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Measures of exercise capacity in adults with congenital heart disease
International Journal of Cardiology 153 (2011) 26–30
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Measures of exercise capacity in adults with congenital heart disease Roselien Buys a, Véronique Cornelissen a, Alexander Van De Bruaene b, An Stevens a, Ellen Coeckelberghs a, Steven Onkelinx a, Tom Thomaes a, Christophe Delecluse c, Werner Budts b, Luc Vanhees a,⁎ a b c
Research Centre for Cardiovascular and Respiratory Rehabilitation, Department of Rehabilitation Sciences, Katholieke Universiteit Leuven, Tervuursevest 101 bus 1501, 3001 Heverlee, Belgium Internal Medicine, Division of Cardiology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium Research Centre for Exercise and Health, Department of Biomedical Kinesiology, Katholieke Universiteit Leuven, Tervuursevest 101 bus 1501, 3001 Heverlee, Belgium
a r t i c l e
i n f o
Article history: Received 23 March 2010 Received in revised form 1 July 2010 Accepted 7 August 2010 Available online 16 September 2010 Keywords: Adult congenital heart disease GUCH Exercise capacity Oxygen uptake efficiency slope Ventilatory anaerobic threshold
a b s t r a c t Background: Exercise capacity in grown-ups with congenital heart disease (GUCH) is mostly reported by peak oxygen consumption (peak VO2). Our aim was to evaluate the maximal character of exercise tests, and to investigate submaximal measures of exercise capacity. Methods: Adults with Coarctation of the Aorta (COA, n = 155), Tetralogy of Fallot (TOF, n = 98), dextroTransposition of the Great Arteries (dTGA, n = 68) and Univentricular Heart (UVH, n = 10), and 122 healthy adults performed cardiopulmonary exercise testing until exhaustion. Gas exchange was measured breath by breath. The maximal performance of the test was evaluated by respiratory exchange ratio (RER), ventilatory equivalent for oxygen and Borg scale. Oxygen uptake efficiency slope (OUES), VE/VCO2 slope and VO2/WR slope were calculated and ventilatory anaerobic threshold (VAT) was defined. Correlations of these measures with peak VO2 were calculated. Results: GUCH showed significantly lower peak VO2 than controls (p b 0.001), declining from 80% in COA, 74% in TOF, 64% in dTGA, to 55% in UVH. Compared to suggested criteria, mean peak RER and median Borg scale indicated a maximal effort in GUCH, however these results were significantly lower than controls (p b 0.05). OUES, VO2/WR slope and VAT were significantly lower in patients compared to controls. OUES (r = 0.853) and VAT (r = 0.840) correlated best with peak VO2; VO2/WR slope (r = 0.551) and VE/VCO2 slope (r = −0.421) correlated to a lesser degree (p b 0.001). Conclusion: The investigated GUCH show reduced exercise tolerance compared to controls, related to the underlying heart defect. Different expressions of exercise tolerance clearly reveal the same differences in exercise capacity across groups of GUCH. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In Belgium, 8.3 per 1000 children are born with a heart defect, which is in line with the prevalence in the western world [1]. Changes in birth prevalence, the availability of new treatment options and improvements in the survival of patients with congenital heart disease, have resulted in an increased number of grown-up patients with congenital heart disease (GUCH). Many of them underwent corrective or palliative surgery, but it remains unclear whether the promising results at young age will persist in late adult life [2,3]. Beneficial effects of physical activity are well-established in the general population as well as in patients with coronary artery disease. The functionality and activity level of GUCH largely depend on their exercise capacity and even though they usually do not report problems with low intensity exercise, they often have difficulties
⁎ Corresponding author. Department of Rehabilitation Sciences, Tervuursevest 101 - bus 01501, B-3001 Heverlee, Belgium. Tel.: +32 16 329158; fax: +32 16 329197. E-mail address: [email protected] (L. Vanhees). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.08.030
with exercise at higher intensity. The results of previous studies in GUCH show that exercise tolerance is diminished in all patient groups compared to a healthy population [4–7]. Generally, cardiopulmonary performance is evaluated by peak oxygen uptake (peak VO2) [8]. However, peak VO2 might be underestimated or less reliable in GUCH because the tests are performed with more caution, which might lead to reduced patient motivation and examiner variability [4]. Furthermore, also in a general population and in patients with acquired heart disease, peak VO2 is influenced by subjective motivation [9,10]. Furthermore, peak VO2 measurement depends on a maximal effort on the exercise test, of which no certainty exists that this physiological maximum is or can always be reached by GUCH. To be independent from this end point, submaximal measures, such as ventilatory anaerobic threshold (VAT), Oxygen Uptake Efficiency Slope (OUES), oxygen uptake versus exercise intensity slope (VO2/WR slope) and the VE/VCO2 slope, have been introduced [9,11–13]. Most of these estimates of exercise tolerance have not been investigated in this population, or often only in small groups without a control group. However, this could be of a larger clinical importance.
R. Buys et al. / International Journal of Cardiology 153 (2011) 26–30
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Therefore, the aim of this study was 1) to describe the maximal exercise capacity in a large group of adult patients with underlying Tetralogy of Fallot (TOF), dextro-transposition of the great arteries (dTGA), Coarctation of the aorta (COA) or with a univentricular heart (UVH), and to compare them with a control group of healthy sedentary adults; 2) to investigate whether GUCH can perform an exercise test at the same intensity as control subjects and 3) to evaluate the usefulness of submaximal measures of exercise capacity.
age, height, weight and gender as covariates. Kruskal–Wallis analysis of variance was used for Borg scale. Bland and Altman limits of agreement were used for the evaluation of the agreement between different calculations of the OUES. Pearson product moment correlation coefficients of the relation of peak VO2 with the OUES, VE/VCO2 slope, VO2/WR slope and VAT were also calculated. All statistical tests were 2-sided at a significance level of ≤ 0.05.
2. Materials and methods
Patients' characteristics are summarized in Table 1. The mean age in the control group was 29.2 (8.6) years, with a range between 16 and 46 years. GUCH patients had a mean age of 25.9 (8.1) years, ranging from 16 to 62 years old.
