Dobutamine stress echocardiography: experience in pediatric heart transplant recipients

Dobutamine stress echocardiography: experience in pediatric heart transplant recipients

PEDIATRICS Dobutamine Stress Echocardiography: Experience in Pediatric Heart Transplant Recipients Elfriede Pahl, MDa, Susan E. Crawford, MDb, Jeanin...

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PEDIATRICS

Dobutamine Stress Echocardiography: Experience in Pediatric Heart Transplant Recipients Elfriede Pahl, MDa, Susan E. Crawford, MDb, Jeanine M. Swenson, MDe, C. Elise Duffy, MBBSa, F. Jay Fricker, MDe, Carl L. Backer, MDd, Constantine Mavroudis, MDd, and Farooq A. Chaudhry, MDc Background: Transplant coronary arteriopathy causes late death and is difficult to detect noninvasively. Dobutamine stress echocardiography is being used for risk stratification in adult recipients at some transplant centers, thus we investigated its role in a pediatric population. Methods: We performed 46 stress echo studies (mean age ⫽ 11.8 years; mean years post transplantation ⫽ 4.3). An atropine/dobutamine protocol (5– 40 mcg/kg/min) was used to attain a predicted target heart rate. Serial echocardiographic images were acquired at baseline and at each increment of dobutamine and recovery, and were digitized online. Data were correlated with endomyocardial biopsy (n ⫽ 23), coronary angiography (n ⫽ 26) or autopsy (n ⫽ 6). All studies were well tolerated. Results: Target heartrate was achieved in 41/46 (89%) studies. The mean heartrate significantly increased from 95 to 169 beats/min and mean systolic blood pressure from 123 to 153 mmHg (p ⬍ .05). The mean peak pressure-rate product was 23,041 beatsmmHg/min. Coronary arteriopathy was confirmed in 5 patients by angiography (n ⫽ 3), explanted heart (n ⫽ 1) or autopsy (n ⫽ 4). In this group, abnormalities included a new reversible wall motion abnormality (n ⫽ 2), left ventricular cavity dilation with stress (n ⫽ 3), ischemia (n ⫽ 2), increased mitral insufficiency (n ⫽ 1) and marked diastolic dysfunction (n ⫽ 1). A positive study predicted death or graft failure (p ⬍ .0005). Conclusions: Echocardiographic abnormalities during stress correlated with coronary arteriopathy in this small cohort of patients; however, larger multi-center studies are warranted to assess the utility of dobutamine stress echocardiography for risk stratification for coronary disease in pediatric transplant recipients. J Heart Lung Transplant 1999;18:725–732.

From The Children’s Memorial Hospital, aDepartments of Pediatrics, bPathology, cMedicine and dSurgery, Northwestern University Medical School, Chicago, Illinois, and the eDepartment of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, Submitted August 28, 1998; accepted January 18, 1999. This study was presented in part at the American Academy of Pediatrics Annual Meeting, Boston, October 1996.

Reprint requests: Elfriede Pahl, MD, Medical Director, Heart Transplantation, Children’s Memorial Hospital, 2300 Children’s Plaza, Chicago, IL 60614. Copyright © 1999 by the International Society for Heart and Lung Transplantation. 1053-2498/99/$–see front matter PII S1053-2498(99)0009-1

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ransplant coronary artery disease (TCAD) limits long-term survival after heart transplantation, and along with rejection is a major cause of late death.1 In adult series, more than 50% of long-term survivors have significant TCAD 5 years after transplantation.2,3 Pediatric patients are also at risk for TCAD,4 although the incidence has not been well established. An overall rate of 7.3% was reported in a multicenter survey with 1–10 years of followup,5 and the rate was as high as 19% in a multicenter series of children surviving more than 5 years after transplantation.6 Because of the asymmetrical nature of TCAD and the remodeling of the coronary vasculature, angiography tends to underestimate the degree of TCAD.3,7 In adults, results of noninvasive testing using DSE to screen for TCAD are contradictory.8 –11 We previously demonstrated the feasibility and safety of DSE in children with either Kawasaki Disease or history of heart transplantation.12 The current study evaluated the potential role of DSE in pediatric heart transplant patients.

