Exercise Capacity Improves With Time in Pediatric Heart Transplant Recipients

Exercise Capacity Improves With Time in Pediatric Heart Transplant Recipients

Exercise Capacity Improves With Time in Pediatric Heart Transplant Recipients Anne I. Dipchand, MD, Cedric Manlhiot, BSc, Jennifer L. Russell, MD, Reb...

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Exercise Capacity Improves With Time in Pediatric Heart Transplant Recipients Anne I. Dipchand, MD, Cedric Manlhiot, BSc, Jennifer L. Russell, MD, Rebecca Gurofsky, Paul F. Kantor, MD, and Brian W. McCrindle, MD, MPH Background: The purpose of this study was to profile the exercise capacity of pediatric heart transplant recipients over time and to identify factors associated with lower exercise capacity. Methods: Pediatric heart transplant (HTx) recipients ⬎6 years of age underwent annual cycle ergometry exercise testing (GXT). Exercise testing values were converted to percent predicted based on age and gender when available. Linear regression analysis adjusted for repeated measures was used to determine trends over time and associated factors. Results: A total of 58 patients (34 males, 59%) had 202 GXTs (2 to 8 years post-transplant). The mean percent predicted maximum heart rate (HR) response was 76 ⫾ 10% predicted, increased non-linearly with time post-transplant (p⬍0.0001), and was associated with a higher resting HR, longer time post-transplant and older age at transplant. Mean percent predicted workload was 66 ⫾ 15%, mildly below normal controls. Mean maximum oxygen consumption (VO2max) was 30 ⫾ 8 ml/kg/min and was found to be influenced over time by an interaction between age at transplantation and time since transplant. Greater systolic blood pressure (BP) response was associated with longer time post-transplant and higher resting systolic BP. Overall, pediatric heart transplant is associated with good exercise capacity. Younger age at transplant is associated with greater exercise capacity (VO2max). Serial trends in HR, BP response and VO2max may provide supportive evidence for graft reinnervation. Deterioration in VO2max was associated with graft loss because of vasculopathy. Conclusion: The utility of serial routine GXT in pediatric heart transplant recipients warrants further study, especially for its role in the detection of graft vasculopathy. J Heart Lung Transplant 2009;28: 585–90. Copyright © 2009 by the International Society for Heart and Lung Transplantation.

After heart transplantation (HTx), physiologic responses to exercise may be impaired due to multiple factors, including age at time of HTx,1 deconditioning prior to HTx, growth of the allograft,2,3 degree of reinnervation,4 –7 chronotropic incompetence,8 –10 comorbidities, and direct medication effects on skeletal muscle (corticosteroids and cyclosporine).11,12 Standardized, graded exercise testing (GXT) is an excellent non-invasive way to test physical functional capacity. Exercise testing in adult HTx recipients demonstrates an increased resting heart rate (HR), a decreased HR response to exercise, and decreased maximum oxygen consumption (VO2max).8,13–15 Previous studies looking

From the Labatt Family Heart Centre, Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. Submitted September 4, 2008; revised January 12, 2009; accepted January 21, 2009. Reprint requests: Anne I. Dipchand, MD, Heart Transplant Program, Labatt Family Heart Centre, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. Telephone: 416-813-6674. Fax: 416-813-7547. E-mail: [email protected] Copyright © 2009 by the International Society for Heart and Lung Transplantation. 1053-2498/09/$–see front matter. doi:10.1016/ j.healun.2009.01.025

at exercise performance in pediatric HTx recipients had limited sample sizes but also demonstrated a blunted HR response to GXT and decreased VO2max.9,16 –18 A group of pediatric HTx patients in whom the HR response was faster and greater has been described.10 Despite near normalization of HR response, there remained sub-maximal VO2. There have been a few studies demonstrating a more normal HR response and a low normal VO2max.1,19 Serial exercise assessment data in the adult population demonstrated either a progressive decrease in VO2max with increasing time post-HTx (mean rate 5% per year),20 or no change in either HR or VO2max.8 There are minimal data in the pediatric HTx population, a previous study found decreased but stable exercise capacity over time, similar to results for adult patients.9 A recent longitudinal assessment demonstrated declining exercise capacity over time despite an initial improvement after HTx.18 The primary purpose of this study was to profile the exercise capacity of pediatric HTx recipients over time and to look at factors associated with exercise capacity in addition to the potential for rehabilitation. Determination of a potential prognostic utility for serial exercise testing was also pursued. Herein, we report the largest 585

