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Homograft insertion for pulmonary regurgitation after repair of tetralogy of Fallot improves cardiorespiratory exercise performance
Homograft Insertion for Pulmonary Regurgitation After Repair of Tetralogy of Fallot Improves Cardiorespiratory Exercise Performance Benedicte Eyskens, MD, Tony Reybrouck, PhD, Jan Bogaert, MD, PhD, Steven Dymarkowsky, MD, Wim Daenen, MD, Monique Dumoulin, MD, and Marc Gewillig, MD, PhD Surgical repair of tetralogy of Fallot (TOF) with reconstruction of the right ventricular (RV) outflow tract invariably results in pulmonary regurgitation. Chronic pulmonary regurgitation has been associated with RV dysfunction and decreased exercise performance. The present study assessed the influence of pulmonary valve replacement (PVR) for severe pulmonary regurgitation after previous TOF repair on cardiorespiratory exercise performance and RV function. Eighteen patients, between the ages of 8 and 18 years, underwent an exercise test and a cardiac magnetic resonance imaging scan at least 1 year after PVR. The exercise data were compared with those obtained from 24 age-matched normal controls and 27 age-matched patients with repaired TOF and a moderate degree of pulmonary regurgitation. A subgroup of 11 patients had an exercise test performed before and after PVR. Cardiopulmonary exercise performance was evaluated by determination of the ventilatory anaerobic threshold (VAT) and by the steepness of the slope of oxygen uptake versus exercise intensity ˙ O2). After PVR there was a significant increase in (SV
VAT (86 ⴞ 11% before to 106.9 ⴞ 14% after, p ⴝ 0.03) ˙ O2 (1.71 ⴞ 0.47 to 2.3 ⴞ 0.39, p ⴝ 0.004). In and in SV ˙ O2 values patients examined after PVR, the VAT and SV were not significantly different from the values in the normal controls (104 ⴞ 15% [p >0.05] and 2.03 ⴞ 0.77 after PVR vs 2.42 ⴞ 0.68 [p >0.25], respectively). In contrast, patients with repaired TOF and a moderate degree of pulmonary regurgitation had a significantly ˙ O2 (1.8 ⴞ 0.74 lower VAT (86 ⴞ 11%, p <0.05) and SV vs 2.42 ⴞ 0.68, p <0.05) than normal controls. Magnetic resonance imaging studies revealed residual RV dilatation and dysfunction. However, there was no correlation between RV dilatation and RV dysfunction and aerobic exercise capacity. It is concluded that aerobic exercise capacity substantially improves after PVR for severe pulmonary regurgitation after previous TOF repair. Although the right ventricle remains significantly dilated and hypocontractile, there is no relation between RV function and exercise performance. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:221–225)
fter surgical repair of tetralogy of Fallot (TOF) most patients have an excellent functional result A and lead a normal active and social life. Neverthe-
ercise testing in a group of patients before and after pulmonary valve replacement (PVR) for severe pulmonary regurgitation after previous TOF repair in infancy. Cardiorespiratory exercise performance was assessed by determination of the ventilatory anaerobic threshold (VAT). The adequacy of the cardiovascular exercise function was more specifically evaluated by assessment of the steepness of the slope of oxygen ˙ O2). In addition, uptake versus exercise intensity (SV RV function after PVR was evaluated using magnetic resonance imaging. RV end-diastolic volume and RV ejection fraction were correlated with the parameters of aerobic exercise capacity. Patients: Between 1989 and 1997, 31 patients underwent PVR with a homograft for severe pulmonary regurgitation at our institution. In a subgroup consisting of 18 patients, aged between 8 and 18 years, exercise performance and RV function were assessed at least 1 year after PVR. Patients aged ⬍8 and ⬎18 years were excluded from the study because of lack of normal values for parameters of aerobic exercise function. Patients were evaluated at a mean age of 16.6 ⫾ 4.2 years at a mean time interval of 2.8 ⫾ 1.4 years after PVR. Five of the 18 patients had initial palliation
1– 4
less, almost all patients have some degree of pulmonary regurgitation as a result of right ventricular (RV) outflow tract reconstruction.2,5 Long-standing significant pulmonary regurgitation has been shown to be associated with RV dysfunction, ventricular arrhythmias,2 and an impaired exercise tolerance.6 –15 Restoration of pulmonary valve competence with insertion of a prosthetic valve or an allograft has been shown to improve RV performance and functional ability.5,16 In most studies, exercise tolerance in these patients has been evaluated by medical history, which lacks sensitivity. The purpose of this study was to assess cardiopulmonary exercise performance during formal exFrom the Departments of Pediatric and Congenital Cardiology, Cardiovascular Rehabilitation, Cardiac Surgery, and Radiology, University Hospital Gasthuisberg, Leuven, Belgium. Manuscript received May 14, 1999; revised manuscript received and accepted August 24, 1999. Address for reprints: Benedicte Eyskens, MD, Department Pediatric Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected]. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 15, 2000
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with a Blalock-Taussig shunt. Age at primary repair was 3.5 ⫾ 3.1 years. Surgical repair was performed through a right ventriculotomy in all patients and 15 of the 18 patients required a transannular patch for relief of RV outflow tract obstruction. Mean age at PVR was 13.5 ⫾ 5.7 years, with a mean time interval of 10.1 ⫾ 4.1 years after primary repair. All patients received an adult-sized homograft. A pulmonary homograft was inserted into 17 patients and an aortic homograft was inserted into 1 patient. Indications for PVR were severe pulmonary regurgitation with progressive signs of RV volume overload, which was assessed by increasing cardiomegaly on chest x-ray, progressive RV dilatation or worsening RV function as seen on echocardiography or angiocardiography, progressive tricuspid valve regurgitation, decreasing exercise tolerance, or ventricular arrhythmias. At the time of PVR the mean RV outflow tract gradient was 12 mm Hg (range 0 to 35). In the study group, no patient developed ventricular arrhythmias before PVR. Exercise performance data from the 18 patients were compared with data obtained from 24 normal healthy controls (mean age 11.6 ⫾ 2.6 years, range 7.2 to 17.7) and from 27 patients with repaired TOF (mean age 12.1 ⫾ 3.3 years, range 5.5 to 16.7) who had not required a homograft and who had only a moderate degree of pulmonary regurgitation. Of these 18 patients, a subgroup of 11 patients also underwent an exercise test before PVR. In these patients the results were compared before and after PVR.