METHODS Study population The study cohort consisted of patients from the Children’s Memorial Hospital (CMH), Chicago, IL (n ⫽ 20) and the Children’s Hospital of Pittsburgh, Pittsburgh, PA (n ⫽ 13). All children who had orthotopic heart transplantation, survived for more than 1 year and who had undergone coronary angiography were asked to participate, and 35% agreed to be studied. All Pittsburgh patients were greater than 3 years from transplantation. From April 1993 to July 1997, 46 studies were performed in 33 patients (22 boys, 11 girls). Patients ranged in age from 1 to 22 years (mean ⫽ 11.8 ⫾ 5.2) and were 1–10 years post transplant (mean ⫽ 4.3 ⫾ 2.1). Serial DSE studies were performed in 9 CMH patients. DSEs were done a median of 2 months after biopsy/angiography. Specifically, DSE was performed within 0 –2 months of biopsy in 21, 2–12 months in 8, and the remainder between 12 and 24 months. Follow-up was available in all patients through February 1998. Informed written consent was obtained from patients or parents and the study was approved by the institutional review boards of both institutions. Sixteen patients from the CMH cohort were reported previously in a feasibility study.

Dobutamine stress echocardiography protocol This protocol was described previously by our group.12 An intravenous line was placed. Sedation was used in 4 patients either with chloral hydrate orally (n ⫽ 1) or Droperidol/fentanyl (n ⫽ 3)

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parenterally. Baseline data were acquired, including a 12 lead electrocardiogram (ECG), blood pressure, and echocardiographic images. Dobutamine infusion was begun at 5–10 mcg/kg/min and increased by 5–10 mcg/kg every 3– 6 minutes to a maximum dose of 40 mcg/kg/min. Atropine (0.01 mg/kg) was given during 12 studies to augment HR response if the patient’s HR was less than 80% of the age-predicted maximum (APM). The rhythm strip was monitored continuously, and a 12-lead ECG and blood pressure were recorded at each stage of the protocol and during recovery. Comprehensive baseline studies included 2-dimensional, M-mode, pulsed and color doppler of all 4 cardiac valves performed in standard views. Transthoracic images were then obtained in parasternal long and short axes, apical four- and two-chamber views at baseline, each stage, and during recovery (Hewlett-Packard Sonos 1500 and 2500 scanners, Andover, Massachusetts). These images were recorded on VHS videotape and digitized online (Tomtec Imaging, Boulder, Colorado).

Wall motion All echocardiographic images were interpreted by at least 2 observers (EP, FC, CD) and a third observer reviewed the study if there was a discrepancy in findings. An experienced adult echocardiographer (FC) reviewed all studies and was blinded to the clinical status of the patients. As recommended by the American Society of Echocardiography guidelines, the left ventricle was divided into 16 segments.13 Each segment was analyzed for the following: endocardial excursion, myocardial thickening and decrease in left ventricular end-systolic volume. DSE was considered abnormal if a new reversible wall motion abnormality was identified or if there was no decrease in left ventricular cavity size.

M-Mode M-mode data were acquired in parasternal short axis views. Measurements of the LV dimensions, and septal and posterior walls were obtained at baseline and peak dose; calculations of percentage shortening and thickening were described previously.9 A decrease in shortening fraction or lack of thickening were considered to be an abnormal response.

Coronary angiography Selective coronary angiography was performed in most transplant recipients annually by using a standard Judkins technique, and results were reviewed

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TABLE I Hemodynamic response HR (bpm) Confirmed TCAD pts Others (n ⫽ 41) SBP (mmHg) Confirmed TCAD pts Others (n ⫽ 41)

Rest Mean ⴞ SD (range)

Peak Mean ⴞ SD (range)

98 ⫾ 18 (77–120) 95 ⫾ 16 (67–138)

155 ⫾ 12 (135–170) 171 ⫾ 10 (153–186)

123 ⫾ 8 123 ⫾ 15

147 ⫾ 14 153 ⫾ 17

p ⬍ .05 NS

Abbreviation: Bpm ⫽ beats/minute; neg ⫽ negative; NS ⫽ not statistically significant; TCAD Pts ⫽ patients identified with coronary arteriopathy; SBP ⫽ systolic blood pressure.

qualitatively. Angiograms were performed within 0 –24 months of DSE, with a mean interval of 6.3 months and median of 1.5 months. Cineangiograms from both institutions were reviewed by at least three observers; all were reviewed by EP.

