Utility of exercise stress echocardiography in pediatric cardiac transplant recipients: A single-center experience

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Utility of exercise stress echocardiography in pediatric cardiac transplant recipients: A single-center experience Ming Hui Chen, MD, MMSc,a,b Elizabeth Abernathey, BA,a Fatima Lunze, MD,a Steven D. Colan, MD,a,c Stephen O’Neill, JD,a Lisa Bergersen, MD,a,c Tal Geva, MD,a,c and Elizabeth D. Blume, MDa,c From the aDepartment of Cardiology, Children’s Hospital Boston, bDepartment of Medicine, Harvard Medical School, and the, c Department of Pediatrics, Harvard Medical School, Boston, Massachusetts

KEYWORDS: stress echocardiography; exercise; pediatrics; cardiac; transplantation

BACKGROUND: Annual coronary angiography (ANG) to assess for significant epicardial coronary artery disease (CAD) is an integral part of follow-up care for pediatric cardiac transplant recipients at Children’s Hospital Boston. Exercise stress echocardiography (ESE) is an important, non-invasive tool for the detection of ischemia in adults but has been rarely used in children. Therefore, the aim of this study was to assess the feasibility and utility of ESE in excluding ANG-detected epicardial CAD at our center, where ESE has been implemented since 2007. METHODS: We conducted a retrospective review of all pediatric cardiac transplant recipients at our institution who had undergone ESE and ANG between January 2007 and December 2010, and with testing performed ⬍ 12 months apart. ESE results were compared against ANG. RESULTS: The study cohort comprised 47 cardiac transplant recipients. One patient’s ESE images were inadequate for interpretation. Of the remaining 46 patients, ESE had a sensitivity of 88.9% (95% confidence limits [CL], 51.8%, 99.7%), a specificity of 91.9% (95% CL, 71.8%, 98.3%), and a negative predictive value of 97% (95% CL, 85.1%, 99.1%) for the ANG-detected CAD. CONCLUSIONS: This large, single-center study showed ESE was feasible and had a high specificity and excellent negative predictive value in excluding epicardial CAD in pediatric cardiac transplant recipients. Future prospective, large-scale studies are needed to confirm these findings and help identify a subset of children for whom a negative ESE could decrease the frequency of routine ANG. J Heart Lung Transplant 2012;31:517–23 © 2012 International Society for Heart and Lung Transplantation. All rights reserved.

Cardiac transplantation is a life-saving procedure for children with end-stage heart disease.1,2 Coronary artery vasculopathy (CAV) threatens long-term graft survival and is the leading cause of retransplantation, morbidity, and death among pediatric heart transplant recipients.1,3– 8 Although coronary vasculopathy involves the epicardial coronary arteries and the microvasculature, only the former is amenable to mechanical intervention during cardiac catheterization. Therefore, the standard follow-up care for these patients at our institution includes annual coronary angiog-

Reprint requests: Ming Hui Chen, MD, MMSc, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. Telephone: 617-355-8366. Fax: 617-734-9930. E-mail address: [email protected]

raphy (ANG) to predominantly assess for significant epicardial coronary artery disease (CAD).1– 4 Given the invasive nature of ANG, non-invasive imaging is invaluable in the assessment of epicardial CAD and may allow for the exclusion of properly selected children from invasive ANG. Traditionally, 2 non-invasive imaging techniques, nuclear scintigraphy and dobutamine stress echocardiography (DSE), have been used to exclude CAD in the pediatric cardiac transplant population with reasonable sensitivity and specificity.3 All imaging techniques, however, have limitations, with nuclear stress imaging being time-intensive, requiring radiation exposure and intravenous catheter placement. DSE entails no radiation and is portable,1,2,5–9 but does not yield physiologic data regarding a patient’s exercise capacity.

