate-pressure product, an index of myocardial oxygen consumption, divided by a linear factor of 10000 in each individual patient6: TEE c -CFR 5 TEE-CFR z SBP z HR/10000 and TEEmeanc-CFR 5 TEEmean-CFR z SBP z HR/10000

where SBP and HR denote baseline systolic blood pressure and heart rate, respectively. Interobserver variability and intraobserver variability were assessed by reviewing velocity recordings obtained in 15 randomly selected patients. Interobserver variability was assessed by having two independent observers blindly evaluating the CFR (by using maximal velocities) in these patients, whereas intraobserver variability was assessed by evaluation of CFR by the same observer at .2-week intervals. Positron Emission Tomography PET imaging was performed with a PET scanner (ECAT 933, CTI Siemens, Knoxville, Tennessee), which simultaneously provides 15 transaxial images over a 10.5 cm field of view. A 2-minute rectilinear scan was performed to ensure optimal patient positioning in the tomograph. A 10-minute transmission scan was obtained to correct for photon attenuation. N-13 ammonia was used as a tracer of myocardial blood flow. An intravenous bolus of 10 mCi was administered over 30 seconds. Acquisition of serial transaxial emission images was started simultaneously to the injection of N-13 ammonia. Dynamic image sequence consisted of twelve 10-second frames, followed by four 30-second frames, and one 360-second frame (total acquisition time 10 minutes). One hour later, after physical decay of the N-13 ammonia activity to near undetectable levels, dipyridamole was infused according to the protocol described in the TEE section. Bolus injection of N-13 ammonia and a new acquisition sequence were started 2 minutes after the end of the infusion (Figure 2). Heart rate, systemic blood pressure, and a 12-lead electrocardiogram

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Figure 2 Representative example of positron emission tomographic image obtained in the mid-cardiac transaxial plane before (left) and after (right) dipyridamole infusion. A similar scale was used in both images to demonstrate the dipyridamole-induced increase in myocardial blood flow. were recorded before the first PET acquisition and every 2 minutes during the infusion of dipyridamole and the second PET acquisition. Image analysis was performed as previously described by using a three-compartment kinetic model.7 Input function was assessed by a blood pool region of interest tailored to the left ventricular cavity and positioned at the basal portion of the ventricle. Regional myocardial blood flow (expressed in ml/min per 100 gm of tissue) was assessed in seven left ventricular myocardial territories corresponding to anatomic tridimensional macroregions, among which the anterior region was used to delineate the left anterior descending artery territory.7 Global myocardial blood flow index was calculated by averaging values in all regions. PET-CFR and PETglobalCFR were defined as the ratio of myocardial blood flow during dipyridamole-induced vasodilatation to myocardial blood flow at rest in the anterior region and in the average of all regions, respectively. As with TEE, resting hemodynamic conditions were taken into account according to the following formulas6: PET c -CFR 5 PET-CFR z SBP z HR/10000 and PETglobalc-CFR 5 PETglobal-CFR z SBP z HR/10000 Coronary Angiography Coronary angiography was performed by using standard views. Visual analysis of cineangiograms was performed independently by two observers blinded to the TEE results. Coronary occlusive disease was defined as any abnormalities on the angiogram of the left coronary artery in the primary (left anterior descending and left circumflex) or secondary coronary arteries (diagonal, obtuse marginal, and posterolateral), and the following grading was performed: Group 1 consisted of patients without any visible lesions, group 2 patients had mild to moderate lesions (,20% reduction in

the proximal, medial, or distal luminal diameter), and group 3 patients had severe coronary lesions ($20% reduction in the luminal diameter). Statistical Analysis Results are expressed as mean 6 standard deviation. Intragroup and intergroup comparisons were performed with paired and unpaired Student t test, respectively. A value of p , 0.05 was considered significant. To determine the correlation between PET-derived and TEE-derived CFR, a regression analysis was performed with a simple linear model, and the correlation coefficient (r) was calculated. The agreement between both methods of measurement is represented by the Bland and Altman plot.8 The correlation between difference and average of the two methods was performed to assess whether there is an increase in bias with magnitude of the measurement.8

RESULTS Feasibility Among the 26 patients initially included, adequate flow recording was obtained in 22 (85%). Failure to obtain flow velocity recording in the left anterior descending coronary artery was observed in 4 of the 8 patients studied with the monoplane probe, whereas adequate recording was obtained in all 18 patients in whom a multiplane probe was used. Because of the systolic motion of the heart, optimal recording of systolic flow could not be obtained in many patients, and this parameter was subsequently discarded. The procedure was well tolerated in all patients. Interobserver and intraobserver variability in CFR measure-