Histopathologic data Endomyocardial biopsies were performed as described previously and graded by standard criteria.14 Only biopsies performed within 1 month of DSE were compared (n ⫽ 23). Autopsies were performed in all 6 patients who subsequently died 1 to 22 months after DSE. Tissue sections were evaluated from the proximal, mid and distal portions of the right and left coronary arteries, and from routine samples of the myocardium in autopsied hearts as well as the explant from a patient who was retransplanted. The extent of graft arteriopathy was assessed qualitatively. Pathologic slides were also assessed for cellular rejection by using accepted criteria.14

Statistical analysis Mean and standard deviation were calculated where appropriate, and Student’s T-test was utilized to compare baseline and peak dose, as well as data from patients identified with TCAD. In patients with serial DSE studies, the most recent test was used for comparison. We compared the differences in heart rate and BP in two groups: patients with confirmed TCAD (n ⫽ 5), and all others (n ⫽ 41; these patients had negative DSE studies). A Chisquare analysis was performed to compare the outcomes of patients with a negative vs positive study, using the endpoint of death/graft loss (p values ⬍.05 were considered to be statistically significant).

RESULTS All studies were well tolerated; however, 2 patients experienced transient headache and 1 had chest

pain. The symptoms subsided within minutes of stopping the infusion. Only 1 patient had a poor acoustic window (ⱕ13/16 segments visualized) which limited diagnostic accuracy. No patients had emesis or significant dysrhythmia. One patient developed hypotension that responded to an intravenous fluid bolus.

Heart rate (HR) and blood pressure (BP) response Table I shows the HR and systolic BP response. The mean peak dose of dobutamine was 37 mcg/kg/min, (range ⫽ 20 – 40). The mean resting HR and BP rose significantly (p ⬍ .05) in both groups, however, patients with confirmed TCAD (n ⫽ 5) had a lower peak HR than all others (n ⫽ 41; p ⬍ .05). The target HR of 80% of APM was reached in 41/46 (89%) studies, and 85% of APM (ie, target HRs of 170 –187 beats/min) was achieved in 32/46 (70%) studies. Four of the 5 patients with inadequate HR response had TCAD. Furthermore, when compared with the studies from patients without TCAD, those with TCAD had significantly lower peak HRs. Atropine was used in 12 (27%) studies and effectively augmented the HR in 5, with a mean increase of 20% (range ⫽ 4%–50%). Five studies were ⬍80% of target HR, including 4 of the patients with TCAD. The double product (HR ⫻ SBP) at peak dose for the study cohort ranged from 17,415 to 32,736 beats-mmHg/min (mean ⫽ 25,662 ⫾ 3,700).

Wall motion abnormalities DSE studies were completely negative in 41, nondiagnostic in 1 and positive in 4. The positive results were all in patients who had TCAD. Two of these 4 positive studies also had a resting WMA. In those patients with a positive DSE, abnormalities included a new reversible wall motion abnormality (n ⫽ 2), left ventricular cavity dilation with stress (n ⫽ 3), increased mitral insufficiency (n ⫽ 1) and marked diastolic dysfunction (n ⫽ 1). Mild ischemia on

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TABLE II M-mode indices

SF% non-tcad pts TCAD pts LVST% non-tcad pts TCAD pts LVPWT% non-tcad pts TCAD pts

Rest (x ⴞ SD)

Peak (x ⴞ SD)

p

38 ⫾ 6 34 ⫾ 12

50 ⫾ 9* 39 ⫾ 2*

⬍.05 NS

46 ⫾ 27 33 ⫾ 17

52 ⫾ 27 43 ⫾ 16

NS NS

75 ⫾ 31† 51 ⫾ 8†

77 ⫾ 29 55 ⫾ 20

NS NS

LVPWT ⫽ left ventricular posterior wall thickening; LVST ⫽ left ventricular septal thickening; pts ⫽ patients SF% ⫽ left ventricular shortening fraction; non-TCAD vs TCAD pts;1 non-TCAD represents 41 studies, TCAD n ⫽ 5. *p ⬍ .001. † p ⬍ .05.