1053-2498/$ -see front matter © 2012 International Society for Heart and Lung Transplantation. All rights reserved. doi:10.1016/j.healun.2011.12.014

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Exercise stress echocardiography (ESE), an important tool for the assessment of ischemia in adults, may provide distinct advantages in this pediatric patient population. Unlike nuclear scintigraphy and DSE, ESE allows for simultaneous assessment of ischemia and acquisition of functional data, without radiation exposure or intravenous catheter placement.10–13 Children’s Hospital Boston has implemented ESE in the evaluation of ischemia in children since 2007. However, very limited data have been published on the operating characteristics of this test in children and, specifically, in the pediatric cardiac transplant population.

Methods Study design We conducted a retrospective study to assess the utility and operating characteristics of ESE, compared with ANG, for the exclusion of significant epicardial CAD in pediatric cardiac transplant recipients at our institution. This study was approved by the Scientific Review Committee of the Department of Cardiology and by the Committee on Clinical Investigation at our institution.

Patients The cohort included all cardiac transplant recipients who received an allograft before age 21 years, monitored at Children’s Hospital Boston, and who had undergone ESE and ANG from January 2007 to December 2010. ESE and ANG had to be performed within 12 months of each other. If a patient underwent more than 1 ESE within a 12-month period, the ESE closest to the time of ANG was selected. All ESE and ANG reports were extracted from medical records by an individual (E.A.) not involved with the interpretation of the imaging studies.

ESE protocol All ESEs were performed according to a standardized institutional laboratory protocol. Symptom-limited exercise was performed on a treadmill, according to the Bruce protocol, or on a stationary bicycle. An iE33 x Matrix Echocardiography System with an x5–1 or an x8 transducer (Philips Medical System, Andover, MA) was used for all imaging. Echocardiographic imaging was obtained at rest and immediately after exercise. Only images acquired within 90 seconds of exercise cessation were selected and used for ischemia assessment. According to clinical laboratory protocol, images of the left ventricle (LV) were obtained from apical 4-chamber, 2-chamber, and 3-chamber views, parasternal long-axis view, and parasternal short-axis views at 3 levels of the LV (base, papillary muscles, and apex; Figures 1 and 2). The American Society of Echocardiography’s 16-segment model was used for wall motion analysis.14 All studies were clinically interpreted for the presence or absence of ischemia by a level III trained, non-invasive cardiologist (M.H.C.) with expertise in ESE, who was blinded to the ANG results and the clinical data and who was not involved in the selection of this cohort. Regional wall motion at rest and with exercise was interpreted as normal, hypokinetic, akinetic, or dyskinetic. Wall motion response to exercise was used to assess for ischemia according to the schematic outlined in Figure 3 and according to standard American Society of

Echocardiography guidelines.14,15 Presence of ischemia was defined as worsening of baseline wall motion, lack of augmentation with function, or development of a new wall motion abnormality with exercise in at least 1 coronary territory. If ischemia was reported, the echocardiogram was coded as positive for ischemia, and if no ischemia was reported, the echocardiogram was coded as negative.

Coronary ANG Standard ANG coronary views were obtained in all patients according to laboratory standards at our institution. ANGs were clinically interpreted by a single interventional cardiologist (L.B.) blinded to the ESE results and not involved in the selection of this retrospective cohort. During the analysis portion of this study, findings on all previously reported ANGs were also categorized according to International Society for Heart and Lung Transplantation (ISHLT) criteria for CAV3: ● ● ●

●

CAV0 (not significant): no detectable lesions. CAV1 (mild): ⬍ 50% left main narrowing or ⬍ 70% narrowing of any primary or branch vessels. CAV2 (moderate): ⬍50% stenosis of the left main and ⱖ 70% stenosis of 1 primary vessel, or ⱖ 70% stenosis in the branches of 2 systems. CAV3 (severe): ⱖ 50% left main narrowing, ⱖ 70% stenosis in ⱖ 2 primary vessels, or ⱖ 70% isolated branch stenosis in all 3 systems.