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cohort of pediatric HTx recipients undergoing serial GXT over the longest period of time. METHODS Exercise Protocol Cycle ergometry exercise testing (GXT) was done annually on all pediatric HTx recipients of appropriate age (ⱖ6 years), size (⬎118 cm) and physical capability, starting at 6 to 12 months post-transplant. Each subject underwent a progressive cardiopulmonary GXT with continuous monitoring by 12-lead electrocardiogram (ECG), ventilation and periodic blood pressure measures every 2 minutes. Subjects were encouraged to exercise until volitional fatigue, but were advised to report any symptoms (i.e., chest pain, dizziness). GXT was performed on a programmable cycle ergometer (800S-Ergoline; Ergometrics, USA), according to an individualized ramp protocol designed to elicit a maximal response in 8 to 12 minutes. Respiratory data were collected and analyzed on a breath-by-breath basis and averaged for a 20-second period using a metabolic cart (Max-2; Physio-Dyne, USA). Volume and gas calibration was done prior to each test. Each patient exercised with a 2-way non-rebreathing valve (Hans Rudolph, USA). Anaerobic threshold was determined using the “V-slope” method in which VCO2 was plotted as a function of VO2. Peak oxygen consumption was taken as the maximum VO2 value obtained during the test, and was considered sub-maximal if the respiratory exchange ratio (RER) failed to exceed 1.0. Institutional research ethics board approval was obtained. Data Analysis Maximum VO2, heart rate and workload were converted into percent predicted based on age and gender normal values.20 Linear regression analysis, based on maximum likelihood estimates, adjusted for repeated measures with an autoregressive covariance structure, was used to determine trends over time in exercise test results since transplantation and associated factors. Univariate models were created for all potential associations. Associations with p-values ⬍0.10 were then included in multivariate models, and backward selection was used to obtain a final model for each of the exercise test variables. Time of exercise testing since heart transplantation was logarithmically transformed. All statistical analysis was performed using SAS statistical software v9.1 (SAS Institute, Cary, NC). RESULTS Patient Population Fifty-eight patients (59% males), who underwent a total of 62 heart transplantations, were included in this study. Median age at transplantation was 6 years (birth to 16 years). Patients underwent a total of 202 GXTs;

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first, GXT was done at a median of 21 months after transplantation (range 6 months to 11 years) and at a median age of 10 years (range 5 to 20 years). Patients had their GXTs over a 2- to 8-year period and had their last study at a median of 7 years post-transplantation (up to 11.5 years). Most patients (86%) underwent serial testing with a median number of tests of 3 (range 1 to 8 tests). All patients had normal systolic ventricular function by echocardiography at the time of GXT. Immunosuppression Regime Routine immunosuppression at our institution consists of induction with thymoglobulin for 2 to 5 days, tacrolimus and mycophenolate mofetil. Corticosteroids are given peri-operatively and then weaned within 6 months post-transplant. A small number of patients receive cyclosporine and/or sirolimus, usually for the management of post-transplant morbidities. Comorbidities Three patients were morbidly obese at the time of exercise testing (body mass index ⬎140%). All biopsies were graded for rejection according to the new International Society for Heart and Lung Transplantation (ISHLT) criteria (Stewart) as 0 (none), 1R (mild), 2R (moderate) or 3R (severe). The highest grade of rejection during the year of each GXT was recorded. Of the 202 exercise tests, 185 (91%) were associated with no or mild rejection (ISHLT Grade 0 or 1R), and 17 (9%) with Grade 2R or 3R on endomyocardial biopsy. Coronary artery vasculopathy (CAV), as diagnosed by a combination of coronary angiography, intravascular ultrasound and/or dobutamine stress echocardiography, was absent in 37 grafts (60%), mild in 19 (31%), moderate in 3 (5%) and severe in 3 (5%). Level of graft vasculopathy was assessed at the time of the last exercise test. Six patients were listed for a second HTx, of whom 5 underwent retransplantation and 1 died while waiting. Chronic respiratory problems were seen in 9 (16%) patients, 2 of whom had a restrictive pattern on pulmonary function testing. No patient had an obstructive pattern on pulmonary function testing. Three patients utilized night-time biphasic intermittent positive airway pressure (BiPAP) ventilation chronically for either nocturnal hypoventilation or sleep-related disordered breathing patterns related to phrenic nerve damage and diaphragm palsy or paresis. Chronic renal failure was seen in 10 (17%) patients, of whom 2 progressed to dialysis within the year of the most recent GXT. One patient had a mitochondrial disorder with mild clinical involvement of peripheral skeletal muscles. No patient had muscular dystrophy, chromosomal abnormalities or global or motor developmental delay.