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Table 1

Unger et al. 615

Baseline hemodynamic parameters

Heart rate (bpm) MAP (mm Hg) RPP (mm Hg z bpm)

Before TEE§

Baseline TEE

Baseline PET

81.1 6 11.7† 105.8 6 11.1* 11252 6 1620*

84.6 6 11.9 110.0 6 11.2 12250 6 2516

82.6 6 10.9 100.5 6 14.9* 11175 6 2397‡

MAP, Mean arterial pressure; RPP, rate-pressure product; No. of patients 5 17. *p , 0.05, †p , 0.01 and ‡p 5 0.059 compared with baseline TEE. §Parameters obtained immediately before probe introduction.

Table 2

Individual data

Patient

Angio

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

2 CF 1 3 1 3 1 3 2 1 2 2 2 1 2 3 1 3 1 3 1 2

TEE-CFR

Baseline TEE RPP

Teec-CFR

PET-CFR

Baseline PET RPP

PETc-CFR

3.06 1.69 2.38 1.18 1.93 1.32 2.04 1.33 3.56 2.66 2.15 1.86 2.72 2.08 3.00 1.12 2.45 1.19 2.74 1.27 2.96 2.69

12480 11050 19305 12240 10440 13775 13910 11340 9600 12035 9600 13050 10150 14025 11424 16150 14350 11880 9570 10260 14880 10800

3.82 1.87 4.59 1.44 2.01 1.82 2.84 1.51 3.41 3.20 2.08 2.43 2.76 2.92 3.43 1.81 3.52 1.41 2.62 1.30 4.40 2.90

2.91 1.35 2.53 1.55 2.22 1.16 NA 1.73 2.45 1.63 1.48 NA 2.05 2.41 NA NA 2.56 NA 2.11 1.28 1.83 2.83

11570 10080 15360 9380 10800 12750 NA 9570 9750 13160 10920 NA 9180 9240 NA NA 10010 NA 12320 7930 17290 10660

3.37 1.36 3.89 1.45 2.40 1.47 NA 1.65 2.39 2.14 1.6 NA 1.88 2.23 NA NA 2.57 NA 2.6 1.02 3.16 3.01

Angio, Angiographic grating; RPP, rate-pressure product; NA, not available; CF, coronary fistula; TEE-CFR, ratio of dipyridamole to rest maximal diastolic velocity; PET-CFR, ratio of dipyridamole to rest myocardial blood flow; TEEc-CFR and PETc-CFR correspond to the ratios corrected according to the respective baseline rate-pressure products.

ments were as follows: the mean difference in TEECFR was 0.09 (4.8%) and 0.08 (3.8%), respectively, and measurement variabilities (standard deviation of the mean difference) were 0.07 and 0.06 for interobserver and intraobserver, respectively. Correlation With Positron Emission Tomography Among the 22 patients with successful TEE examination, 18 underwent the PET study. Because of technical problems, CFR could not be obtained with PET in 1 patient, thus enabling a comparison in 17 patients. At the moment of baseline Doppler acquisition, that is, 2 minutes after probe introduction, the rate-pressure product was significantly higher compared with before probe introduction and tended to be higher compared with PET at baseline (Table 1). TEE-CFR measured from peak diastolic velocities correlated significantly but weakly with PET-CFR (Figure 3, top). The agreement

between the two approaches as represented by the Bland and Altman plot is shown in Figure 4 (top). The mean difference between maximal flow velocity reserve and perfusion reserve was 0.24 6 0.54. Taking into account the rate-pressure product during basal image acquisition increased the correlation (Table 2 and Figure 3, bottom). However, TEEc led to larger values of CFR in comparison to PETc, with a difference between both methods of 0.47 6 0.48, significantly different from zero (p 5 0.001) and with a trend toward larger discrepancy for larger CFR, as shown in the BlandAltman plot (Figure 4, bottom); the correlation between the difference and the average of TEEc-CFR and PETcCFR was y 5 0.26x-0.18 (r 5 0.48; p 5 0.06). The use of mean instead of maximal diastolic velocities led to similar results (Table 3). Assessment of CFR with TEE in the anterior region (i.e., TEEc - CFR) also correlated with global CFR derived from PET (PETglobalc-CFR) (Figure 5).