None of the patients were studied with intravascular ultrasound (IVUS).

Data analysis The ability of patients to perform the ESE, as well as any adverse events during testing, were documented in all ESE reports and noted for the purposes of this study. Exercise duration, peak heart rate, percentage predicted peak heart rate, peak blood pressure, and peak metabolic equivalents (METs) were recorded. An ESE report was issued for all patients on whom an ESE was attempted regardless of whether testing could be completed. ESE findings were compared with those of ANG to determine agreement statistics. If the ESE report documented no ischemia, and the ANG report documented no significant CAD (ISHLT CAV0), or if the ESE report documented ischemia and the ANG report documented mild to severe CAD (ISHLT CAV1 to CAV3), the 2 modalities were considered to be in agreement. ESE and ANG results were otherwise categorized as discordant.

Statistical analysis All data are presented as a median with range, or as a percentage. Sensitivity, specificity, and positive and negative predictive values with 95% confidence limits (CL) were calculated using standard definitions and methodology.

Results The study cohort consisted of 47 cardiac transplant patients who met inclusion criteria. Demographics of the study population and exercise details are reported in Table 1. ESE was successfully performed and well tolerated by all patients.

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Figure 1 Pre-exercise and post-exercise stress echocardiography shows apical 4-chamber, 2-chamber, and 3-chamber long-axis views of the left ventricle. CV, chamber view.

ANG showed that 9 of the 47 patients (19%) had CAD (ISHLT CAV1 to CAV3).

Exercise and electrocardiographic data Of the 47 study patients, 26 (55%) underwent treadmill testing according to the Bruce protocol, and the reminder underwent the upright bicycle protocol. Two patients did not have documentation of peak workload. The median peak workload achieved for the 45 patients was 7.4 METs (range, 3.3–17.2). Baseline electrocardiograms in 25 patients (53%) showed incomplete or complete right bundle branch block. Of these 25 patients, 1 also had a left bundle branch block. Two patients developed ST-T wave depressions with exercise to suggest ischemia, but had normal ESE imaging and negative ANG.

ESE imaging Of the 47 cohort patients, 46 (98%) had ESE images that were clinically interpretable for ischemia. One patient was excluded from further analysis secondary to lack of adequate acoustic windows after exercise. Of the remaining 46 patients, ESE had 88.9% sensitivity (95% CL, 51.8%, 99.7%) and 91.9% specificity (95% CL, 71.8%, 98.3%) in

detecting significant epicardial CAD among pediatric heart transplant recipients. The positive predictive value of ESE was 72.7%, and the negative predictive value was 97.1%. These results are summarized in Table 2. ESE and ANG were negative for CAD in 34 patients (68% female), who were a median age of 17.1 years (range, 5.9 –26.7 years) and were 7.6 years (range, 1.0 –21.1 years) post-transplant. Their peak work load was 7.3 METs (range, 3.5–17.2 METs; Table 3). Of the 9 patients with positive ANG for CAD, ESE was positive in 8 patients, who were a median age of 17.1 years (range, 10.9 –22.9 year) and had a median peak workload of 6.9 METs (range, 3.3–9.7 METs). Clinical characteristics are detailed in Table 4. The median time between testing in the entire cohort was 3.0 months (range, 0.0 – 8.8 months). There was no difference in the mean time between testing in patients with ANG-detected CAD (4.3 months) and those without CAD (3.0 months, p ⫽ 0.17). Discordant ANG and ESE results are reported in Table 5. ESE was interpreted as negative for patient 1, who had 50% narrowing of the distal left anterior descending artery on ANG. Conversely, ESEs were categorized as false positive for patients 2, 3, and 4, whose ESE was interpreted as positive for ischemia and whose ANG was negative for CAD. Patient 4 had left ventricular (LV) systolic dysfunction at rest (LV ejection frac-

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Figure 2 Pre-exercise and post-exercise stress echocardiography shows parasternal long-axis (LAX) and short-axis (SAX) views of the left ventricle at the base, mid, and apex.

tion, 45%), and the other 2 patients had normal resting LV ejection fraction.