ECG was noted in 2, including the patient with the nondiagnostic study who was subsequently diagnosed with TCAD. One study was initially interpreted as negative, but when FC, an adult cardiologist and EP performed the second review, they found the study was positive. For all other studies, there was concordance among all observers. Table II shows the M-mode response. When resting indices were compared to peak, only the % shortening fraction increased significantly (p ⬍ .05).

Septal and posterior wall thickening was unchanged in both groups when baseline data was compared to stress parameters. M-mode indices from the nonTCAD group were also compared to those with TCAD, and peak shortening fraction achieved was significantly higher in the non-TCAD patients (p ⬍ .001). Additionally, resting LVPWT% was lower in the TCAD group (p ⬍ .001).

Coronary angiography and endomyocardial biopsy Selective coronary angiography was performed within 6 months of DSE in 26 patients. Coronary angiography was qualitatively normal in 23 patients. Three patients had abnormal coronary angiograms: 2 were diagnosed with moderate (⬍50% stenosis) and 1 with severe coronary arteriopathy (⬎75% stenosis) on angiography performed within 2– 6 weeks of DSE. Figure 1 shows selective coronary angiograms of a patient at 5 years post-transplantation who underwent retransplantation for TCAD. The angiogram markedly underestimated the extent of his coronary disease when compared to his explanted graft 2 months later. Endomyocardial biopsy was done within 1 month of DSE in 23 patients. The biopsy was Grade 0 –1A in 19, 1B in 2, and Grade 3A in 2 patients. One of the positive studies was from a patient with a Grade 3A biopsy. The other patient with biopsy score of 3A had a negative DSE.

FIGURE 1 Selective cineangiograms of the right and left coronary arteries from Patient 4 in right anterior oblique views show subtle, diffuse irregularities, but no discrete stenoses. This angiogram was performed 1 month before DSE, and 2 months before retransplant.

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TABLE III Patients with confirmed TCAD Outcome and age (yrs) 1. 2. 3. 4. 5.

Died—2 months (10) Died—22 months (15) Died—1 month (3) Died—1 month (18) Died—9 months (11)

ECG

ECHO WMA/other

CA

BX

Histo

Dose (ug/kg/min)

Peak hour

Symptoms

Time Tx(y)

⫹ ⫺ ⫺ ⫺ ⫹

⫾LD ⫾LD ⫾DD ⫾MR ND*

⫹ NR ⫹ ⫹ NR

2 3a 1b 1b NR

⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹

20 30 35 35 40

170 160 163 135 155

None Headache Hypotension None Chest pain

8.5 3.5 2.3 4.9 4.0

Age ⫽ age at time of DSE; BX ⫽ biopsy; CA ⫽ coronary angiography; Dose ⫽ peak dobutamine dose; DD ⫽ diastolic dysfunction; Histo ⫽ autopsy confirmation of TCAD; ⫹ ⫽ mild to moderate, ⫹⫹ ⫽ severe; HR ⫽ HR; LD ⫽ left ventricular dilatation; m ⫽ months; MR ⫽ mitral regurgitation; ND ⫽ not diagnostic; NR ⫽ no recent study; pt ⫽ patient; retx ⫽ retransplantation; timetx ⫽ time from transplant to study; WMA ⫽ wall motion abnormality; y ⫽ years.

TCAD group Patients who were diagnosed with significant coronary arteriopathy by either angiography or autopsy are listed in Table III. They were 2 to 8 years post transplant (mean ⫽ 4.3 years ⫾ 2.5), and all died or received a second transplant 1–22 months after DSE. Patient 1 had diffuse coronary disease on angiography, LV dilation on stress echo, and ECG ischemic changes suggesting inferolateral ischemia. An episode of rejection was treated with steroids; however, this patient died of acute myocardial infarction resulting from a left anterior descending (LAD) coronary thrombus. On autopsy, she had diffuse TCAD and cellular rejection. Patient 2 also had LV cavity dilatation with stress and concurrent cellular rejection (Grade 3A). From the time of DSE to death, he had persistent refractory cellular rejection. At autopsy, he had total occlusion of the right and ⬎75% stenosis of the left anterior descending and circumflex coronary arteries. Patient 3 had severe diastolic dysfunction at rest as evidenced by reversal of flow to the pulmonary veins during diastole and a restrictive mitral doppler pattern. Despite no ischemia on ECG, he developed a reversible WMA in the apical anterior wall and apical septum. He developed hypotension at peak dose that responded to a saline bolus. This child was asymptomatic, and had striking abnormalities on routine scheduled coronary angiography, with severe tubular narrowing of the distal right coronary artery and thinning of the LAD. He died 17 days after the DSE study, and acute LAD thrombosis and severe diffuse transplant arteriopathy were confirmed at autopsy. Patient 4 had severe TCAD on his explanted heart, despite only minimal changes on coronary