2.1. Patients Between October 2000 and August 2009, all GUCH with repaired TOF, dTGA, COA and UVH, who were referred to the outpatient clinic of adult congenital heart disease in the University Hospital of Leuven for follow-up, and who were scheduled to perform an exercise test until exhaustion, were subject to inclusion in the study. Healthy sedentary adults were recruited amongst friends and family of the investigators, in order to compose a control group. Inclusion criteria were: 1) aged 16 years or older, 2) able to understand the exercise testing protocol and 3) able to perform a maximal graded exercise test until exhaustion. Exhaustion was defined as shortness of breath and/or fatigue of the legs. Patients with concomitant pathology were excluded. Three hundred twenty-five patients (93 patients with TOF, 67 with dTGA, 155 with COA and 10 patients with UVH) performed a bicycle exercise test until exhaustion. The control group (CON) was composed of 122 healthy, sedentary adults between 16 and 46 years old. Forty TOF patients underwent palliative surgery. Final correction was established in 37 patients with a valvotomy and in 56 patients with a transannular patch. The dTGA group consists of 22 patients who underwent Mustard repair and 45 patients who received a Senning repair. All COA patients underwent a coarctectomy. A Fontan circulation was established in the patients with a univentricular heart, two of the ten patients were slightly cyanotic at rest because of persistent fenestration. 2.2. Measurements Maximal exercise tests on the bicycle ergometer (Ergometrics 800S, Ergometrics, Bitz, Germany) were performed in a laboratory where room temperature was stabilized at 18 to 22 °C. The initial workload of 20 W was increased by 20 W every minute until exhaustion. Exhaustion, based on clinical criteria, was defined as shortness of breath and/or fatigue of the legs. A 12-lead electrocardiogram (Max Personal Exercise Testing, Marquette, Wisconsin, USA) and respiratory data through breath-by-breath analysis (Oxygen AlphaR, Jaeger, Mijnhardt, Bunnik, The Netherlands) were continuously registered. Heart rate was calculated from the electrocardiogram. The gas analyzers and the flow meter were calibrated before each test according to the manufacturer's instructions. Oxygen uptake (VO2) and carbon dioxide output (VCO2) were determined from the continuous measurement of oxygen and carbon dioxide concentration in the inspired and expired air. The respiratory gas exchange ratio (RER) and ventilatory equivalent for oxygen (VEO2) were calculated. Peak VO2 was defined as the highest 30-s average of VO2 at the end of the test. The first VAT was determined according to Binder [14]. Single linear regression analyses on the respiratory data during exercise were used to calculate slopes. In these regression analyses respiratory data were averaged every 30 s. The first minute of exercise was excluded because of the often very irregular breathing pattern at the onset of exercise [15]. The OUES was determined by the method of Baba and co-workers who used the following equation: VO2 = a log10 VE+ b, where a is the OUES [9]. The steeper the slope or higher the OUES, the more efficient the oxygen uptake is. The OUES was also calculated based on the first 75% (OUES75) and 90% (OUES90) of the exercise test in order to calculate the agreement between submaximal and maximal measures. VE/VCO2 slope was calculated from the equation: VE= m (VCO2) + b, in which m = VE/VCO2 slope. The non-linear part of this slope after the respiratory compensation point was not used in the regression analysis by excluding the last 10% of the exercise test. The VE/VCO2 slope is used to evaluate the ventilatory response to exercise and thus the efficiency of pulmonary gas exchange. A steeper slope is an indication of a less efficient pulmonary gas exchange [16]. The adequacy of the oxygen transport was assessed by calculating the steepness of the slope of oxygen uptake versus exercise intensity during the graded exercise. To estimate the exercise intensity, we used the external work load [12]. Data from the entire exercise test were used in the regression analysis, except for the first minute. A steeper oxygen uptake versus exercise intensity slope (VO2/WR slope) indicates a better oxygen flow to the exercising tissues. 2.3. Statistical analysis We used SAS statistical software version 9.1 for windows (Sas Institute Inc, Cary, NC, USA). Data are reported as means (standard deviation) or as numbers for dichotomous variables. Distributions were checked for normality with the Shapiro– Wilk statistic. Single regression analyses were used to calculate slopes. Analysis of covariance and Scheffé's comparison of means between groups were performed with
3. Results 3.1. Patients
3.2. Maximal exercise data and submaximal measures of exercise tolerance As shown in Table 2, significant differences between groups were found for all exercise parameters (p b 0.0001). Scheffé's comparison of means showed that all GUCH reached significantly lower peak VO2 compared to healthy controls. Moreover, a gradual decline in peak VO2 could be observed across the spectrum of congenital heart disease (see Fig. 1A). There was a large variation in peak VO2 in all patient groups (range from 10.6 till 56.4 ml/kg/min). In addition, peak heart rate and mean peak RER in GUCH were significantly lower compared to the control group (p b 0.05 for both). In the control group, 89.3% of the subject reached a RER of at least 1.10. In the patient groups, this percentage was lower; 78.7% in COA, 61.5% in TOF, 59.7% in dTGA and 60% in UVH. All groups reached a VEO2 well above 30. Finally, the median score on the Borg scale was significantly higher in the control group compared to GUCH (p b 0.05). With regard to the submaximal measures of exercise tolerance we calculated OUES, OUES75, OUES90, VO2/WR slope and VE/VCO2 slope for all patients and control subjects. VAT was not reached or could not be determined in 33 patients (2 controls, 12 patients with COA, 7 patients with TOF, 11 patients with dTGA and 1 patient with UVH). As shown in Table 2, all patient groups had a significantly lower mean VAT when compared to the control group (p b 0.05) (see Fig. 1B). The mean OUES showed significant differences between patients and control group (p b 0.05) and a gradual decline with higher complexity of the heart defect (see Fig. 1C). Results were similar for OUES75 and OUES90. In addition, Bland and Altman analysis demonstrated good agreement between the measurements of OUES and OUES75 in CON and COA whereas agreement was poor for the other patient groups. On the other hand, OUES90 was in good agreement with OUES in all groups. The VE/VCO2 slope was higher in dTGA patients, which was significantly different from the control group as well as the TOF group. Also the steepness of the VO2/WR slope showed a gradual decline across the patient groups according to the underlying heart defect (see Fig. 1D). All means of the patient groups were significantly lower than the mean slope of the control group (p b 0.05). Of all submaximal parameters, OUES and VAT correlated best with peak VO2, VO2/WR slope and VE/VCO2 slope correlated to a lesser degree (see Table 3). In the control group, VO2/work slope was not correlated with peak VO2.
4. Discussion In the present study, we showed that GUCH have a significantly lower exercise capacity compared to healthy, sedentary controls, Table 1 Patient's characteristics. CON
COA
TOF
dTGA
UVH
n 122 155 93 67 10 Male/ 78/44 108/47 65/28 47/20 7/3 female Age 29.2 (8.6) 27.5 (8.8) 25.6 (7.7) a 22.6 (6.0) ac 22.9 (5.0) (years) Weight 71.3 (12.1) 71.4 (14.3) 67.3 (13.9) 66.4 (13.6) 66.2 (10.2) (kg) 169 (11) Height 177 (10) 174 (11) 173 (9) 172 (9) a (cm) ce 6.9 (6.3) 5.7 (4.5) 1.0 (1.2) 8.6 (5.8) g Age at surgery (years) Data are presented as means (SD) for continuous variables and as numbers for dichotomous variables. CON: control group; COA: Coarctation of the aorta; TOF: Tetralogy of Fallot; dTGA: Transposition of the great arteries; UVH: univentricular heart. Scheffé's comparison of means (p b 0.05): a = significantly different from CON; c = significant difference between COA and dTGA; e =significant difference between TOF and dTGA; g=significant difference between dTGA and UVH.