Discussion This retrospective review demonstrates that ESE is a feasible, well-tolerated clinical tool with 92% specificity (95% CL, 78%, 98%) and 97% negative predictive value (95% CL, 85%, 100%) for the exclusion of significant ANGdetected CAD in pediatric cardiac transplant recipients. ESE requires neither intravenous catheter placement nor radiation exposure and also allows for the concurrent physiologic assessment of the patient’s exercise tolerance. ESE had a reasonable sensitivity of 89% (95% CL, 52%, 100%) for the detection of significant epicardial CAD, but the 95% CL is large, secondary to the small number of patients who had CAD on ANG. Although the cohort size of 47 patients

is small, this study systematically used and assessed the operating characteristics of ESE for the exclusion of ANGdetected epicardial CAD in pediatric cardiac transplant recipients. ESE detected 8 of the 9 patients with positive ANG (Tables 4 and 5). For patient 1 in Table 5, ANG demonstrated mild CAD (ISHLT CAV1) but ESE indicated no evidence of ischemia. This patient had no cardiac symptoms and normal cardiac pressures on catheterization. In general, ESE is less sensitive when there is single-vessel CAD instead of multi-vessel CAD.16 Several patient-related and imaging-related factors may help explain the high specificity and high negative predictive value achieved in this study: First, many of these patients had received allografts more than 5 years earlier. The risk of developing graft vasculopathy increases with time since transplantation. If graft CAV is detected, the disease is progressive.3 In our 9 patients

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521 Table 2 Agreement Statistics of Exercise Stress Echocardiography Compared With Coronary Angiography (N ⫽ 46) Variable

Percentage (95% CL)

Sensitivity Specificity Positive predictive value Negative predictive value

88.9 91.9 72.7 97.1

(51.8, (78.1, (39.0, (85.1,

99.7) 98.3) 94.0) 99.9)

CL, confidence limits.

Figure 3

Schematic used to assess for ischemia.

with positive ANGs, 56% had moderate-to-severe CAD (ISHLT CAV2 or CAV3). Second, these patients were relatively young and, therefore, had good acoustic windows. Lower sensitivity and specificity values would be expected among patients with poor acoustic windows or in those with single-vessel CAD.14 –16 Third, the ESE protocol of our institution includes several additional views (apical 3-chamber and short-axis at multiple levels) that are not always included in standard protocols for pediatric or adult stress imaging. These supplementary views afforded additional opportunities to assess for ischemia and regional wall motion abnormalities. Finally, training and experience with the performance and interpretation of ESE for CAD is important.14 Although cardiac transplant recipients develop both epicardial and microvascular disease, we focused solely on the detection of epicardial CAD in this study because it is amenable to mechanical intervention. Because ANG is performed annually for these patients, we were interested in

Table 1

Patient Demographics

Variable Female sex Age, years Age at transplant, years Time post-transplant, years Interval between ESE and ANG, months Peak workload, METs (n ⫽ 45) Heart rate Peak beats/minute Predicted peak, % Peak blood pressure (n ⫽ 42) Systolic, mm Hg Diastolic, mm Hg

No. (%) or median (range) (N ⫽ 47) 26 16.9 8.7 7.9 3.0

(55) (5.9–26.7) (0.4–22.8) (1.0–21.1) (0–9)