angiography (Figure 2). During DSE, he only reached a HR of 135 bpm; however, he developed a new WMA. At rest, he had mild hypokinesis of the anterior LV wall, and with stress he developed moderate hypokinesis of the septum as well as of the apical and mid-anterior walls. He also had mild mitral regurgitation at rest that increased to moderate at peak dose. The positive DSE, as well as progression of symptoms, warranted listing for retransplantation. Patient 5 could not be imaged adequately; however, she developed angina, and ECG changes suggestive of ischemia. She died of multifactorial causes, including acute Epstein-Barr virus infection, respiratory failure, severe diastolic dysfunction and refractory ventricular arrhythmias. Autopsy revealed moderate TCAD.

FIGURE 2 Histologic section from proximal left main

coronary artery from Patient 4’s explanted heart. There is marked stenosis due to proliferation of the media (M) and neointima (N), H & E, 40⫻.

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Histopathology

study demonstrating a high concordance rate with intracoronary ultrasound for detecting graft coronary disease in 46 adults. Both DSE and coronary ultrasound were superior to angiography alone, with a sensitivity of 79% and specificity of 83%.9 This is the first report to investigate the potential role of high-dose DSE in the pediatric heart transplant population, with particular attention to M-mode as well as two-dimensional echocardiographic findings. The HRs and blood pressures increased significantly in these children. Although the incidence of TCAD in this population was low, all patients who had an abnormality detected by DSE were subsequently diagnosed with TCAD. In contrast to a report of inadequate chronotropic response with exercise in transplant recipients,20 high-dose dobutamine was well tolerated in the current study, and target HR was achieved in most patients with rate-pressure (i.e, double products) in a satisfactory range. The double products were greater than 20,000 in most cases, that is adequate for adults and presumably adequate for children. To date, there are no recommendations for optimal double product in the pediatric age group. We initially intended to use the adult criterion of 85% of APM for the target HR, using a protocol of 40 mcg/kg/min as our maximum dose; however, only 70% of studies achieved this goal. Although not attempted in this study, increasing the protocol to 50 mcg/kg/min of dobutamine for patients with suboptimal HRs may result in an additional increase in HR. Using 80% of APM as our target HR, 41 of 46 (89%) studies attained this goal. Despite using a lower target HR in this cohort, we correctly identified all patients diagnosed with TCAD during the followup period. Interestingly, 4 of 5 patients with TCAD did not achieve target HR. This tendency for the HR to plateau despite increasing dobutamine dose concurs with findings in a study of adult recipients, where the patients with significant coronary lesions had lower target HRs, and low peak HR was an independent predictor of severe stenosis.10 Despite the fact that transplant patients have a “denervated” heart, atropine was found to be useful in 5/12 studies, and its effectiveness suggests that reinnervation may actually occur in transplanted hearts. A minimal number of side effects were encountered during DSE. One patient developed chest pain, that is surprising because transplant patients generally do not develop angina.21 This patient also had a technically limited imaging study because the endocardium was not well visualized. During this

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All patients who died had autopsies. Three had severe TCAD with ⬎90% stenosis or complete occlusion of one or more epicardial coronary arteries, and 2 of these patients had a myocardial infarction from acute coronary thrombosis and died suddenly. One patient had moderate TCAD (50%–75% stenosis) of major epicardial coronary arteries. Two others had acute rejection and only mild evidence of TCAD (⬍50% stenosis); both had negative DSE studies. The explanted heart from a patient who received a retransplant demonstrated severe graft arteriopathy with marked myointimal proliferation (Figure 2).