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Electrocardiographic Abnormalities ST-segment changes (ⱖ2 mm depression in the limb leads, downsloping, T-wave inversion) on ECG were noted in 2 GXTs (1%). One of these patients underwent retransplantation for CAV and 1 was diagnosed with mild CAV. There were 2 documented significant arrhythmias (ventricular tachycardia)—1 with moderate CAV, who underwent retransplantation, and 1 with mild CAV. Heart Rate The mean peak HR for all 202 exercise tests was 158 ⫾ 20 beats per minute (bpm). The mean percent predicted maximum heart rate (PPmaxHR) was 76 ⫾ 10%. A small but statistically significant increase was observed in PPmaxHR over time (Figure 1). Other factors found to be associated with higher PPmaxHR were longer duration of time since transplant (p ⬍ 0.0001), older age at transplantation (p ⫽ 0.05), higher resting HR (p ⬍ 0.0001) and not having undergone retransplantation (p ⫽ 0.002) (Table 1). Workload Eight patients had a percent predicted maximum workload (PPmaxWL) of ⬍40%, all but 1 of whom clearly had other comorbidities that could affect workload. These patients were excluded from this part of the analysis in order to be able to assess the effect of HTx alone. The mean PPmaxWL was 66 ⫾ 15%, which is just mildly reduced in comparison to accepted values in a population of normal controls (Figure 2). PPmaxWL was not found to change with time since transplantation (p ⫽ 0.84). Higher weight at the time of exercise testing (p ⬍ 0.001), arrhythmia (p ⫽ 0.005) or STsegment changes (p ⫽ 0.0003) during the exercise test were associated with lower PPmaxWL. Oxygen Consumption The mean maximum VO2 (VO2max) was 30 ⫾ 8 ml/kg/min, giving a mean predicted maximum VO2

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Table 1. Independent Factors Associated With Exercise Variables Estimate (SE) Higher percent predicted maximum heart rate Longer time since transplantation Older age at transplantation Higher pre-test heart rate Not having undergone retransplantation Higher percent predicted maximum work load Lower weight at exercise testing No arrhythmia during exercise test No ST changes during exercise test Higher percent predicted maximum VO2 Time since transplantation Younger age at transplantation Interaction: time since transplantation and age at transplantation Lower grade of graft vasculopathy Higher peak systolic blood pressure Longer time since transplantation Higher grade of rejection at time of testing Higher weight at time of testing Higher systolic blood pressure at rest Not having undergone retransplantation Higher systolic blood pressure response to exercise Longer time since transplantation Higher grade of rejection at time of testing Higher weight at time of testing Lower systolic blood pressure at rest Lower heart rate at rest Not having undergone retransplantation

p

0.053 (0.014) 0.006 (0.003) 0.003 (0.001)

0.0001 0.05 ⬍0.0001

0.082 (0.026)

0.002

0.010 (0.003) 0.085 (0.030) 0.218 (0.059)

0.001 0.005 0.0003

⫺0.169 (0.093) 0.045 (0.019)

0.07 0.02

0.018 (0.009) 0.061 (0.027)

0.05 0.03

0.014 (0.006)

0.01

0.020 (0.009) 0.003 (0.001)

0.02 ⬍0.0001

0.005 (0.001)

⬍0.0001

0.032 (0.014)

0.03

0.061 (0.026)

0.02

0.101 (0.037) 0.011 (0.002)

0.007 ⬍0.0001

0.009 (0.003) 0.005 (0.002)

0.0002 0.02

0.155 (0.064)

0.02

Time since transplantation and age at transplantation in years, weight in kilograms.

Figure 1. Change over time in percent predicted maximal heart rate.

(PPVO2max) of 67 ⫾ 17%. Mean PPVO2max was found to be influenced over time by an interaction between age at transplantation and time since transplantation. Patients transplanted at a very young age had exercise testing only many years later, and thus mean PPVO2max in these patients was stable over time, with a nonsignificant trend toward lower PPVO2max (p ⫽ 0.71 for children ⬍1 year of age at time of transplantation) (Figure 3). In older patients, who underwent exercise testing much closer to transplantation, a significant increase over time in PPVO2max was observed, especially in the 2 years after heart transplantation (Figure

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Figure 2. Change over time in percent predicted workload.