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Table 2 Maximal and submaximal exercise measures. CON Peak VO2 (ml/min) Peak VO2/kg (ml/min/kg) % of predicted peak VO2 Peak HR (beats/min) Peak load (W) Peak RER Peak VEO2 Borg scale OUES OUES75 OUES90 VE/VCO2 slope VO2/WRslope VAT (ml/min/kg)
2755 38.6 99.2 184 235 1.23 38.4 17 3067 3110 3104 25.0 10.3 24.1
COA (800) (8.6) (17.2) (20) (73) (0.12) (7.39) (13-20) (810) (802) (818) (4.1) (1.6) (6.1)
2249 31.7 80.0 173 202 1.16 32.6 16 2646 2605 2630 24.7 9.2 20.8
(675)a (8.3)a (14.7)a (19)a (56.6)a (0.09)a (5.6)a (9-19)a (761)a (761) a (753) a (4.2) (1.2)a (5.7)a
TOF
dTGA
UVH
F-value
2015 (640)ab 30.0 (7.8)a 74.1 (15.6)a 169 (22)a 171(59)ab 1.13 (0.12)a 35.1 (7.0)b 15 (11-20)ab 2506 (742)a 2702 (828) a 2628 (771) a 26.2 (5.5) 9.0 (1.6)a 21.4 (5.4)a
1761 (510)ace 27.1 (8.1)ac 64.3 (13.7)ace 173 (23) a 153 (45)ac 1.12 (0.10)a 40.0 (9.6) ce 16 (12-20)a 2324 (783)ac 2495 (863) a 2412 (818) a 32.4 (14.4)ace 8.6 (1.9)a 19.8 (5.2)a
1466 (431)adf 22.6 (6.9)adf 54.5 (11.7)adf 155 (26)a 142 (29)ad 1.12 (0.10) 39.8 (5.74)d 15 (13-19) 1881 (584)ad 1791 (516) adf 1820 (513) adf 29.9 (6.18) 7.4 (1.2)ad 14.7 (4.0)ad
105.35⁎ 67.61⁎ 65.37⁎ 10.20⁎ 78.20⁎ 11.13⁎ 13.27⁎ 6.65⁎ 47.39⁎ 29.60⁎ 36.73⁎ 9.65⁎ 17.45⁎ 38.49⁎
Data are presented as means (SD) or as median (range) for Borg scale. CON: control group; COA: Coarctation of the aorta; TOF: Tetralogy of Fallot; dTGA: dextro-Transposition of the great arteries; UVH: univentricular heart; HR: heart rate; RER: respiratory exchange ratio; VEO2: ventilatory equivalent for oxygen; OUES: oxygen uptake efficiency slope; VE/VCO2: ventilatory efficiency slope; VO2/WR: oxygen consumption versus exercise intensity slope; VAT: ventilatory anaerobic threshold. Scheffé's comparison of means (p b 0.05): a = significantly different from CON; b = significant difference between COA and TOF; c = significant difference between COA and dTGA; d = significant difference between COA and UVH; e = significant difference between TOF and dTGA; f = significant difference between TOF and UVH. ⁎ p b 0.0001.
and the degree of this exercise intolerance seems to be related to the underlying heart defect. Furthermore, similar patterns could be observed for submaximal measures of exercise tolerance; i.e. ventilatory anaerobic threshold, oxygen uptake efficiency slope and VO2/WR slope. Finally, although the criteria for a maximal exercise performance were reached in all groups, our results showed that the RER and Borg scale were significantly lower in patients compared to the healthy sedentary controls. Peak VO2 is the golden standard to measure the exercise tolerance and is widely used in patients with heart disease. Concordant to others we found a significantly reduced peak VO2 across the four investigated GUCH groups compared to healthy sedentary individuals [4–6,17–20]. Diller et al. reported that the degree of this exercise
intolerance is related to underlying anatomical features [4]. Indeed, our results clearly showed that the underlying heart defect has an influence on the results of a maximal exercise test. Patients with a less severe, non-cyanotic congenital heart defect, such as coarctation of the aorta, performed better on the exercise test than patients with heart defects as Tetralogy of Fallot or Transposition of the great arteries, even though the difference with patients with corrected Tetralogy of Fallot is rather small. The complexity of the univentricular heart and blood circulation after Fontan-repair had the greatest influence on exercise capacity, resulting in even lower values of peak VO2. Further, this decreased peak VO2 in GUCH could also be related to an impaired chronotropic response to exercise, pulmonary arterial hypertension, cyanosis or an impaired lung function [4].
Fig. 1. A graphic view of peak VO2 (A), VAT (B), OUES (C) and VO2/WR slope (D) across heart defect groups, with indication of significant differences between groups. CON: control group; COA: coarctation of the aorta; TOF: tetralogy of Fallot; dTGA: dextro-Transposition of the great arteries; UVH: univentricular heart. Data are presented as means ± SD. p b 0.05 for all comparisons (ANOVA for unbalanced data with correction for age, gender, weight and height; comparison of means by Scheffé's comparison).
R. Buys et al. / International Journal of Cardiology 153 (2011) 26–30 Table 3 Pearson correlation of submaximal measures with peak VO2.
ALL CON COA TOF dTGA UVH
OUES
OUES75
OUES90
VE/VCO2
VO2/WR
VAT
0.853⁎ 0.872⁎ 0.841⁎ 0.823⁎ 0.739⁎ 0.876⁎⁎
0.735⁎ 0.765⁎ 0.747⁎ 0.728⁎ 0.602⁎ 0.873⁎⁎
0.801⁎ 0.840⁎ 0.817⁎ 0.753⁎ 0.649⁎ 0.901⁎⁎
− 0.421⁎ − 0.372⁎ − 0.371⁎ − 0.485⁎ − 0.502⁎ − 0.499
0.551⁎ 0.165 0.692⁎ 0.577⁎ 0.518⁎ 0.865⁎⁎
0.840⁎ 0.854⁎ 0.818⁎ 0.839⁎ 0.775⁎ 0.630
ALL: all groups together; CON: control group; COA: coarctation of the aorta; TOF: tetralogy of Fallot; dTGA: Mustard/Senning repair for transposition of the great arteries; UVH: Fontan circulation for univentricular heart; OUES: oxygen uptake efficiency slope; VE/VCO2: ventilatory efficiency slope; VO2/WR: oxygen consumption versus exercise intensity slope; VAT: ventilatory anaerobic threshold; ⁎ p b 0.0001. ⁎⁎ p b 0.005.