Patient followup During the followup period there was one retransplant and 6 deaths that occurred 1–22 months post DSE. In the group of patients who died, there were 4 boys and 2 girls. Deaths occurred a mean of 4.1 ⫾ 2.3 years post-transplantation. Severe TCAD caused 3 deaths, and 2 other deaths were related to acute rejection in adolescents who were known to be noncompliant. One patient died of multisystem failure. Survivors (n ⫽ 26) are alive and well 1.3– 4.9 years (mean ⫽ 3.8 ⫾ 0.5 years) post dobutamine study. The Chi-square analysis comparing the patients with positive DSE study with outcome reveals a high positive predictive value for poor outcome (death or graft loss) in patients with positive DSE study (p ⬍ .0005).

DISCUSSION Noninvasive screening and risk stratification for TCAD has been difficult and the results unsatisfactory in adult studies comparing coronary angiography to functional studies such as ECG stress or nuclear studies.15,16 Similar predictive values have been reported in nontransplant patients at risk for coronary atherosclerosis, when screened by nuclear scans or stress echocardiograms.17 Exercise echocardiography in adult transplant recipients has been compared to angiography and intracoronary ultrasound. It has an unacceptably high false negative rate for detection of coronary stenosis and a sensitivity of only 25%.18 Most investigators believe that DSE is a superior modality in adult recipients, and studies comparing DSE to angiography found sensitivities ranging from 88%–95% and specificities from 55%–91%,8,10,19 although another study concluded that the correlation was poor.11 DSE appears even more promising in a recent

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episode, however, her ECG suggested ischemia, thus this patient likely had a positive study as well. As suggested in one study, we used WMAs along with additional parameters to increase the likelihood of detecting TCAD. Geleijnse and colleagues reviewed 28 DSE reports of 2,246 adult studies and found the following determinants of ischemia: 1) ECG changes, 2) diastolic dysfunction (abnormal mitral doppler indices) and 3) increase in mitral regurgitation.22 Hypotension was excluded because it more likely results from left ventricular cavity obliteration at higher doses than from ischemia. As in adult studies suggesting that stress ECG has a very low sensitivity,23 only 2 patients identified with TCAD in our study had ECG suggestion of ischemia. Notably, the two patients with discrete WMA had no ischemic changes on ECG. It is recognized that diastolic dysfunction precedes systolic dysfunction and may predict severe coronary dysfunction. The patient with the most striking coronary angiogram showed severe diastolic dysfunction at rest. We intend to include mitral doppler indices in future protocols to determine whether all patients with TCAD have abnormal diastolic indices, as suggested in an adult study.24 There are known limitations to utilizing that indices that are not specific for TCAD; altered diastolic indices may instead suggest restrictive physiology of a multifactorial etiology in transplant recipients.25 This study evaluated parameters for transplant recipients with respect to M-mode indices and showed an increase in fractional shortening in negative studies. There was no significant change in percentage of LV wall thickening in patients with confirmed TCAD, in contrast to an adult study reporting a decrease in LV septal and posterior wall thickening in patients with significant graft atherosclerosis (ie, moderate to severe intimal hyperplasia).9 Left ventricular volume changes during DSE have been suggested as another parameter to help identify patients with more severe CAD in the absence of regional WMA.26 This blockage may induce a global reduction in contractility from the low to peak dose stages without an apparent regional abnormality.23 In one patient (Patient 2), there was concurrent moderate cellular rejection found on a biopsy obtained the same day as the DSE. His resting LV function was normal, and biopsy results were not known at the time the DSE was performed. It is possible that rejection affected the hemodynamic response and interpretation of this study. Because his baseline LV function was normal and subsequent