Figure 4. Change over time in systolic blood pressure.

3). Presence of CAV at the last exercise test was found to be associated with lower PPVO2max. The reduction in PPVO2max was proportional to the extent of vasculopathy observed (Table 1).

DISCUSSION This is the largest cohort of pediatric HTx recipients undergoing serial GXTs over the longest period of time reported to date. There are few data in the literature

describing changes in exercise capacity with time posttransplant, especially in the pediatric population. Hsu et al reviewed 31 patients (6.4 to 17 years old at time of transplant) within 2 years post-transplant with one follow-up study 2 to 4 years post-transplant, and concluded that exercise capacity was decreased but stable over time in pediatric patients after HTx.9 Conversely, Davis et al found that exercise capacity decreases over time after an initial improvement post-transplantation.18 Exercise capacity is better in children transplanted at a younger age, specifically infant transplant recipients. Abarbanell et al1 demonstrated exercise capacity in infant recipients in the low normal range (VO2max of 32.3 ⫾ 5.6 ml/kg/min), which was higher than findings from older children and adolescents.9,16,17 Our data also demonstrate that infant and child HTx recipients exhibit evidence of better functional adaptation as evidenced by higher PPVO2max (VO2max 31.4 ⫾ 5.4 ml/kg/min for ⬍1 year old, 33.2 ⫾ 6.7 ml/kg/min for 1 to 10 years old, 24.6 ⫾ 6.8 for ⬎10 years old) (Table 1 and Figure 3). The difference in VO2max is not attributable to younger recipients being later post-transplant at the time of GXT because greater PPVO2max at any time was significantly associated with younger age at transplant (Table 1). Marconi also demonstrated a de-

Figure 3. Change over time in percent predicted VO2max.

Figure 5. Change over time in systolic blood pressure response to exercise.

Systolic Blood Pressure Response to Exercise Peak systolic blood pressure was 136 ⫾ 16 mm Hg, whereas the systolic response to exercise was, on average, 31 ⫾ 12 mm Hg. Both measures were found to increase significantly with longer time since transplantation (Figures 4 and 5). Other factors associated with higher peak systolic blood pressure were higher weight (p ⬍ 0.0001) and grade of rejection (p ⫽ 0.02) at the time of exercise testing, higher resting systolic blood pressure (p ⬍ 0.0001), and not having undergone retransplantation (p ⫽ 0.03) (Table 1). Factors associated with a higher systolic response to exercise were similar with the exception of being associated with lower resting systolic BP (p ⬍ 0.0002) and lower resting HR (p ⫽ 0.02).

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crease in peak VO2 with increasing age at time of transplant.14 There are several reports in the literature detailing peak HR in response to exercise in the post-transplant population. In one study on adults, the reported peak HR in 57 HTx recipients was, on average, 120 to 130 bpm.8 The reported HR response to exercise in the pediatric population has varied across a several studies with small numbers of patients.9,16,17 Hsu et al reported a mean peak HR similar to that of an adult population at 136 ⫾ 22 bpm in 31 older children and young adolescents.9 In two other studies looking specifically at adolescent HTx recipients, Christos et al17 reported a peak HR of 154 ⫾ 8 bpm (n ⫽ 7) and Nixon et al16 of 134 bpm (n ⫽ 16), respectively. In contrast, Pastore et al reported a peak HR of 169 ⫾ 5 bpm in 14 older children and early adolescent HTx recipients.19 In the Abarbanell report, the 24 infant transplant recipients had a peak HR of 158 ⫾ 15 bpm.1 Marconi reported a group of pediatric HTx patients (“responders”) with a faster and greater HR response (177 ⫾ 16 vs 151 ⫾ 25 bpm) and hypothesized that this may reflect some degree of allograft reinnervation, specifically the donor sinus node.14 The average peak HR response in our patient cohort was 158 ⫾ 20 bpm across the spectrum of age at time of transplant and time post-transplant, with an overall PPmaxHR of 76 ⫾ 10%. As noted earlier, there were age-related differences. The chronotropic response in the adult population has been shown previously to improve within the first year post-transplant,8,10,21 and also over the long term.22 The data on cardiac reinnervation are primarily based in animal or adult studies and the findings have been varied and often contradictory.7,23 One pediatric study found clinical evidence of late autonomic reinnervation in cardiac allografts.24 There are data to suggest that there is better exercise performance in adult HTx recipients with evidence of reinnervation.4 – 6 Reinnervation seems to be a time-dependent phenomenon, more likely with earlier age at transplant and with younger donors (even in adults), and is associated with improved HR response and myocardial contractility in the adult population.4 – 6,10 In our cohort, there was a significant positive relationship between HR and time post-transplant for older recipients. As noted earlier, this is hypothesized to be related to the earlier GXT and sequential follow-up (Figure 1). Younger transplant recipients (i.e., infants) do not undergo exercise testing until 6 to 8 years post-transplant and show higher PPVO2max but less of a chronotropic response on serial studies, which raises the possibility of a time-related phenomenon in incremental improvement in exercise performance (Figure 1). The reported VO2max in the pediatric population, as with peak HR, is also quite variable, as are the conclu-