However, it has to be taken into account that peak VO2 is an effortdependent measure. Therefore, it is important to evaluate the maximal character of the performed exercise test. According to the guidelines of the European Association for Cardiovascular Prevention and Rehabilitation, the achievement of a real maximal effort can be assumed when, among others, peak RER ≥ 1.10–1.15 and the rating of perceived exertion is at least 15 on the 20-point Borg scale [13]. In our GUCH groups, the mean RER at peak exercise was well above this minimum level for considering a test as maximally executed. However, a larger part of patients than controls did not reach a RER ≥ 1.10 and mean RER was significantly higher in the healthy controls. Therefore our results indicate that some patients stopped the exercise test at lower intensities than the healthy individuals. Moreover, the median Borg scale values of the patient groups were significantly lower than those of the control group. Whereas the obtained values indicated that a maximal effort at the end of the exercise test might be assumed in COA and dTGA patients, the lower median values in TOF and UVH patients are on the limit of what would be acceptable for a maximal exercise test. It is uncertain whether this indicates that the evaluation of peak VO2 in GUCH is less reliable. Furthermore, our results did not show significant differences in VEO2 between the groups, so this parameter could not contribute to the interpretation of the test's maximal character. As we measured mean levels of VEO2 above 30, we might assume that at least near maximal exercise levels are reached. But the increase in VEO2 may in some patients partly be caused by an increased dead space ventilation, and therefore not be an indication for the maximal character of the exercise test. Based on our results, it seems plausible that not all patients reach their physiological maximum according to the earlier mentioned guidelines [13]. This supports the rationale for a search for alternative exercise parameters to assess the exercise tolerance in these patients. The VAT can be a valuable parameter to assess the exercise tolerance without requiring a maximal effort [21]. Compared to healthy controls, VAT was significantly lower in GUCH. Our results showed a similar tendency as peak VO2 according to differences of the VAT between the different GUCH groups, but these differences were not significant. In agreement with others, we observed a good correlation of VAT with peak VO2. However, a disadvantage of the VAT is that it is highly depending on the exercise protocol, the detection method and the observer [22,23]. Moreover, the VAT could not be determined in 33 patients. A second alternative measure is the OUES. It shows how efficiently the oxygen is extracted by the lungs and used in the periphery. We reported that the OUES is lower in GUCH compared to control subjects and that the OUES declines with an increase in the complexity of the heart defect. Similar to peak VO2, a reduced OUES may be caused by a number of different underlying mechanisms such as an impaired blood flow to the exercising muscles, a smaller muscle mass, less efficient extraction and use of oxygen at the muscular level, an increase in dead space ventilation and a lower blood hemoglobin
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level [10]. However, in agreement with other investigators, we showed that the OUES, both measured on the entire exercise time and on the first 90% of the test, correlates well with peak VO2 and might therefore be a very good alternative for peak VO2 in GUCH [9,24]. Next, the VO2/WR slope showed in the patient groups a significant but weaker correlation with peak VO2. Subnormal values have been associated with important residual hemodynamic defects after correction of the congenital heart lesion [11]. The lower values in our patient groups, might indicate an impaired oxygen flow to the peripheral exercising muscles, or alterations in the metabolism of the skeletal muscles [12]. These unknown peripheral factors may be the result of underlying congenital disturbances, or can be caused by low daily physical activity levels [6]. Earlier, Reybrouck et al. explained the reduced oxygen delivery to exercising muscles in dTGA patients by an inappropriate right ejection fraction and a subnormal cardiac output, and in TOF patients by hemodynamic dysfunction which might be caused by pulmonary valve incompetence [11]. Especially in dTGA patients, the VO2/WR slope might be an interesting measure to use for the evaluation of their functional status, as the systemic ventricle function tends to progressively decrease with age [25]. It is of notice that a significant correlation of the VO2/WR slope with peak VO2 could only be observed in GUCH but not in healthy controls. This might be explained by the fact that healthy individuals show a similar pattern of the adaptation of VO2 to workload, but with less variability, probably because no underlying heart defect or inadequacies of oxygen transport are present in this group. Furthermore, this slope is influenced by the oxygen kinetics. As some patient groups might show delayed oxygen kinetics, a different exercise testing protocol probably would have been more appropriate in these cases. Finally, higher values of the VE/VCO2 slope were found in TOF, dTGA and UVH compared to the control group, although only significant for the dTGA group. The reasons for a higher VE/VCO2 slope in adults with Mustard/Senning repair for dTGA are not clear yet. The steeper VE/VCO2 slope could be the result of abnormal ventilation when the CO2 concentration increases during exercise [5]. A higher VE/VCO2 slope has also been associated with the presence of pulmonary hypertension, right ventricular dysfunction and reduced exercise capacity [26]. In agreement with other investigators, we showed that the VE/VCO2 slope was poorly correlated with peak VO2. Therefore it is inappropriate to use the VE/VCO2 slope to evaluate the exercise capacity in GUCH. However, it can be useful for its prognostic value [5,26,27]. Our study has some limitations. First of all, only patients who were supposed to be able to perform a maximal graded exercise test until exhaustion, based on the judgment of the cardiologist, were included in the study. Therefore, our results might be overestimating the average exercise capacity. Furthermore, the number of UVH patients was very low, which holds us back to generalize their results. In conclusion, adults with COA, TOF, dTGA and FON show a reduced exercise tolerance compared to healthy sedentary adults, and the impaired exercise tolerance is associated to the underlying heart defect. Although near maximal exercise testing can be performed in GUCH, not all patients reach the same exercise intensity on the exercise test compared to healthy adults. Oxygen uptake efficiency slope, ventilatory anaerobic threshold and oxygen uptake versus exercise intensity slope — parameters that correlated with peak VO2 — may be useful to accurately interpret the exercise tolerance. Different expressions of exercise tolerance clearly show similar differences in exercise capacity across groups of patients with different congenital heart diseases. Acknowledgements We especially appreciate the work of Dirk Schepers and Jan Meertens in the exercise testing laboratory. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [28].