METHODS
Exercise testing procedures: Submaximal exercise tests were performed on a calibrated motor-driven treadmill. The speed was set at 5.6 km/hour. During the test, patients were not allowed to hold the bars of the treadmill. Exercise testing was started at 0% inclination and the level was increased by 2% every minute until a target heart rate of 170 beats/min was reached. Respiratory gas exchange was measured on a breath-by-breath basis by mass spectrometry. Oxygen ˙ O2), carbon dioxide output (V ˙ CO2), and uptake (V ˙ minute ventilation (VE) were calculated using a previously reported method.17 The validity and reproducibility of the breath-by-breath method for analysis of gas exchange has previously been evaluated in our laboratory.18,19 During the test, a 12-lead electrocardiogram was continuously monitored and recorded every minute for a 15-second interval. Cardiorespiratory exercise function was assessed by determination of the VAT. This was defined as the inflection point in ˙ CO2 versus V ˙ O2 slope (V-slope method), which the V ˙ CO2 above the VAT.20 shows a steeper increase in V The VAT was calculated using a computer algorithm17 and was further checked by visual inspection. The values for VAT are expressed in ml/min/kg or as a percentage of the normal mean value for age and gender, which was obtained from a large pool of 237 healthy children.21 The adequacy of the O2 transport system was further assessed by analysis of the ˙ O2,22,23 expressed as ml O2/min/kg. In this regresSV sion analysis, data were calculated using all breaths 222 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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˙ O2 versus exercise FIGURE 1. Typical example of the slope of V intensity in a patient after TOF repair (closed circles) and a normal control (open circles).
averaged every 10 seconds. A typical example of the ˙ O2 versus exercise intensity is shown in slope of V Figure 1. Informed consent was obtained from the parents of the patients. The protocol was approved by the local medical ethical committee. Magnetic resonance imaging: Magnetic resonance was used to measure right and left ventricular volumes and to quantify volumetric flow in the ascending aorta, pulmonary trunk, and through the mitral and tricuspid valve. The studies were performed on a 1.5 Tesla scan (Siemens Vision, Erlangen, Germany) using commercially available electrocardiographic triggering. Ventricular volumes were quantified by means of breathhold segmented gradient-recalled echo sequences. The ventricles were encompassed by means of contiguous short-axis views from base to apex. A horizontal longaxis view was also obtained to correct for longitudinal ventricular shortening during systole. Ventricular volumes were calculated after delineation of the endocardial surfaces of the end-diastolic and end-systolic images. Multiplication of the delineated cavity area with the slice thickness yielded slice volume, and summation of all slice volumes yielded ventricular volume at end-diastole and end-systole. End-diastole was defined as the time frame associated with the maximum ventricular volume, and end-systole with that of minimum ventricular volume. Stroke volume was determined by the subtraction of end-systolic volume from end-diastolic volume. Ejection fraction was calculated as stroke volume/end-diastolic volume ⫻ 100%. Flow volumes were quantified by means of velocity-encoded cine magnetic resonance sequences. Aortic and pulmonary blood flow were quantified just above the level of the semilunar valve in a plane perpendicular through the vessel of interest. For the atrioventricular valves, a plane perpendicular through the base of the valve was chosen. Subsequently, the forward flow, backward flow, and effective forward flow were quantified. The accuracy and reproducibility of measurements have been previously assessed in a normal group of volunteers.24 JANUARY 15, 2000
FIGURE 2. VAT before and after PVR.
Statistical analysis: Difference between the mean values were calculated by univariate analysis of variance and for heart rate, by analysis of variance with repeated measurements. For regression analysis a linear regression technique was applied and for correlation analysis the Pearson correlation method was used. The SAS computer software (SAS institute, Inc. Cary, North Carolina) was used for statistical analysis. The significance level was set at p ⬍0.05.
RESULTS
FIGURE 3. Slope of oxygen uptake versus exercise intensity ˙ O2) before and after PVR. (SV
TABLE I Heart Rate Response to Graded Treadmill Exercise in Patients Surgically Treated for TOF Before and After Pulmonary Valve Replacement (PVR) Heart rate
0%
2%
4%
6%
Before PVR After PVR
88 ⫾ 14 77 ⫾ 13
89 ⫾ 15 80 ⫾ 12
92 ⫾ 15 82 ⫾ 11
94 ⫾ 15 85 ⫾ 13
0%, 2%, 4%, 6% ⫽ increasing degree of inclination of the treadmill. The values for heart rate are expressed as percentages of the normal mean value for age- and gender-matched controls. The data are represented as mean ⫾ SD of the mean. F analysis of variance: before and after PVR, 3.10; p ⬎0.05.