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sions regarding exercise capacity in this patient population. Values reported include 20 ⫾ 6,9 22 ⫾ 8,17 22.3,16 25 ⫾ 7,18 33 ⫾ 2119 and 33 ⫾ 6 ml/kg/min in Abarbanall et al’s1 infant population. There have been multiple observations made of differences depending on age at time of transplant, as discussed earlier, but even some of this is conflicting as Pastore’s group of older children and young adolescents had a nearnormal reported VO2max of 33 ⫾ 2.1 ml/kg/min.19 Our VO2max of 30 ⫾ 8 ml/kg/min across the spectrum of age at transplant and time post-transplant indicates a good exercise capacity in pediatric HTx recipients overall. PPVO2max was mildly reduced compared with accepted values in a population of normal patients. PPVO2max increased with time in the earlier posttransplant period (Figure 3), which differs markedly from the available data in adult recipients8,21 as well as the previous pediatric data.9,18 Our cohort is more representative of the entire pediatric age range and a wide range of times post-transplant with serial data available. Again, as with VO2 and HR, peak systolic BP and mean BP response to exercise increased with time post-transplant (Figures 4 and 5). Peak systolic BP and BP response were the only parameters having any association with rejection, which is difficult to explain (Table 1). One could hypothesize that these patients may have had recent steroid use affecting BP and/or, overall, had a higher immunosuppression load. Workload was just mildly reduced overall (66 ⫾ 15%), as compared with accepted values in a population of normal controls, and higher than reported in the literature among other pediatric HTx recipients, such as those studied by Hsu et al (61%).9 However, there was no change in PPmaxWL with time post-transplant. Of note, all 3 patients with morbid obesity had PPmaxWL ⬍40%. Conversely, lower weight was significantly associated with higher PPmaxWL (p ⫽ 0.001) (Table 1). Looking at the patients with CAV, there was an association between a progressive decline in PPmaxVO2 on serial studies and the presence of moderate to severe CAV, although the numbers were low (Table 1). Fifty percent of the patients with significant CAV leading to graft loss had ischemic changes and/or a significant arrhythmia at the time of GXT. No patient with improvement or stability in PPVO2max had graft loss for any reason (regardless of history of rejection or degree of CAV). These observations are particularly intriguing given the ongoing need to determine better diagnostic and prognostic tests for the presence and significance of CAV. Our study suggests that serial reduction in exercise PPVO2max could potentially be used as a marker of graft vasculopathy and may thus improve detection of this major late complication of HTx.