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Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc Prev Rehabil 2009;13(3):249–67. Binder RK, Wonisch M, Corra U, et al. Methodological approach to the first and second lactate threshold in incremental cardiopulmonary exercise testing. Eur J Cardiovasc Prev Rehabil 2008;15(6):726–34. Wasserman K, Hansen J, Sue D, et al. Physiology of Exercise. Philadelphia: Lea and Febiger; 1999. p. 10–61. Clark AL, Gatzoulis MA, Redington AN. Ventilatory responses to exercise in adults after repair of tetralogy of Fallot. Br Heart J 1995;73(5):445–9. Fredriksen PM, Therrien J, Veldtman G, et al. Aerobic capacity in adults with tetralogy of Fallot. Cardiol Young 2002;12(6):554–9. Hechter SJ, Webb G, Fredriksen PM, et al. Cardiopulmonary exercise performance in adult survivors of the Mustard procedure. Cardiol Young 2001;11(4):407–14. Harisson DA, Liu P, Walters JE, et al. Cardiopulmonary function in adult patients late after Fontan repair. J Am Coll Cardiol 1995;26(4):1016–21. Glaser S, Opitz CF, Bauer U, et al. Assessment of symptoms and exercise capacity in cyanotic patients with congenital heart disease. Chest 2004;125(2):368–76. Defoor J, Schepers D, Reybrouck T, Fagard R, Vanhees L. Oxygen uptake efficiency slope in coronary artery disease: clinical use and response to training. Int J Sports Med 2006;27(9):730–7. Yeh MP, Gardner RM, Adams TD, Yanowitz FG, Crapo RO. “Anaerobic threshold”: problems of determination and validation. J Appl Physiol 1983;55(4):1178–86. Shimizu M, Myers J, Buchanan N, et al. The ventilatory threshold: method, protocol and evaluator agreement. Am Heart J 1991;122(2):509–16. Giardini A, Specchia S, Gargiulo G, Sangiorgi D, Picchio FM. Accuracy of oxygen uptake efficiency slope in adults with congenital heart disease. Int J Cardiol 2009;133(1): 74–9. Budts W, Scheurwegs C, Stevens A, Moons P, Van Deyk K, Vanhees L. The future of adult patients after Mustard or Senning repair for transposition of the great arteries. Int J Cardiol 2006;113(2):209–14. Giardini A, Hager A, Lammers AE, et al. Ventilatory efficiency and aerobic capacity predict event-free survival in adults with atrial repair for complete transposition of the great arteries. J Am Coll Cardiol 2009;53(17):1548–55. Arena R, Myers M, Guazzi M. The clinical and research applications of aerobic capacity and ventilatory efficiency in heart failure: an evidence-based review. Heart Fail Rev 2008;13(2):245–69. Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
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International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Measures of exercise capacity in adults with congenital heart disease Roselien Buys a, Véronique Cornelissen a, Alexander Van De Bruaene b, An Stevens a, Ellen Coeckelberghs a, Steven Onkelinx a, Tom Thomaes a, Christophe Delecluse c, Werner Budts b, Luc Vanhees a,⁎ a b c
Research Centre for Cardiovascular and Respiratory Rehabilitation, Department of Rehabilitation Sciences, Katholieke Universiteit Leuven, Tervuursevest 101 bus 1501, 3001 Heverlee, Belgium Internal Medicine, Division of Cardiology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium Research Centre for Exercise and Health, Department of Biomedical Kinesiology, Katholieke Universiteit Leuven, Tervuursevest 101 bus 1501, 3001 Heverlee, Belgium
a r t i c l e
i n f o
Article history: Received 23 March 2010 Received in revised form 1 July 2010 Accepted 7 August 2010 Available online 16 September 2010 Keywords: Adult congenital heart disease GUCH Exercise capacity Oxygen uptake efficiency slope Ventilatory anaerobic threshold
a b s t r a c t Background: Exercise capacity in grown-ups with congenital heart disease (GUCH) is mostly reported by peak oxygen consumption (peak VO2). Our aim was to evaluate the maximal character of exercise tests, and to investigate submaximal measures of exercise capacity. Methods: Adults with Coarctation of the Aorta (COA, n = 155), Tetralogy of Fallot (TOF, n = 98), dextroTransposition of the Great Arteries (dTGA, n = 68) and Univentricular Heart (UVH, n = 10), and 122 healthy adults performed cardiopulmonary exercise testing until exhaustion. Gas exchange was measured breath by breath. The maximal performance of the test was evaluated by respiratory exchange ratio (RER), ventilatory equivalent for oxygen and Borg scale. Oxygen uptake efficiency slope (OUES), VE/VCO2 slope and VO2/WR slope were calculated and ventilatory anaerobic threshold (VAT) was defined. Correlations of these measures with peak VO2 were calculated. Results: GUCH showed significantly lower peak VO2 than controls (p b 0.001), declining from 80% in COA, 74% in TOF, 64% in dTGA, to 55% in UVH. Compared to suggested criteria, mean peak RER and median Borg scale indicated a maximal effort in GUCH, however these results were significantly lower than controls (p b 0.05). OUES, VO2/WR slope and VAT were significantly lower in patients compared to controls. OUES (r = 0.853) and VAT (r = 0.840) correlated best with peak VO2; VO2/WR slope (r = 0.551) and VE/VCO2 slope (r = −0.421) correlated to a lesser degree (p b 0.001). Conclusion: The investigated GUCH show reduced exercise tolerance compared to controls, related to the underlying heart defect. Different expressions of exercise tolerance clearly reveal the same differences in exercise capacity across groups of GUCH. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction In Belgium, 8.3 per 1000 children are born with a heart defect, which is in line with the prevalence in the western world [1]. Changes in birth prevalence, the availability of new treatment options and improvements in the survival of patients with congenital heart disease, have resulted in an increased number of grown-up patients with congenital heart disease (GUCH). Many of them underwent corrective or palliative surgery, but it remains unclear whether the promising results at young age will persist in late adult life [2,3]. Beneficial effects of physical activity are well-established in the general population as well as in patients with coronary artery disease. The functionality and activity level of GUCH largely depend on their exercise capacity and even though they usually do not report problems with low intensity exercise, they often have difficulties
⁎ Corresponding author. Department of Rehabilitation Sciences, Tervuursevest 101 - bus 01501, B-3001 Heverlee, Belgium. Tel.: +32 16 329158; fax: +32 16 329197. E-mail address: [email protected] (L. Vanhees). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.08.030
with exercise at higher intensity. The results of previous studies in GUCH show that exercise tolerance is diminished in all patient groups compared to a healthy population [4–7]. Generally, cardiopulmonary performance is evaluated by peak oxygen uptake (peak VO2) [8]. However, peak VO2 might be underestimated or less reliable in GUCH because the tests are performed with more caution, which might lead to reduced patient motivation and examiner variability [4]. Furthermore, also in a general population and in patients with acquired heart disease, peak VO2 is influenced by subjective motivation [9,10]. Furthermore, peak VO2 measurement depends on a maximal effort on the exercise test, of which no certainty exists that this physiological maximum is or can always be reached by GUCH. To be independent from this end point, submaximal measures, such as ventilatory anaerobic threshold (VAT), Oxygen Uptake Efficiency Slope (OUES), oxygen uptake versus exercise intensity slope (VO2/WR slope) and the VE/VCO2 slope, have been introduced [9,11–13]. Most of these estimates of exercise tolerance have not been investigated in this population, or often only in small groups without a control group. However, this could be of a larger clinical importance.
R. Buys et al. / International Journal of Cardiology 153 (2011) 26–30
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Therefore, the aim of this study was 1) to describe the maximal exercise capacity in a large group of adult patients with underlying Tetralogy of Fallot (TOF), dextro-transposition of the great arteries (dTGA), Coarctation of the aorta (COA) or with a univentricular heart (UVH), and to compare them with a control group of healthy sedentary adults; 2) to investigate whether GUCH can perform an exercise test at the same intensity as control subjects and 3) to evaluate the usefulness of submaximal measures of exercise capacity.
age, height, weight and gender as covariates. Kruskal–Wallis analysis of variance was used for Borg scale. Bland and Altman limits of agreement were used for the evaluation of the agreement between different calculations of the OUES. Pearson product moment correlation coefficients of the relation of peak VO2 with the OUES, VE/VCO2 slope, VO2/WR slope and VAT were also calculated. All statistical tests were 2-sided at a significance level of ≤ 0.05.