Feasability of determination of ventilatory anaerobic ˙ O2 versus exercise intensity: threshold and slope of V
The VAT could be determined in 15 of the 18 patients. In 2 patients the VAT could not be calculated because of hyperventilation, and in 1 patient because the threshold was already surpassed at the onset of the exercise test. Eleven of the 18 subjects performed an exercise test before and after PVR. In 9 of them the VAT could be determined on both occasions. The ˙ O2 could be calculated in all patients and normal SV controls. Aerobic exercise performance: Aerobic exercise performance was assessed by determination of the VAT. In the 15 patients in whom a VAT could be determined after PVR, its value averaged 104 ⫾ 15%, expressed as a percentage of the normal mean value obtained for age- and gender-matched controls.21 This is not significantly different from the value obtained in normal controls (p ⬎0.05). Only 4 of these 15 patients had a subnormal value for VAT (⬍92%; 95% confidence limits 92% to 108%). In contrast, patients with TOF repair had a mean VAT of only 86 ⫾ 11%, which is significantly lower than the mean value obtained in normal controls (p ⬍0.05). In 11 patients, an exercise test was performed both before and after PVR. Seven of these 9 subjects in whom a VAT could be determined showed an increase in VAT after PVR (Figure 2). After PVR there was a significant improvement in VAT, which increased from 86 ⫾ 11% to 106.9 ⫾
14% (p ⫽ 0.03). The 2 patients without an increase in VAT after PVR had peripheral pulmonary arterial stenoses, which may explain their limited increase in cardiac output during exercise.25 The adequacy of the O2 transport system was more ˙ O2.22 In specifically evaluated by calculating the SV ˙ patients with PVR the SVO2 was not significantly ˙ O2 obtained in normal controls different from the SV (2.03 ⫾ 0.77 after PVR vs 2.42 ⫾ 0.68 in the normal controls, p ⬎0.25). Only 6 of the 18 patients with ˙ O2 (⬍2.14; 95% confidence PVR had subnormal SV limits 2.14 to 2.69). In contrast, patients with repaired ˙ O2 of only 1.82 ⫾ 0.74, which TOF had a mean SV was significantly lower (p ⬍0.05) than in normal controls. In the 24 normal subjects no significant cor˙ O2 and age (r ⫽ 0.093, relation was found between SV ˙ O2 increased significantly p ⫽ 0.66). Furthermore, SV after PVR (1.71 ⫾ 0.47 before vs 2.3 ⫾ 0.39 after PVR, p ⫽ 0.004). Ten of the 11 patients had an ˙ O2 after PVR (Figure 3). In the 11 increase in SV patients who were serially studied, heart rate, expressed as a percentage of the age- and gender-predicted normal value, was not significantly different before and after PVR (p ⬎0.25). However for both groups, before and after PVR, heart rate was lower compared with normal control values (Table I).
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Ventricular function assessed by magnetic resonance imaging: Cine magnetic resonance imaging and veloc-
ity mapping were successfully performed in 16 of the 18 patients after PVR. End-diastolic RV volumes were significantly larger than end-diastolic left ventricular volumes (74.2 vs 57 ml/m2, respectively, p ⬍0.0001). Right and left ventricular stroke volumes were not significantly different (37.5 vs 39.3 ml/m2, respectively, p ⫽ 0.29), which excludes important pulmonary valvular regurgitation. Left ventricular ejection fractions were significantly larger than RV ejection fractions (68.8 ⫾ 6.1% vs 51.3 ⫾ 12.9%, p ⬍0.0001). Stroke volumes measured with velocity mapping through the mitral valve correlated well with left ventricular stroke volumes obtained by volumetric measurements (64.4 ⫾ 22.3 vs 62.7 ⫾ 22.3 ml, p ⫽ 0.6001). There was a good correlation between volumetric flow through the ascending aorta and left ventricular stroke volume (68.6 ⫾ 24.3 vs 62.7 ⫾ 22.3 ml, p ⫽ 0.0817). RV stroke volume showed good agreement with effective forward tricuspid volumetric flow per cardiac cycle (59.6 vs 65.8 ml, p ⫽ 0.18). Volumetric flow obtained with velocity mapping in the pulmonary trunk, however, overestimated RV stroke volume (75.5 ⫾ 28.7ml vs 59.6 ⫾ 21.5 ml, p ⫽ 0.012). The reason for this discrepancy remains unclear. There is no correlation between RV end-dia˙ O2 (r ⫽ stolic diameter and VAT (r ⫽ 0.17) or SV 0.31). Furthermore, RV ejection fraction did not cor˙ O2 (r ⫽ ⫺0.23). relate with VAT (r ⫽ ⫺0.39) and SV