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autopsy nearly 2 years later demonstrated significant coronary vasculopathy, it appears more likely that the positive study was due to diffuse TCAD rather than rejection. There are no published data regarding the impact of rejection on interpretation of DSE. Any patient with one or more determinants of ischemia had a poor outcome, and in 3 patients, death or retransplant occurred within 2 months of positive DSE study. In contrast, most patients with a normal study have survived for several years followup. It is possible that a positive DSE identified only those patients with severe TCAD, and who are therefore at greatest risk for a cardiac event. Two recent adult studies similarly concluded that a negative DSE identified patients at low risk for developing an ischemic event in the next year, although one report was unusual because there was a very high incidence of positive studies.27,28 Furthermore, a recent study by Akosah and colleagues concluded that dobutamine-induced wall motion abnormalities were predictive of the development of angiographic TCAD, myocardial infarction or death.29

LIMITATIONS This study was retrospective in nature and the majority of patients did not have angiograms performed on the same day as DSE study. This factor as well as the small number of positive studies did not allow for statistical calculations such as sensitivity or specificity. Furthermore, one of the positive studies occurred in a patient with concurrent rejection, and no angiogram was performed at the time. Despite these issues, we demonstrated that a positive study portends a grim prognosis.

CONCLUSION This study proposes DSE protocol guidelines for use in the pediatric population and suggests that this technique may be a useful adjunct in the surveillance of TCAD and in determining the significance of abnormal angiograms. Evaluation of M-mode indices during DSE enhances the likelihood of identifying patients with TCAD. We strongly recommend blinded review of each dobutamine study by a cardiologist with extensive experience in the interpretation of WMAs to avoid false positive or false negative studies, since abnormalities may be subtle. Acquisition of images of high quality is crucial, and use of digitally stored on line frame grabbing equipment allows for simultaneous comparison of low and peak doses. Further prospective studies on larger

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cohorts are necessary to validate DSE for risk stratification of TCAD in children. The authors acknowledge Dale Chrystof for technical assistance and Tammy Tarsa for secretarial assistance. We also would like to thank the members of the transplant teams of Children’s Memorial Hospital, especially Sherrie Rodgers, RN, MSN and the Children’s Hospital of Pittsburgh for help in patient recruitment.

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REFERENCES 1. Weis M, von Scheidt W. Cardiac allograft vasculopathy: a review. Circulation 1997;96:2069 –77. 2. Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol 1988;12:334 – 40. 3. St Goar FG, Pinto FJ, Alderman EL, et al. Intracoronary ultrasound in cardiac transplant recipients: in vivo evidence of “angiographically silent” intimal thickening. Circulation 1987;76:24 –34. 4. Pahl E, Fricker FJ, Armitage J, et al. Coronary arteriosclerosis in pediatric heart transplant survivors: limitation of long-term survival. J Pediatr 1990;115:177– 83. 5. Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Post-transplant coronary artery disease in children. A multicenter national survey. Circulation 1994;90:II-56 –II-60. 6. Sigfusson G, Fricker FJ, Bernstein D, et al. Long-term survivors of pediatric heart transplantation: a multicenter report of sixty-eight children who have survived longer than five years. J Pediatr 1997;130:862–71. 7. Rickenbacher PR, Pinto FJ, Chenzbraun A, et al. Incidence and severity of transplant coronary disease early and up to 15 years after transplantation as detected by intravascular ultrasound. J Am Coll Cardiol. 1995;25:171–7. 8. Akosah KO, Mohanty PK. Role of dobutamine stress echocardiography in heart transplant patients. Chest 1998;113:809 –15. 9. Spes CH, Mudra H, Schnaack SD, et al. Dobutamine stress echocardiography for noninvasive diagnosis of cardiac allograft vasculopathy: a comparison with angiography and intravascular ultrasound. Am J Cardiol 1996;78:168 –74. 10. Derumeaux G, Redonnet M, Mouton-Schleifer D, et al. Dobutamine stress echocardiography in orthotopic heart transplant recipients. VACOMED Research Group. J Am Coll Cardiol 1995;25:1665–72. 11. Herregods M, Anastassiou I, Van Cleemput J, et al. Dobutamine stress echocardiography after heart transplantation. J Heart Lung Transplant 1994;13:1038 – 44. 12. Pahl E, Chrystof D, Webb CL, Shulman ST, Chaudhry FA. The feasibility of high-dose dobutamine stress echocardiography in children. Cardiol Young 1997;7:56 – 62. 13. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiography 1989;2:358 – 67. 14. Billingham ME, Cary NRB, Hammond ME, et al. A working

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