2. Materials and methods
Patients' characteristics are summarized in Table 1. The mean age in the control group was 29.2 (8.6) years, with a range between 16 and 46 years. GUCH patients had a mean age of 25.9 (8.1) years, ranging from 16 to 62 years old.
2.1. Patients Between October 2000 and August 2009, all GUCH with repaired TOF, dTGA, COA and UVH, who were referred to the outpatient clinic of adult congenital heart disease in the University Hospital of Leuven for follow-up, and who were scheduled to perform an exercise test until exhaustion, were subject to inclusion in the study. Healthy sedentary adults were recruited amongst friends and family of the investigators, in order to compose a control group. Inclusion criteria were: 1) aged 16 years or older, 2) able to understand the exercise testing protocol and 3) able to perform a maximal graded exercise test until exhaustion. Exhaustion was defined as shortness of breath and/or fatigue of the legs. Patients with concomitant pathology were excluded. Three hundred twenty-five patients (93 patients with TOF, 67 with dTGA, 155 with COA and 10 patients with UVH) performed a bicycle exercise test until exhaustion. The control group (CON) was composed of 122 healthy, sedentary adults between 16 and 46 years old. Forty TOF patients underwent palliative surgery. Final correction was established in 37 patients with a valvotomy and in 56 patients with a transannular patch. The dTGA group consists of 22 patients who underwent Mustard repair and 45 patients who received a Senning repair. All COA patients underwent a coarctectomy. A Fontan circulation was established in the patients with a univentricular heart, two of the ten patients were slightly cyanotic at rest because of persistent fenestration. 2.2. Measurements Maximal exercise tests on the bicycle ergometer (Ergometrics 800S, Ergometrics, Bitz, Germany) were performed in a laboratory where room temperature was stabilized at 18 to 22 °C. The initial workload of 20 W was increased by 20 W every minute until exhaustion. Exhaustion, based on clinical criteria, was defined as shortness of breath and/or fatigue of the legs. A 12-lead electrocardiogram (Max Personal Exercise Testing, Marquette, Wisconsin, USA) and respiratory data through breath-by-breath analysis (Oxygen AlphaR, Jaeger, Mijnhardt, Bunnik, The Netherlands) were continuously registered. Heart rate was calculated from the electrocardiogram. The gas analyzers and the flow meter were calibrated before each test according to the manufacturer's instructions. Oxygen uptake (VO2) and carbon dioxide output (VCO2) were determined from the continuous measurement of oxygen and carbon dioxide concentration in the inspired and expired air. The respiratory gas exchange ratio (RER) and ventilatory equivalent for oxygen (VEO2) were calculated. Peak VO2 was defined as the highest 30-s average of VO2 at the end of the test. The first VAT was determined according to Binder [14]. Single linear regression analyses on the respiratory data during exercise were used to calculate slopes. In these regression analyses respiratory data were averaged every 30 s. The first minute of exercise was excluded because of the often very irregular breathing pattern at the onset of exercise [15]. The OUES was determined by the method of Baba and co-workers who used the following equation: VO2 = a log10 VE+ b, where a is the OUES [9]. The steeper the slope or higher the OUES, the more efficient the oxygen uptake is. The OUES was also calculated based on the first 75% (OUES75) and 90% (OUES90) of the exercise test in order to calculate the agreement between submaximal and maximal measures. VE/VCO2 slope was calculated from the equation: VE= m (VCO2) + b, in which m = VE/VCO2 slope. The non-linear part of this slope after the respiratory compensation point was not used in the regression analysis by excluding the last 10% of the exercise test. The VE/VCO2 slope is used to evaluate the ventilatory response to exercise and thus the efficiency of pulmonary gas exchange. A steeper slope is an indication of a less efficient pulmonary gas exchange [16]. The adequacy of the oxygen transport was assessed by calculating the steepness of the slope of oxygen uptake versus exercise intensity during the graded exercise. To estimate the exercise intensity, we used the external work load [12]. Data from the entire exercise test were used in the regression analysis, except for the first minute. A steeper oxygen uptake versus exercise intensity slope (VO2/WR slope) indicates a better oxygen flow to the exercising tissues. 2.3. Statistical analysis We used SAS statistical software version 9.1 for windows (Sas Institute Inc, Cary, NC, USA). Data are reported as means (standard deviation) or as numbers for dichotomous variables. Distributions were checked for normality with the Shapiro– Wilk statistic. Single regression analyses were used to calculate slopes. Analysis of covariance and Scheffé's comparison of means between groups were performed with
3. Results 3.1. Patients
3.2. Maximal exercise data and submaximal measures of exercise tolerance As shown in Table 2, significant differences between groups were found for all exercise parameters (p b 0.0001). Scheffé's comparison of means showed that all GUCH reached significantly lower peak VO2 compared to healthy controls. Moreover, a gradual decline in peak VO2 could be observed across the spectrum of congenital heart disease (see Fig. 1A). There was a large variation in peak VO2 in all patient groups (range from 10.6 till 56.4 ml/kg/min). In addition, peak heart rate and mean peak RER in GUCH were significantly lower compared to the control group (p b 0.05 for both). In the control group, 89.3% of the subject reached a RER of at least 1.10. In the patient groups, this percentage was lower; 78.7% in COA, 61.5% in TOF, 59.7% in dTGA and 60% in UVH. All groups reached a VEO2 well above 30. Finally, the median score on the Borg scale was significantly higher in the control group compared to GUCH (p b 0.05). With regard to the submaximal measures of exercise tolerance we calculated OUES, OUES75, OUES90, VO2/WR slope and VE/VCO2 slope for all patients and control subjects. VAT was not reached or could not be determined in 33 patients (2 controls, 12 patients with COA, 7 patients with TOF, 11 patients with dTGA and 1 patient with UVH). As shown in Table 2, all patient groups had a significantly lower mean VAT when compared to the control group (p b 0.05) (see Fig. 1B). The mean OUES showed significant differences between patients and control group (p b 0.05) and a gradual decline with higher complexity of the heart defect (see Fig. 1C). Results were similar for OUES75 and OUES90. In addition, Bland and Altman analysis demonstrated good agreement between the measurements of OUES and OUES75 in CON and COA whereas agreement was poor for the other patient groups. On the other hand, OUES90 was in good agreement with OUES in all groups. The VE/VCO2 slope was higher in dTGA patients, which was significantly different from the control group as well as the TOF group. Also the steepness of the VO2/WR slope showed a gradual decline across the patient groups according to the underlying heart defect (see Fig. 1D). All means of the patient groups were significantly lower than the mean slope of the control group (p b 0.05). Of all submaximal parameters, OUES and VAT correlated best with peak VO2, VO2/WR slope and VE/VCO2 slope correlated to a lesser degree (see Table 3). In the control group, VO2/work slope was not correlated with peak VO2.