DISCUSSION This study demonstrates that PVR for severe pulmonary regurgitation after previous TOF repair dramatically improves aerobic exercise capacity. Patients with repaired TOF are well known to have reduced exercise performance, based on maximal endurance ˙ O2, VAT, and maximal workload.6 –15,19 time, maximal V The impaired exercise capacity has been attributed to hemodynamic dysfunction as well as pulmonary abnormalities.11,26 –28 Failure to increase cardiac output can be due to an impaired chronotropic response6,8,28 or an inadequate increase in stroke volume.7,28,29 A failure to increase heart rate during exercise has been ascribed to sinus node dysfunction,9 an impaired function of the autonomic nervous system,8 a compensatory increase in diastolic filling time,28 or the presence of conduction disturbances (e.g., right bundle branch block).28 After PVR, no significant change in heart rate response during exercise was found. This suggests that the impaired chronotropic response after TOF repair cannot be attributed to pulmonary regurgitation, per se, and the decreased preload of the left ventricle. The inadequate increase in stroke volume and cardiac output has been attributed to multiple factors. These include residual pulmonary regurgitation, RV fibrosis and scarring, a noncontractile ventricular septal or RV outflow tract patch, and an impaired coronary blood supply.5,8,15 In addition, physical deconditioning is an important determinant of exercise performance.8 Furthermore, pulmonary abnormalities have been 224 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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shown to limit exercise capacity in patients with repaired TOF. The degree of pulmonary regurgitation has been associated with a decreased vital capacity, a lower breathing reserve capacity, and an inadequate decrease in physiologic dead space, resulting in an excessive ventilatory response during exercise. In addition, an increase in lung blood volume and interstitial water may decrease lung compliance.11,26,27 PVR has been shown to result in an improved exercise capacity. Exercise performance has been evaluated by medical history or endurance time.5,13 However, because these measurements are dependent on the motivation of the subjects, these assessments lack sensitivity. To the best of our knowledge, clinical improvement after PVR has not been previously documented by quantitative data of exercise performance. In the present study, aerobic exercise performance was assessed more specifically by analysis of the ˙ O2 and by determination of the VAT in steepness of V a group of patients before and after PVR. These measurements, however, are independent of the motivation of the subject to perform a true maximal exercise ˙ O2 has previously been shown to be a test. The SV valid and reproducible parameter of cardiovascular exercise function.22,23 It reflects the O2 delivery to the exercising tissues and is a measure of the increase in cardiac output. ˙ O2 and a After PVR a significant increase in the SV significantly higher value for VAT were observed. The 2 patients who did not demonstrate an increase in VAT after PVR were shown to have peripheral pulmonary arterial stenoses. These have been reported to cause ventilation/perfusion mismatch and an exces˙ E) during exercise.24 sively high minute ventilation (V They prevent the normal decrease in pulmonary vascular resistance during exercise and impair the ability of the right ventricle to increase cardiac output.24 Furthermore, the patient group studied after PVR had ˙ O2 and a mean value for VAT, which was a mean SV comparable to the values obtained in normal controls. ˙ O2 At variance, significantly reduced values for SV and VAT were observed in the patient group with repaired TOF and moderate pulmonary regurgitation compared with normal controls. Magnetic resonance imaging studies after PVR revealed a residual RV dilatation and a decreased ejection fraction. However, there was no correlation between RV dilatation or RV function and aerobic exercise performance. Hemodynamic measurements performed at rest have been shown to be poor predictors of maximal exercise performance.30 Study limitations: Magnetic resonance imaging studies were performed only at rest and not during exercise testing. However, it can be expected that RV ejection fraction increases during exercise. In conclusion, our data show that aerobic exercise performance substantially improves after PVR for severe pulmonary regurgitation after previous TOF repair in infancy. Although the right ventricle remains significantly dilated and hypocontractile, there is no correlation between RV function evaluated at rest and exercise performance. JANUARY 15, 2000
1. Katz NM, Blackstone EH, Kirklin JW, Pacifico AD, Bargeron LM. Late
survival and symptoms after repair of tetralogy of Fallot. Circulation 1982;65: 405– 410. 2. Bove EL, Byrum CJ, Thomas FD, Kavey RW, Sondheimer HM, Blackman MS, Parker FB. The influence of pulmonary insufficiency on ventricular function following repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1983;85:691– 696. 3. Murphy JG, Gersh BJ, Phil D, Mair DD, Fuster V, McGoon MD, Ilstrup DM, McGoon DC, Kirklin JW, Danielson GK. Long-term outcome in patients undergoing surgical repair of tetralogy of Fallot. N Engl J Med 1993;329:593–599. 4. Nollert G, Fischlein T, Bouterwek S, Bo¨hmer C, Klinner W, Reichart B. Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol 1997;5:1374 –1383. 