assessing if the application of ESE in the pediatric cardiac transplant population could identify ANG-detected CAD. We understand that using ANG-detected CAD as the standard with which to compare ESE findings may lead to categorizing some ESEs as false positives when microvascular but not epicardial disease is present. Three patients (patients 2, 3, and 4; Table 5) had no CAD on ANG but were interpreted as positive for ischemia with exercise-induced wall motion abnormalities on ESE. Patients 2 and 3 represent the limitations of ESE; however, patient 4 had long-standing LV systolic dysfunction. Given the history of chronic graft dysfunction, it is possible that this patient had significant microvascular disease or CAV, without having significant epicardial CAD on ANG. Although IVUS is a more sensitive method than ANG for detection of microvascular disease, IVUS was not routinely performed in pediatric cardiac transplant patients at our institution. To be conservative, therefore, this patient’s ESE study was categorized as a false positive along with the other 2 patients. There is paucity of published data on the utility of ESE in children. We are aware of 1 study to date that has used ESE to detect ischemia in pediatric cardiac transplant recipients. Maiers and Hurwitz4 retrospectively reviewed 20 pediatric heart transplant patients who had received myocardial perfusion imaging, of whom 10 also underwent ESEs and 4 underwent ANGs. However, the operating characteristics of ESE could not be assessed, given the different protocols each patient underwent. Therefore, the current study cohort of 47 patients represents a large systematic assessment of ESE’s utility for ischemia testing in the pediatric population.

Table 3 Exercise Stress Echocardiography and Coronary Angiography Findings of Ischemia and Coronary Artery Disease (N ⫽ 46)

7.4 (3.3–17.2)

ANG

155 (104–210) 78 (53–106) 130 (86–180) 70 (58–100)

ANG, coronary angiography; ESE, exercise stress echocardiography; METs, metabolic equivalents.

ESE Positive Negative Total

Positive

Negative

Total

8 1 9

3 34 37

11 35

ANG, coronary angiogram; ESE, exercise stress echocardiography.

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Table 4 Clinical and Exercise Characteristics of Patients With Coronary Artery Disease Confirmed by Exercise Stress Echocardiography and Coronary Angiography Clinical characteristics Pt

Sex

1 2 3 4 5 6 7 8

F F M M M M M F

Exercise characteristics

CAD detection

Age (years)

Time since Tx (years)

BSA (m2)

Protocol

Peak METs

ESE

15.9 17.3 19.4 10.9 22.2 16.9 14.7 19.3

11.3 3.9 3.1 8.0 8.6 10.2 4.5 14.1

1.32 1.51 1.90 1.27 2.09 1.49 1.86 2.09

Cycle Cycle Cycle Cycle Bruce Bruce Bruce Bruce

4.8 3.4 3.3 9.7 7.6 7.1 9.7 6.6

Positive Positive Positive Positive Positive Positive Positive Positive

ANG ISHLT CAV CAV3 CAV3 CAV1 CAV1 CAV3 CAV1 CAV3 CAV2

(severe) (severe) (mild) (mild) (severe) (mild) (severe) (moderate)

ANG, coronary angiography; BSA, body surface area; Bruce, Bruce treadmill protocol. CAD, coronary artery disease; CAV, coronary artery vasculopathy; Cycle, bicycle protocol at 15-watts, ESE, exercise stress echocardiography; F, female; ISHLT, International Society for Heart and Lung Transplantation; M, male; METs, metabolic equivalents; Tx, cardiac transplant.

The sensitivity and specificity values for ESE in this study compare favorably with those of ESE in the general adult population. Although data are lacking on the sensitivity and specificity of ESE in the pediatric cardiac transplant population, this study’s values of 89% and 92%, are at least comparable if not better than those reported in the general adult population who undergo ESE.14 In a review of 12 large ESE studies, Armstrong and Zoghbi11 reported ESE as having sensitivities ranging from 71% to 97%, specificities of 41% to 91%, positive predictive values of 71% to 97%, and negative predictive values of 40% to 91%. The sensitivity and specificity values for ESE in this study compare favorably with those of DSE in pediatric cardiac transplant recipients. Unlike with ESE, a number of studies have compared DSE vs ANG in children.1,2,5–9 One study of 70 pediatric heart transplant patients found the sensitivity and specificity values of DSE were 72% and 80%.6 In another study of 102 pediatric heart transplant recipients, DSE had a sensitivity of 35% and specificity of 94%.2 In both of these studies, DSE demonstrated a relatively high specificity in this population, similar to what we found with ESE. However, in patients who are able to exercise, ESE, unlike DSE, allows for correlation of patient symptoms with physical exertion without intravenous cath-