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Figure 4 Difference between transesophageal echocardiography– derived coronary flow velocity reserve measured from peak diastolic velocities (TEE) and regional positron emission tomographic coronary flow reserve (PET) against the mean of both methods (Bland-Altman plot) before (top) and after (bottom) correction for the corresponding resting rate-pressure product (TEEc and PETc, respectively).

lower hyperemic flow in response to dipyridamole, whereas it did not reach statistical significance for patients with mild to moderate lesions (Table 4), leading to a significant reduction of CFR in patients with severe coronary lesions only (Figure 6). Figure 3 Correlation between positron emission tomographic coronary flow reserve assessed in the anterior region (PET-CFR) and transesophageal echocardiographic coronary flow velocity reserve measured from peak diastolic velocities (TEE-CFR) before (top) and after (bottom) correction for corresponding resting rate-pressure product (PETc-CFR and TEEc-CFR, respectively).

Correlation With Angiography No patient had $50% stenosis in the proximal left anterior descending artery. One patient with a left anterior descending coronary artery– dependent fistula, resulting in a markedly dilated and tortuous vessel, was excluded from the angiographic analysis. There was no significant difference in basal flow between the three groups defined by angiography (Table 4). Compared with patients with normal angiography, patients with severe lesions had a significantly

DISCUSSION This study shows that TEE assessment of CFR is feasible in orthotopic heart transplant recipients: The percentage of our patients adequately assessed (85%) is in the 80% to 90% range previously reported in nontransplanted populations.5,9 Furthermore, although the study was not designed to test the incremental value of multiplane TEE, the use of a multiplane probe in this setting appears to increase its feasibility, probably by allowing a more accurate positioning of the Doppler sampling. PET was used in our study as a noninvasive method of reference because it has been validated for measurement of regional myocardial blood flow.10,11 Because acute rejection is associated with a reversible reduction of CFR12 and because TEE and PET were not

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Table 3 Correlation between CFR assessed with TEE (TEEmean-CFR) and PET-CFR TEEmean-CFR versus PET-CFR

Equation r p Mean difference 6 SD

TEEmeanc-CFR versus PETc-CFR

y 5 0.75x 1 0.62 0.67 0.003 0.13 6 0.48

y 5 1.05x 1 0.24 0.89 ,0.0001 0.33 6 0.42

TEEmean-CFR, Radio of dipyridamole to rest mean diastolic velocity; PET-CFR, ratio of dipyridamole to rest myocardial blood flow. TEEmeanc-CFR 5 TEE-CFR z RPP/10000, where RPP 5 baseline TEE rate-pressure product. PETc-CFR 5 PET-CFR z RPP/10000, where RPP 5 baseline PET rate-pressure product. Mean difference 5 TEE minus PET.

Table 4 Baseline and dipyridamole coronary flow velocities according to angiographic grading Group 1

No. of patients Baseline peak diastolic flow (cm/sec) Dipyridamole peak diastolic flow (cm/sec)

Group 2

Group 3

8 49.9 6 14.0

7 40.9 6 14.2

6 51.6 6 12.8

117.9 6 28.6

107.8 6 35.7

67.3 6 23.5*

*p , 0.05 compared with group 1.

performed on the same day, patients with biopsyproven rejection were excluded from the study to allow a comparison between TEE and PET. Nevertheless, the correlation between values of CFR obtained with TEE and with PET was weak. Taking into account their respective baseline rate-pressure product by correction to a standard workload increased the correlation. Indeed, rate-pressure product tended to be higher during baseline image acquisition with TEE compared with PET, probably as the result of discomfort induced by probe introduction, because it was also higher compared with the rate-pressure product observed immediately before probe introduction. Basal coronary flow is related to myocardial oxygen consumption and therefore not taking into account the rate-pressure product should lead to a lower TEE-derived CFR compared with PET-derived CFR. Surprisingly, such a relative underestimation by TEE was not observed. Correction for ratepressure product led to significantly higher CFR values with TEE compared with PET. A likely explanation is that PET acquisition is performed during a 10-minute interval, during which coronary flow may vary13 and from which an average flow is derived, whereas only higher diastolic flow velocities are taken into account during TEE. The inability of PET to measure the real peak coronary blood flow because of this longer acquisition time may account for some of the discrepancies observed between the two methods. The trend toward larger bias for higher CFR may be related to larger flow variations during the acquisition time. Because of the specific nature of the coronary le-