5. Ilbawi MN, Idriss FS, DeLeon SY, Muster AJ, Gidding SS, Berry TE, Paul MH. Factors that exaggerate the deleterious effects of pulmonary insufficiency on the right ventricle after tetralogy repair. J Thorac Cardiovasc Surg 1987;93:36 – 44. 6. James FW, Kaplan S, Schwartz DC, Chou T, Sandker MJ, Naylor V. Response to exercise in patients after total correction of Tetralogy of Fallot. Circulation 1976;54:671– 679. 7. Hirschfeld S, Tuboku-Metzger AJ, Borkat G, Ankeney J, Clayman J, Liebman J. Comparison of exercise and catheterization results following total surgical correction of tetralogy of Fallot. J Thorac Cardiovasc Surg 1978;75:446 – 451. 8. Wessel HU, Cunningham WJ, Paul MH, Bastanier CK, Muster AJ, Idriss FS. Exercise performance in tetralogy of Fallot after intracardiac repair. J Thorac Cardiovasc Surg 1980;80:582–593. 9. Reybrouck T, Weymans M, Stijns H, Van Der Hauwaert LG. Exercise testing after correction of tetralogy of fallot: the fallacy of a reduced heart rate response. Am Heart J 1986;112:998 –1003. 10. Marx G, Hicks RW, Allen HD, Goldberg SJ. Noninvasive assessment of hemodynamic responses to exercise in pulmonary regurgitation after operations to correct pulmonary outflow obstruction. Am J Cardiol 1988;61:595– 601. 11. Rowe SA, Zahka KG, Manolio TA, Horneffer PJ, Kidd L. Lung function and pulmonary regurgitation limit exercise capacity in postoperative tetralogy of Fallot. J Am Coll Cardiol 1991;17:461– 466. 12. Carvalho JS, Shinebourne EA, Busst C, Rigby ML, Redington AN. Exercise capacity after complete repair of tetralogy of Fallot: deleterious effects of residual pulmonary regurgitation. Br Heart J 1992;67:470 – 473. 13. Warner KG, Anderson JE, Fulton DR, Payne DD, Geggel RL, Marx GR. Restoration of the pulmonary valve reduces right ventricular volume overload after previous repair of tetralogy of Fallot. Circulation 1993;88:189 –197. 14. Jonsson H, Ivert T, Jonasson R, Holmgren A, Bjork VO. Work capacity and central hemodynamics thirteen to twenty-six years after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 1995;110:416 – 426. 15. Singh GS, Greenberg SB, Yap YS, Delany DP, Keeton BP, Monro JL. Right ventricular function and exercise performance late after primary repair of tetral-
ogy of Fallot with the transannular patch in infancy. Am J Cardiol 1998;81:1378 – 1382. 16. Bove EL, Kavey RW, Byrum CJ, Sondheimer HM, Blackman MS, Thomas FD. Improved right ventricular function following late pulmonary valve replacement for residual pulmonary insufficiency or stenosis. J Thorac Cardiovasc Surg 1985;90:50 –55. 17. Beaver WL, Wasserman K, Whipp BJ. A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986;60:2020 –2027. 18. Reybrouck T, Deroost F, Van Der Hauwaert LG. Evaluation of breath-bybreath measurement of respiratory gas exchange in pediatric exercise testing. Chest 1992;102:147–152. 19. Reybrouck T, Mertens L, Kalis N, Weymans M, Dumoulin M, Daenen W, Gewillig M. Dynamics of respiratory gas exchange during exercise after correction of congenital heart disease. J Appl Physiol 1996;80:458 – 463. 20. Wasserman K, Beaver WL, Whipp BJ. Gas exchange theory and the lactic acidosis (anaerobic) threshold. Circulation 1990;81(suppl II):II-14 –II-30. 21. Reybrouck T, Weymans M, Stijns H, Knops J, Van der Hauwaert L. Ventilatory anaerobic threshold in healthy children: age and sex differences. Eur J Appl Physiol 1985;54:278 –284. 22. Cohen-Solal A, Chabernaud JM, Gourgon R. Comparison of oxygen uptake during bicycle exercise in patients with chronic heart failure and normal subjects. J Am Coll Cardiol 1990;16:80 – 85. 23. Hansen JE, Dy S, Oren A, Wasserman K. Relation of oxygen uptake to workrate in normal men and men with circulatory disorders. Am J Cardiol 1987;59:669 – 674. 24. Bogaert JG, Bosmans H, Rademakers F, Bellon E, Herregods M-C, Verschakelen J, Van de Werf F, Marchal G. Left ventricular quantification with breath-hold MR imaging: comparison with echocardiography. MAGMA 1995;3: 5–12. 25. Rhodes J, Dave A, Pulling MC, Geggel RL, Marx GR, Fulton DR, Hijazi ZM. Effect of pulmonary artery stenoses on the cardiopulmonary response to exercise following repair of tetralogy of Fallot. Am J Cardiol 1998;81:1217–1219. 26. Mocellin R, Bastanier C, Hofacker W, Buhlmeyer K. Exercise performance in children and adolescents after surgical repair of tetralogy of Fallot. Eur J Cardiol 1976;4:367–374. 27. Strieder DJ, Aziz K, Zaver AG, Fellows KE. Exercise tolerance after repair of tetralogy of Fallot. Ann Thorac Surg 1975;19:397– 405. 28. Rigolin VH, Li JS, Hanson MW, Sullivan MJ, Robiolio PA, Hearne SE, Baker WA, Harrison JK, Bashore TM. The role of right ventricular and pulmonary functional abnormalities in limiting exercise capacity in adults with congenital heart disease. Am J Cardiol 1997;80:315–322. 29. Bjarke B. Oxygen uptake and cardiac output during submaximal and maximal exercise in adult subjects with totally corrected tetralogy of Fallot. Acta Med Scand 1975;197:177–186. 30. Cowburn PJ, Cleland JGF, Coats AJS, Komajda M. Risk stratification in chronic heart failure. Eur Heart J 1998;19:696 –710.