eter placement and without the side effects of dobutamine infusion.10,17 Although this study was not designed to correlate outcomes in patients with ANG-detected CAD, 2 patients died of CAV after the conclusion of this study. One patient presented with ESE and ANG-detected CAD (ISHLT CAV1) during the study. The other patient had a negative ESE and negative ANG, but a repeat ANG 3 years later showed ISHLT CAV3. A repeat ESE was not performed at that time. This study has a few limitations. We excluded patients for whom exercise was not possible, because ESE, by definition, can only be used in patients who are old enough or are physically able to exercise on a bicycle or treadmill. Therefore, ESE cannot typically be performed in children younger than 6 or 7 years, who may be uncomfortable walking on a treadmill or cycling on a stationary bicycle. Another limitation of this retrospective study was that ESE and ANG were generally performed within months of each other instead of days. Despite this limitation, the operating characteristics for ESE are still quite high. Furthermore, the study cohort consisted of children who were at higher risk for CAD. Despite the higher pretest probability

Table 5 Clinical and Exercise Characteristics of Patients with Discordant Exercise Stress Echocardiography and Coronary Angiography Clinical characteristics Pt

Sex

1 2 3 4

M M M M

Exercise characteristics

CAD detection

Age (years)

Time since Tx (years)

BSA (m2)

Protocol

Peak METs

ESE

ANG ISHLT CAV

20.9 16.4 8.7 16.9

7.3 15.4 7.2 16.0

1.68 1.57 0.9 1.35

Bruce Bruce Bruce Bruce

11.8 13.6 13 13.4

Negative Positive Positive Positive

CAV1 CAV0 CAV0 CAV0

(mild) (NS) (NS) (NS)

ANG, coronary angiography; BSA, body surface area; CAD, coronary artery disease; CAV, coronary artery vasculopathy; ESE, exercise stress echocardiography; ISHLT, International Society for Heart and Lung Transplantation; M, male; METs, metabolic equivalents; NS, not significant; Tx, cardiac transplant.

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of CAD, ESE was able to accurately exclude those patients without CAD. Although we included all eligible pediatric cardiac transplant patients studied by ESE during a 4-year period and are not aware of any larger cohorts of pediatric patients studied by ESE to date, our study is still limited by its relatively small sample size. Given the few pediatric heart transplants performed, small sample sizes are somewhat difficult to avoid in a study of a single center, even one that has a relatively large number of pediatric cardiac transplant recipients. Larger, multi-center studies from institutions skilled in pediatric ESE are needed to further define and generalize the operating characteristics of this modality. In conclusion, the experience with this cohort suggests that ESE is feasible in pediatric cardiac transplant recipients and has a high degree of specificity and excellent negative predictive value in the exclusion of ANG-detected epicardial CAD. Because these patients routinely undergo annual ANG, the ability of ESE to rule out ANG-detected CAD may be of equal or even greater clinical importance than a very sensitive test. Although this study has one of the largest pediatric cohorts to be assessed for ischemia by ESE, larger, prospective studies should be undertaken to confirm our findings. In the future, ESE may help to identify a subgroup of pediatric cardiac transplant recipients in need of less frequent cardiac catheterization.

10.

Disclosure statement

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The authors acknowledge support received by the Department of Cardiology, the Translational Fund for Research in Cardiology and Oncology, the Heart Transplant Program, and the staff and sonographers of the Echocardiography Lab and Exercise Physiology Lab at Children’s Hospital Boston; the assistance of Jing Zhou and Kimberlee Gauvreau in review of the statistical analyses; and the help of Lauren Blackington in the preparation of this manuscript. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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