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There are limitations to this study. Although the GXT was done prospectively as part of a clinical protocol, there was no standardization of therapy and interventions for the management of post-transplant patients at our institution. The utility of GXT is limited from the outset to appropriate age, size and capability of each individual patient. Finally, the highest achievable VO2max determination requires that anaerobic threshold is reached and maximum workload at peak exercise assumes that there is appropriate effort. Both of these assumptions were made prior to data analysis. However, if either were incorrect, it would lead to underestimation, meaning that the data would reflect minimum exercise capacity. In conclusion, in contrast to the experience with adult HTx recipients, pediatric HTx is generally associated with near-normal exercise capacity with low normal oxygen consumption and just mildly reduced workload. Younger age at transplant is associated with greater exercise capacity (oxygen consumption). Heart rate, systolic blood pressure response and oxygen consumption all demonstrate significant increments with time post-transplant, possibly providing supportive evidence for reinnervation of the allograft. In serial studies, deterioration in percent predicted VO2max has been associated with a need for retransplantation for allograft vasculopathy. The utility of serial routine graded exercise tests in pediatric HTx recipients warrants further study, especially for its role in the detection of allograft vasculopathy. REFERENCES 1. Abarbanell G, Mulla N, Chinnock R, et al. Exercise assessment in infants after cardiac transplantation. J Heart Lung Transplant 2004;23:1334 – 8. 2. Bernstein D, Kolla S, Sanders M, et al. Cardiac growth after pediatric heart transplantation. Circulation 1992;85:1433–9. 3. Zales VR, Wright KL, Pahl E, et al. Normal left ventricular muscle mass and mass/volume ratio after pediatric heart transplantation. Circulation 1994;90(suppl):II-61–5. 4. Schwaiblmair M, von Scheidt W, Uberfuhr P, et al. Functional significance of cardiac reinnervation in heart transplant recipients. J Heart Lung Transplant 1999;18:838 – 45. 5. Bengal FM, Uberfuhr P, Schiepel N, et al. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med 2001;345:731– 8. 6. Bengal FM, Uberfuhr P, Hesse T, et al. Clinical determinants of ventricular sympathetic reinnervation after orthotopic heart transplantation. Circulation 2002;106:831–5.

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7. Mancini DM. Surgically denervated cardiac transplant. Rewired or permanently unplugged? Circulation 1997;96:6 – 8. 8. Givertz MM, Hartley LH, Colucci WE. Long-term sequential changes in exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation 1997;96:232–7. 9. Hsu DT, Garofano RP, Douglas JM, et al. Exercise performance after pediatric heart transplantation. Circulation 1993;88(suppl): II-238 – 42. 10. Marconi C, Marzorati M, Fiocchi R, et al. Age-related heart rate response to exercise in heart transplant recipients. Functional significance. Eur J Physiol 2002;443:698 –706. 11. Biring MS, Fournier M, Ross DJ, et al. Cellular adaptations of skeletal muscles to cyclosporine. J Appl Physiol 1998;84: 1967–75. 12. Tegtbur U, Busse MW, Jung K, et al. Time course of physical reconditioning during exercise rehabilitation late after heart transplantation. J Heart Lung Transplant 2005;24:270 – 4. 13. Renlund DG, Taylor DO, Ensley RD, et al. Exercise capacity after heart transplantation: influence of donor and recipient characteristics. J Heart Lung Transplant 1996;15:16 –24. 14. Marconi C. Pathophysiology of cardiac transplantation and the challenge of exercise. Int J Sports Med 2000;21(suppl): S106 – 8. 15. Kavanagh T, Yacoub MH, Mertens DJ, et al. Cardiorespiratory responses to exercise training after orthotropic cardiac transplantation. Circulation 1988;77:162–71. 16. Nixon PA, Fricker FJ, Noyes BE, et al. Exercise testing in pediatric heart, heart–lung and lung transplant recipients. Chest 1995;107: 1328 –35. 17. Christos SC, Katch V, Crowley DC, et al. Hemodynamic responses to upright exercise of adolescent cardiac transplant recipients. J Pediatr 1992;121:312– 6. 18. Davis JA, McBride MG, Christant MRK, et al. Longitudinal assessment of cardiovascular exercise performance after pediatric heart transplantation. J Heart Lung Transplant 2006;25: 626 –33. 19. Pastore E, Turchetta A, Attias L, et al. Cardiorespiratory functional assessment after pediatric heart transplantation. Pediatr Transplant 2001;5:425–9. 20. Mandak JS, Aaronson KD, Mancini DM. Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant 1995;14:468 –78. 21. Washington RL, van Gundy JC, Cohen C, et al. Normal aerobic and anaerobic exercise data for North American children. J Pediatr 1988;112:223–33. 22. Pope SE, Stinson EB, Daughters GT, et al. Exercise response of the denervated heart in long-term cardiac transplant recipients. Am J Cardiol 1980;46:213– 8. 23. Wilson RF, Johnson TH, Haidet GC, et al. Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation. Circulation 2000;101:2727–33. 24. Singh TP, Gauvreau K, Rhodes J, et al. Longitudinal changes in heart rate recovery after maximal exercise in pediatric heart transplant recipients: evidence of autonomic re-innervation? J Heart Lung Transplant 2007;26:1306 –12.