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VAT (86 ⴞ 11% before to 106.9 ⴞ 14% after, p ⴝ 0.03) ˙ O2 (1.71 ⴞ 0.47 to 2.3 ⴞ 0.39, p ⴝ 0.004). In and in SV ˙ O2 values patients examined after PVR, the VAT and SV were not significantly different from the values in the normal controls (104 ⴞ 15% [p >0.05] and 2.03 ⴞ 0.77 after PVR vs 2.42 ⴞ 0.68 [p >0.25], respectively). In contrast, patients with repaired TOF and a moderate degree of pulmonary regurgitation had a significantly ˙ O2 (1.8 ⴞ 0.74 lower VAT (86 ⴞ 11%, p <0.05) and SV vs 2.42 ⴞ 0.68, p <0.05) than normal controls. Magnetic resonance imaging studies revealed residual RV dilatation and dysfunction. However, there was no correlation between RV dilatation and RV dysfunction and aerobic exercise capacity. It is concluded that aerobic exercise capacity substantially improves after PVR for severe pulmonary regurgitation after previous TOF repair. Although the right ventricle remains significantly dilated and hypocontractile, there is no relation between RV function and exercise performance. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:221–225)
fter surgical repair of tetralogy of Fallot (TOF) most patients have an excellent functional result A and lead a normal active and social life. Neverthe-
ercise testing in a group of patients before and after pulmonary valve replacement (PVR) for severe pulmonary regurgitation after previous TOF repair in infancy. Cardiorespiratory exercise performance was assessed by determination of the ventilatory anaerobic threshold (VAT). The adequacy of the cardiovascular exercise function was more specifically evaluated by assessment of the steepness of the slope of oxygen ˙ O2). In addition, uptake versus exercise intensity (SV RV function after PVR was evaluated using magnetic resonance imaging. RV end-diastolic volume and RV ejection fraction were correlated with the parameters of aerobic exercise capacity. Patients: Between 1989 and 1997, 31 patients underwent PVR with a homograft for severe pulmonary regurgitation at our institution. In a subgroup consisting of 18 patients, aged between 8 and 18 years, exercise performance and RV function were assessed at least 1 year after PVR. Patients aged ⬍8 and ⬎18 years were excluded from the study because of lack of normal values for parameters of aerobic exercise function. Patients were evaluated at a mean age of 16.6 ⫾ 4.2 years at a mean time interval of 2.8 ⫾ 1.4 years after PVR. Five of the 18 patients had initial palliation
1– 4
less, almost all patients have some degree of pulmonary regurgitation as a result of right ventricular (RV) outflow tract reconstruction.2,5 Long-standing significant pulmonary regurgitation has been shown to be associated with RV dysfunction, ventricular arrhythmias,2 and an impaired exercise tolerance.6 –15 Restoration of pulmonary valve competence with insertion of a prosthetic valve or an allograft has been shown to improve RV performance and functional ability.5,16 In most studies, exercise tolerance in these patients has been evaluated by medical history, which lacks sensitivity. The purpose of this study was to assess cardiopulmonary exercise performance during formal exFrom the Departments of Pediatric and Congenital Cardiology, Cardiovascular Rehabilitation, Cardiac Surgery, and Radiology, University Hospital Gasthuisberg, Leuven, Belgium. Manuscript received May 14, 1999; revised manuscript received and accepted August 24, 1999. Address for reprints: Benedicte Eyskens, MD, Department Pediatric Cardiology, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: [email protected]. ©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 15, 2000
0002-9149/00/$–see front matter PII S0002-9149(99)00640-2
221
with a Blalock-Taussig shunt. Age at primary repair was 3.5 ⫾ 3.1 years. Surgical repair was performed through a right ventriculotomy in all patients and 15 of the 18 patients required a transannular patch for relief of RV outflow tract obstruction. Mean age at PVR was 13.5 ⫾ 5.7 years, with a mean time interval of 10.1 ⫾ 4.1 years after primary repair. All patients received an adult-sized homograft. A pulmonary homograft was inserted into 17 patients and an aortic homograft was inserted into 1 patient. Indications for PVR were severe pulmonary regurgitation with progressive signs of RV volume overload, which was assessed by increasing cardiomegaly on chest x-ray, progressive RV dilatation or worsening RV function as seen on echocardiography or angiocardiography, progressive tricuspid valve regurgitation, decreasing exercise tolerance, or ventricular arrhythmias. At the time of PVR the mean RV outflow tract gradient was 12 mm Hg (range 0 to 35). In the study group, no patient developed ventricular arrhythmias before PVR. Exercise performance data from the 18 patients were compared with data obtained from 24 normal healthy controls (mean age 11.6 ⫾ 2.6 years, range 7.2 to 17.7) and from 27 patients with repaired TOF (mean age 12.1 ⫾ 3.3 years, range 5.5 to 16.7) who had not required a homograft and who had only a moderate degree of pulmonary regurgitation. Of these 18 patients, a subgroup of 11 patients also underwent an exercise test before PVR. In these patients the results were compared before and after PVR.
METHODS
Exercise testing procedures: Submaximal exercise tests were performed on a calibrated motor-driven treadmill. The speed was set at 5.6 km/hour. During the test, patients were not allowed to hold the bars of the treadmill. Exercise testing was started at 0% inclination and the level was increased by 2% every minute until a target heart rate of 170 beats/min was reached. Respiratory gas exchange was measured on a breath-by-breath basis by mass spectrometry. Oxygen ˙ O2), carbon dioxide output (V ˙ CO2), and uptake (V ˙ minute ventilation (VE) were calculated using a previously reported method.17 The validity and reproducibility of the breath-by-breath method for analysis of gas exchange has previously been evaluated in our laboratory.18,19 During the test, a 12-lead electrocardiogram was continuously monitored and recorded every minute for a 15-second interval. Cardiorespiratory exercise function was assessed by determination of the VAT. This was defined as the inflection point in ˙ CO2 versus V ˙ O2 slope (V-slope method), which the V ˙ CO2 above the VAT.20 shows a steeper increase in V The VAT was calculated using a computer algorithm17 and was further checked by visual inspection. The values for VAT are expressed in ml/min/kg or as a percentage of the normal mean value for age and gender, which was obtained from a large pool of 237 healthy children.21 The adequacy of the O2 transport system was further assessed by analysis of the ˙ O2,22,23 expressed as ml O2/min/kg. In this regresSV sion analysis, data were calculated using all breaths 222 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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˙ O2 versus exercise FIGURE 1. Typical example of the slope of V intensity in a patient after TOF repair (closed circles) and a normal control (open circles).