4. Discussion In the present study, we showed that GUCH have a significantly lower exercise capacity compared to healthy, sedentary controls, Table 1 Patient's characteristics. CON
COA
TOF
dTGA
UVH
n 122 155 93 67 10 Male/ 78/44 108/47 65/28 47/20 7/3 female Age 29.2 (8.6) 27.5 (8.8) 25.6 (7.7) a 22.6 (6.0) ac 22.9 (5.0) (years) Weight 71.3 (12.1) 71.4 (14.3) 67.3 (13.9) 66.4 (13.6) 66.2 (10.2) (kg) 169 (11) Height 177 (10) 174 (11) 173 (9) 172 (9) a (cm) ce 6.9 (6.3) 5.7 (4.5) 1.0 (1.2) 8.6 (5.8) g Age at surgery (years) Data are presented as means (SD) for continuous variables and as numbers for dichotomous variables. CON: control group; COA: Coarctation of the aorta; TOF: Tetralogy of Fallot; dTGA: Transposition of the great arteries; UVH: univentricular heart. Scheffé's comparison of means (p b 0.05): a = significantly different from CON; c = significant difference between COA and dTGA; e =significant difference between TOF and dTGA; g=significant difference between dTGA and UVH.
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R. Buys et al. / International Journal of Cardiology 153 (2011) 26–30
Table 2 Maximal and submaximal exercise measures. CON Peak VO2 (ml/min) Peak VO2/kg (ml/min/kg) % of predicted peak VO2 Peak HR (beats/min) Peak load (W) Peak RER Peak VEO2 Borg scale OUES OUES75 OUES90 VE/VCO2 slope VO2/WRslope VAT (ml/min/kg)
2755 38.6 99.2 184 235 1.23 38.4 17 3067 3110 3104 25.0 10.3 24.1
COA (800) (8.6) (17.2) (20) (73) (0.12) (7.39) (13-20) (810) (802) (818) (4.1) (1.6) (6.1)
2249 31.7 80.0 173 202 1.16 32.6 16 2646 2605 2630 24.7 9.2 20.8
(675)a (8.3)a (14.7)a (19)a (56.6)a (0.09)a (5.6)a (9-19)a (761)a (761) a (753) a (4.2) (1.2)a (5.7)a
TOF
dTGA
UVH
F-value
2015 (640)ab 30.0 (7.8)a 74.1 (15.6)a 169 (22)a 171(59)ab 1.13 (0.12)a 35.1 (7.0)b 15 (11-20)ab 2506 (742)a 2702 (828) a 2628 (771) a 26.2 (5.5) 9.0 (1.6)a 21.4 (5.4)a
1761 (510)ace 27.1 (8.1)ac 64.3 (13.7)ace 173 (23) a 153 (45)ac 1.12 (0.10)a 40.0 (9.6) ce 16 (12-20)a 2324 (783)ac 2495 (863) a 2412 (818) a 32.4 (14.4)ace 8.6 (1.9)a 19.8 (5.2)a
1466 (431)adf 22.6 (6.9)adf 54.5 (11.7)adf 155 (26)a 142 (29)ad 1.12 (0.10) 39.8 (5.74)d 15 (13-19) 1881 (584)ad 1791 (516) adf 1820 (513) adf 29.9 (6.18) 7.4 (1.2)ad 14.7 (4.0)ad
105.35⁎ 67.61⁎ 65.37⁎ 10.20⁎ 78.20⁎ 11.13⁎ 13.27⁎ 6.65⁎ 47.39⁎ 29.60⁎ 36.73⁎ 9.65⁎ 17.45⁎ 38.49⁎
Data are presented as means (SD) or as median (range) for Borg scale. CON: control group; COA: Coarctation of the aorta; TOF: Tetralogy of Fallot; dTGA: dextro-Transposition of the great arteries; UVH: univentricular heart; HR: heart rate; RER: respiratory exchange ratio; VEO2: ventilatory equivalent for oxygen; OUES: oxygen uptake efficiency slope; VE/VCO2: ventilatory efficiency slope; VO2/WR: oxygen consumption versus exercise intensity slope; VAT: ventilatory anaerobic threshold. Scheffé's comparison of means (p b 0.05): a = significantly different from CON; b = significant difference between COA and TOF; c = significant difference between COA and dTGA; d = significant difference between COA and UVH; e = significant difference between TOF and dTGA; f = significant difference between TOF and UVH. ⁎ p b 0.0001.
and the degree of this exercise intolerance seems to be related to the underlying heart defect. Furthermore, similar patterns could be observed for submaximal measures of exercise tolerance; i.e. ventilatory anaerobic threshold, oxygen uptake efficiency slope and VO2/WR slope. Finally, although the criteria for a maximal exercise performance were reached in all groups, our results showed that the RER and Borg scale were significantly lower in patients compared to the healthy sedentary controls. Peak VO2 is the golden standard to measure the exercise tolerance and is widely used in patients with heart disease. Concordant to others we found a significantly reduced peak VO2 across the four investigated GUCH groups compared to healthy sedentary individuals [4–6,17–20]. Diller et al. reported that the degree of this exercise
intolerance is related to underlying anatomical features [4]. Indeed, our results clearly showed that the underlying heart defect has an influence on the results of a maximal exercise test. Patients with a less severe, non-cyanotic congenital heart defect, such as coarctation of the aorta, performed better on the exercise test than patients with heart defects as Tetralogy of Fallot or Transposition of the great arteries, even though the difference with patients with corrected Tetralogy of Fallot is rather small. The complexity of the univentricular heart and blood circulation after Fontan-repair had the greatest influence on exercise capacity, resulting in even lower values of peak VO2. Further, this decreased peak VO2 in GUCH could also be related to an impaired chronotropic response to exercise, pulmonary arterial hypertension, cyanosis or an impaired lung function [4].
Fig. 1. A graphic view of peak VO2 (A), VAT (B), OUES (C) and VO2/WR slope (D) across heart defect groups, with indication of significant differences between groups. CON: control group; COA: coarctation of the aorta; TOF: tetralogy of Fallot; dTGA: dextro-Transposition of the great arteries; UVH: univentricular heart. Data are presented as means ± SD. p b 0.05 for all comparisons (ANOVA for unbalanced data with correction for age, gender, weight and height; comparison of means by Scheffé's comparison).
R. Buys et al. / International Journal of Cardiology 153 (2011) 26–30 Table 3 Pearson correlation of submaximal measures with peak VO2.