sions, with concentric and tubular stenosis, coronary angiography is relatively insensitive at detecting cardiac allograft vasculopathy.14,15 Measurement of CFR and hyperemic responses to non– endotheliumdependent vasodilators may allow functional assessment of this peculiar form of vasculopathy. Coronary vasodilator capacity has been shown to be preserved after cardiac transplantation in patients devoid of angiographically visible coronary artery lesions,16 whereas in patients with mild to moderate coronary lesions, controversial results have been described.17,18 In this study, we found a markedly reduced CFR only in patients with severe coronary lesions, whereas no significant difference between patients with mild to moderate lesions and those with normal angiography was found. It is difficult to ascribe with certainty the latter finding to a preserved CFR in patients with mild to moderate coronary lesions. Indeed, the small number of patients studied may explain the failure to detect a difference. It could also be related to the confounding effects of other determinants of CFR because patients with left ventricular hypertrophy and patients with altered left ventricular function, both conditions that may result in reduced CFR,19,20 were not excluded from the study. Despite some discomfort associated with TEE, this approach for CFR assessment is associated with a minimal morbidity rate and offers the advantage of being less time consuming and less expensive than PET examination, requiring less personnel and costly laboratory equipment than other methods. Therefore, it can be performed on an ambulatory basis and has the potential to be used more easily in serial studies.

618 Unger et al.

Figure 5 Correlation between global myocardial blood flow reserve assessed by positron emission tomography and transesophageal echocardiographic coronary flow velocity reserve measured from peak diastolic velocities, both after correction for the corresponding resting rate-pressure product (PETglobalc-CFR and TEEc-CFR, respectively).

A limitation of our study is that some delay occurred between completion of TEE and PET studies because of logistic problems. This delay allows differences between resting hemodynamic parameters and myocardial oxygen consumption. However, this was partially compensated by taking into account the resting rate-pressure product, correcting measurement from each technique to a standard workload.6,13 Of note, this correction does not take into account hemodynamic parameters obtained after dipyridamole infusion, assuming a maximal hyperemic flow independent of the rate-pressure product. In addition, the classic limitations of the TEE technique still hold true: (1) Because of the effect of the angle between blood flow direction and ultrasound beam, measured velocities can be lower than real velocities. Because TEE-derived evaluation of CFR is obtained by the ratio of two velocities, the effect of angle can be avoided if care is taken to position the sample volume at the same place during serial flow acquisition. In this study, the angle between the exploring ultrasound and the coronary artery was not assessed, but we have assumed that it is not significantly modified by dipyridamole infusion, as previously shown in patients without transplantation.1 (2) A limitation inherent to the technique is that it measures velocities and not blood flow, which would require cross-sectional area

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Figure 6 Distribution of coronary flow velocity reserve assessed by transesophageal echocardiography, measured from peak diastolic velocities, and corrected for the resting rate-pressure product (TEEc-CFR) in heart transplantation recipients without (Group 1), with mild to moderate (Group 2), and with severe (Group 3) coronary lesions at angiography. NS, Nonsignificant.

measurement. Because dipyridamole only minimally dilates epicardial coronary arteries, changes in flow velocities closely reflect changes in blood flow. Nevertheless, the lack of blood flow measurement may be a disadvantage in patients with heart transplantation because alterations in basal flow may be an early sign of graft dysfunction.21 (3) Dipyridamole-TEE allows only regional CFR measurements. However, myocardial blood flow in the transplanted heart is homogeneously distributed, both at rest and after dipyridamole infusion,22 and cardiac allograft vasculopathy frequently results in a diffuse vascular alteration.3 Therefore, left anterior descending artery flow velocity reserve measurement should reflect the global perfusion reserve. Our study supports this assumption because regional assessment of CFR with TEE correlated significantly with PET-derived global myocardial blood flow reserve. In conclusion, TEE is a feasible method of CFR assessment in orthotopic cardiac transplant recipients. However, resting hemodynamic conditions

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Unger et al. 619

should be taken into account when comparing TEE with other methods. Furthermore, comparison with PET should be done with caution because of a trend toward higher CFR values obtained with TEE.

11.

We thank the nurses of the Echocardiography Laboratory and the Cyclotron Unit for their expert technical assistance as well as Marie-The´re`se Gautier for her kind assistance in preparing the figures.

12.

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