averaged every 10 seconds. A typical example of the ˙ O2 versus exercise intensity is shown in slope of V Figure 1. Informed consent was obtained from the parents of the patients. The protocol was approved by the local medical ethical committee. Magnetic resonance imaging: Magnetic resonance was used to measure right and left ventricular volumes and to quantify volumetric flow in the ascending aorta, pulmonary trunk, and through the mitral and tricuspid valve. The studies were performed on a 1.5 Tesla scan (Siemens Vision, Erlangen, Germany) using commercially available electrocardiographic triggering. Ventricular volumes were quantified by means of breathhold segmented gradient-recalled echo sequences. The ventricles were encompassed by means of contiguous short-axis views from base to apex. A horizontal longaxis view was also obtained to correct for longitudinal ventricular shortening during systole. Ventricular volumes were calculated after delineation of the endocardial surfaces of the end-diastolic and end-systolic images. Multiplication of the delineated cavity area with the slice thickness yielded slice volume, and summation of all slice volumes yielded ventricular volume at end-diastole and end-systole. End-diastole was defined as the time frame associated with the maximum ventricular volume, and end-systole with that of minimum ventricular volume. Stroke volume was determined by the subtraction of end-systolic volume from end-diastolic volume. Ejection fraction was calculated as stroke volume/end-diastolic volume ⫻ 100%. Flow volumes were quantified by means of velocity-encoded cine magnetic resonance sequences. Aortic and pulmonary blood flow were quantified just above the level of the semilunar valve in a plane perpendicular through the vessel of interest. For the atrioventricular valves, a plane perpendicular through the base of the valve was chosen. Subsequently, the forward flow, backward flow, and effective forward flow were quantified. The accuracy and reproducibility of measurements have been previously assessed in a normal group of volunteers.24 JANUARY 15, 2000
FIGURE 2. VAT before and after PVR.
Statistical analysis: Difference between the mean values were calculated by univariate analysis of variance and for heart rate, by analysis of variance with repeated measurements. For regression analysis a linear regression technique was applied and for correlation analysis the Pearson correlation method was used. The SAS computer software (SAS institute, Inc. Cary, North Carolina) was used for statistical analysis. The significance level was set at p ⬍0.05.
RESULTS
FIGURE 3. Slope of oxygen uptake versus exercise intensity ˙ O2) before and after PVR. (SV
TABLE I Heart Rate Response to Graded Treadmill Exercise in Patients Surgically Treated for TOF Before and After Pulmonary Valve Replacement (PVR) Heart rate
0%
2%
4%
6%
Before PVR After PVR
88 ⫾ 14 77 ⫾ 13
89 ⫾ 15 80 ⫾ 12
92 ⫾ 15 82 ⫾ 11
94 ⫾ 15 85 ⫾ 13
0%, 2%, 4%, 6% ⫽ increasing degree of inclination of the treadmill. The values for heart rate are expressed as percentages of the normal mean value for age- and gender-matched controls. The data are represented as mean ⫾ SD of the mean. F analysis of variance: before and after PVR, 3.10; p ⬎0.05.
Feasability of determination of ventilatory anaerobic ˙ O2 versus exercise intensity: threshold and slope of V
The VAT could be determined in 15 of the 18 patients. In 2 patients the VAT could not be calculated because of hyperventilation, and in 1 patient because the threshold was already surpassed at the onset of the exercise test. Eleven of the 18 subjects performed an exercise test before and after PVR. In 9 of them the VAT could be determined on both occasions. The ˙ O2 could be calculated in all patients and normal SV controls. Aerobic exercise performance: Aerobic exercise performance was assessed by determination of the VAT. In the 15 patients in whom a VAT could be determined after PVR, its value averaged 104 ⫾ 15%, expressed as a percentage of the normal mean value obtained for age- and gender-matched controls.21 This is not significantly different from the value obtained in normal controls (p ⬎0.05). Only 4 of these 15 patients had a subnormal value for VAT (⬍92%; 95% confidence limits 92% to 108%). In contrast, patients with TOF repair had a mean VAT of only 86 ⫾ 11%, which is significantly lower than the mean value obtained in normal controls (p ⬍0.05). In 11 patients, an exercise test was performed both before and after PVR. Seven of these 9 subjects in whom a VAT could be determined showed an increase in VAT after PVR (Figure 2). After PVR there was a significant improvement in VAT, which increased from 86 ⫾ 11% to 106.9 ⫾
14% (p ⫽ 0.03). The 2 patients without an increase in VAT after PVR had peripheral pulmonary arterial stenoses, which may explain their limited increase in cardiac output during exercise.25 The adequacy of the O2 transport system was more ˙ O2.22 In specifically evaluated by calculating the SV ˙ patients with PVR the SVO2 was not significantly ˙ O2 obtained in normal controls different from the SV (2.03 ⫾ 0.77 after PVR vs 2.42 ⫾ 0.68 in the normal controls, p ⬎0.25). Only 6 of the 18 patients with ˙ O2 (⬍2.14; 95% confidence PVR had subnormal SV limits 2.14 to 2.69). In contrast, patients with repaired ˙ O2 of only 1.82 ⫾ 0.74, which TOF had a mean SV was significantly lower (p ⬍0.05) than in normal controls. In the 24 normal subjects no significant cor˙ O2 and age (r ⫽ 0.093, relation was found between SV ˙ O2 increased significantly p ⫽ 0.66). Furthermore, SV after PVR (1.71 ⫾ 0.47 before vs 2.3 ⫾ 0.39 after PVR, p ⫽ 0.004). Ten of the 11 patients had an ˙ O2 after PVR (Figure 3). In the 11 increase in SV patients who were serially studied, heart rate, expressed as a percentage of the age- and gender-predicted normal value, was not significantly different before and after PVR (p ⬎0.25). However for both groups, before and after PVR, heart rate was lower compared with normal control values (Table I).