ALL CON COA TOF dTGA UVH
OUES
OUES75
OUES90
VE/VCO2
VO2/WR
VAT
0.853⁎ 0.872⁎ 0.841⁎ 0.823⁎ 0.739⁎ 0.876⁎⁎
0.735⁎ 0.765⁎ 0.747⁎ 0.728⁎ 0.602⁎ 0.873⁎⁎
0.801⁎ 0.840⁎ 0.817⁎ 0.753⁎ 0.649⁎ 0.901⁎⁎
− 0.421⁎ − 0.372⁎ − 0.371⁎ − 0.485⁎ − 0.502⁎ − 0.499
0.551⁎ 0.165 0.692⁎ 0.577⁎ 0.518⁎ 0.865⁎⁎
0.840⁎ 0.854⁎ 0.818⁎ 0.839⁎ 0.775⁎ 0.630
ALL: all groups together; CON: control group; COA: coarctation of the aorta; TOF: tetralogy of Fallot; dTGA: Mustard/Senning repair for transposition of the great arteries; UVH: Fontan circulation for univentricular heart; OUES: oxygen uptake efficiency slope; VE/VCO2: ventilatory efficiency slope; VO2/WR: oxygen consumption versus exercise intensity slope; VAT: ventilatory anaerobic threshold; ⁎ p b 0.0001. ⁎⁎ p b 0.005.
However, it has to be taken into account that peak VO2 is an effortdependent measure. Therefore, it is important to evaluate the maximal character of the performed exercise test. According to the guidelines of the European Association for Cardiovascular Prevention and Rehabilitation, the achievement of a real maximal effort can be assumed when, among others, peak RER ≥ 1.10–1.15 and the rating of perceived exertion is at least 15 on the 20-point Borg scale [13]. In our GUCH groups, the mean RER at peak exercise was well above this minimum level for considering a test as maximally executed. However, a larger part of patients than controls did not reach a RER ≥ 1.10 and mean RER was significantly higher in the healthy controls. Therefore our results indicate that some patients stopped the exercise test at lower intensities than the healthy individuals. Moreover, the median Borg scale values of the patient groups were significantly lower than those of the control group. Whereas the obtained values indicated that a maximal effort at the end of the exercise test might be assumed in COA and dTGA patients, the lower median values in TOF and UVH patients are on the limit of what would be acceptable for a maximal exercise test. It is uncertain whether this indicates that the evaluation of peak VO2 in GUCH is less reliable. Furthermore, our results did not show significant differences in VEO2 between the groups, so this parameter could not contribute to the interpretation of the test's maximal character. As we measured mean levels of VEO2 above 30, we might assume that at least near maximal exercise levels are reached. But the increase in VEO2 may in some patients partly be caused by an increased dead space ventilation, and therefore not be an indication for the maximal character of the exercise test. Based on our results, it seems plausible that not all patients reach their physiological maximum according to the earlier mentioned guidelines [13]. This supports the rationale for a search for alternative exercise parameters to assess the exercise tolerance in these patients. The VAT can be a valuable parameter to assess the exercise tolerance without requiring a maximal effort [21]. Compared to healthy controls, VAT was significantly lower in GUCH. Our results showed a similar tendency as peak VO2 according to differences of the VAT between the different GUCH groups, but these differences were not significant. In agreement with others, we observed a good correlation of VAT with peak VO2. However, a disadvantage of the VAT is that it is highly depending on the exercise protocol, the detection method and the observer [22,23]. Moreover, the VAT could not be determined in 33 patients. A second alternative measure is the OUES. It shows how efficiently the oxygen is extracted by the lungs and used in the periphery. We reported that the OUES is lower in GUCH compared to control subjects and that the OUES declines with an increase in the complexity of the heart defect. Similar to peak VO2, a reduced OUES may be caused by a number of different underlying mechanisms such as an impaired blood flow to the exercising muscles, a smaller muscle mass, less efficient extraction and use of oxygen at the muscular level, an increase in dead space ventilation and a lower blood hemoglobin
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level [10]. However, in agreement with other investigators, we showed that the OUES, both measured on the entire exercise time and on the first 90% of the test, correlates well with peak VO2 and might therefore be a very good alternative for peak VO2 in GUCH [9,24]. Next, the VO2/WR slope showed in the patient groups a significant but weaker correlation with peak VO2. Subnormal values have been associated with important residual hemodynamic defects after correction of the congenital heart lesion [11]. The lower values in our patient groups, might indicate an impaired oxygen flow to the peripheral exercising muscles, or alterations in the metabolism of the skeletal muscles [12]. These unknown peripheral factors may be the result of underlying congenital disturbances, or can be caused by low daily physical activity levels [6]. Earlier, Reybrouck et al. explained the reduced oxygen delivery to exercising muscles in dTGA patients by an inappropriate right ejection fraction and a subnormal cardiac output, and in TOF patients by hemodynamic dysfunction which might be caused by pulmonary valve incompetence [11]. Especially in dTGA patients, the VO2/WR slope might be an interesting measure to use for the evaluation of their functional status, as the systemic ventricle function tends to progressively decrease with age [25]. It is of notice that a significant correlation of the VO2/WR slope with peak VO2 could only be observed in GUCH but not in healthy controls. This might be explained by the fact that healthy individuals show a similar pattern of the adaptation of VO2 to workload, but with less variability, probably because no underlying heart defect or inadequacies of oxygen transport are present in this group. Furthermore, this slope is influenced by the oxygen kinetics. As some patient groups might show delayed oxygen kinetics, a different exercise testing protocol probably would have been more appropriate in these cases. Finally, higher values of the VE/VCO2 slope were found in TOF, dTGA and UVH compared to the control group, although only significant for the dTGA group. The reasons for a higher VE/VCO2 slope in adults with Mustard/Senning repair for dTGA are not clear yet. The steeper VE/VCO2 slope could be the result of abnormal ventilation when the CO2 concentration increases during exercise [5]. A higher VE/VCO2 slope has also been associated with the presence of pulmonary hypertension, right ventricular dysfunction and reduced exercise capacity [26]. In agreement with other investigators, we showed that the VE/VCO2 slope was poorly correlated with peak VO2. Therefore it is inappropriate to use the VE/VCO2 slope to evaluate the exercise capacity in GUCH. However, it can be useful for its prognostic value [5,26,27]. Our study has some limitations. First of all, only patients who were supposed to be able to perform a maximal graded exercise test until exhaustion, based on the judgment of the cardiologist, were included in the study. Therefore, our results might be overestimating the average exercise capacity. Furthermore, the number of UVH patients was very low, which holds us back to generalize their results. In conclusion, adults with COA, TOF, dTGA and FON show a reduced exercise tolerance compared to healthy sedentary adults, and the impaired exercise tolerance is associated to the underlying heart defect. Although near maximal exercise testing can be performed in GUCH, not all patients reach the same exercise intensity on the exercise test compared to healthy adults. Oxygen uptake efficiency slope, ventilatory anaerobic threshold and oxygen uptake versus exercise intensity slope — parameters that correlated with peak VO2 — may be useful to accurately interpret the exercise tolerance. Different expressions of exercise tolerance clearly show similar differences in exercise capacity across groups of patients with different congenital heart diseases. Acknowledgements We especially appreciate the work of Dirk Schepers and Jan Meertens in the exercise testing laboratory. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [28].
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