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Ventricular function assessed by magnetic resonance imaging: Cine magnetic resonance imaging and veloc-
ity mapping were successfully performed in 16 of the 18 patients after PVR. End-diastolic RV volumes were significantly larger than end-diastolic left ventricular volumes (74.2 vs 57 ml/m2, respectively, p ⬍0.0001). Right and left ventricular stroke volumes were not significantly different (37.5 vs 39.3 ml/m2, respectively, p ⫽ 0.29), which excludes important pulmonary valvular regurgitation. Left ventricular ejection fractions were significantly larger than RV ejection fractions (68.8 ⫾ 6.1% vs 51.3 ⫾ 12.9%, p ⬍0.0001). Stroke volumes measured with velocity mapping through the mitral valve correlated well with left ventricular stroke volumes obtained by volumetric measurements (64.4 ⫾ 22.3 vs 62.7 ⫾ 22.3 ml, p ⫽ 0.6001). There was a good correlation between volumetric flow through the ascending aorta and left ventricular stroke volume (68.6 ⫾ 24.3 vs 62.7 ⫾ 22.3 ml, p ⫽ 0.0817). RV stroke volume showed good agreement with effective forward tricuspid volumetric flow per cardiac cycle (59.6 vs 65.8 ml, p ⫽ 0.18). Volumetric flow obtained with velocity mapping in the pulmonary trunk, however, overestimated RV stroke volume (75.5 ⫾ 28.7ml vs 59.6 ⫾ 21.5 ml, p ⫽ 0.012). The reason for this discrepancy remains unclear. There is no correlation between RV end-dia˙ O2 (r ⫽ stolic diameter and VAT (r ⫽ 0.17) or SV 0.31). Furthermore, RV ejection fraction did not cor˙ O2 (r ⫽ ⫺0.23). relate with VAT (r ⫽ ⫺0.39) and SV
DISCUSSION This study demonstrates that PVR for severe pulmonary regurgitation after previous TOF repair dramatically improves aerobic exercise capacity. Patients with repaired TOF are well known to have reduced exercise performance, based on maximal endurance ˙ O2, VAT, and maximal workload.6 –15,19 time, maximal V The impaired exercise capacity has been attributed to hemodynamic dysfunction as well as pulmonary abnormalities.11,26 –28 Failure to increase cardiac output can be due to an impaired chronotropic response6,8,28 or an inadequate increase in stroke volume.7,28,29 A failure to increase heart rate during exercise has been ascribed to sinus node dysfunction,9 an impaired function of the autonomic nervous system,8 a compensatory increase in diastolic filling time,28 or the presence of conduction disturbances (e.g., right bundle branch block).28 After PVR, no significant change in heart rate response during exercise was found. This suggests that the impaired chronotropic response after TOF repair cannot be attributed to pulmonary regurgitation, per se, and the decreased preload of the left ventricle. The inadequate increase in stroke volume and cardiac output has been attributed to multiple factors. These include residual pulmonary regurgitation, RV fibrosis and scarring, a noncontractile ventricular septal or RV outflow tract patch, and an impaired coronary blood supply.5,8,15 In addition, physical deconditioning is an important determinant of exercise performance.8 Furthermore, pulmonary abnormalities have been 224 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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shown to limit exercise capacity in patients with repaired TOF. The degree of pulmonary regurgitation has been associated with a decreased vital capacity, a lower breathing reserve capacity, and an inadequate decrease in physiologic dead space, resulting in an excessive ventilatory response during exercise. In addition, an increase in lung blood volume and interstitial water may decrease lung compliance.11,26,27 PVR has been shown to result in an improved exercise capacity. Exercise performance has been evaluated by medical history or endurance time.5,13 However, because these measurements are dependent on the motivation of the subjects, these assessments lack sensitivity. To the best of our knowledge, clinical improvement after PVR has not been previously documented by quantitative data of exercise performance. In the present study, aerobic exercise performance was assessed more specifically by analysis of the ˙ O2 and by determination of the VAT in steepness of V a group of patients before and after PVR. These measurements, however, are independent of the motivation of the subject to perform a true maximal exercise ˙ O2 has previously been shown to be a test. The SV valid and reproducible parameter of cardiovascular exercise function.22,23 It reflects the O2 delivery to the exercising tissues and is a measure of the increase in cardiac output. ˙ O2 and a After PVR a significant increase in the SV significantly higher value for VAT were observed. The 2 patients who did not demonstrate an increase in VAT after PVR were shown to have peripheral pulmonary arterial stenoses. These have been reported to cause ventilation/perfusion mismatch and an exces˙ E) during exercise.24 sively high minute ventilation (V They prevent the normal decrease in pulmonary vascular resistance during exercise and impair the ability of the right ventricle to increase cardiac output.24 Furthermore, the patient group studied after PVR had ˙ O2 and a mean value for VAT, which was a mean SV comparable to the values obtained in normal controls. ˙ O2 At variance, significantly reduced values for SV and VAT were observed in the patient group with repaired TOF and moderate pulmonary regurgitation compared with normal controls. Magnetic resonance imaging studies after PVR revealed a residual RV dilatation and a decreased ejection fraction. However, there was no correlation between RV dilatation or RV function and aerobic exercise performance. Hemodynamic measurements performed at rest have been shown to be poor predictors of maximal exercise performance.30 Study limitations: Magnetic resonance imaging studies were performed only at rest and not during exercise testing. However, it can be expected that RV ejection fraction increases during exercise. In conclusion, our data show that aerobic exercise performance substantially improves after PVR for severe pulmonary regurgitation after previous TOF repair in infancy. Although the right ventricle remains significantly dilated and hypocontractile, there is no correlation between RV function evaluated at rest and exercise performance. JANUARY 15, 2000
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