Cardiorespiratory response during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation and in patients with congestive heart failure

International Journal of Cardiology 66 (1998) 241–251

Cardiorespiratory response during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation and in patients with congestive heart failure Hideo Ohuchi*, Yoshio Arakaki, Yoshimi Hiraumi, Hiroshi Tasato, Tetsuro Kamiya Department of Pediatrics, National Cardiovasular Center, Fujishiro-dai, Suita, Osaka, Japan Received 19 February 1998; received in revised form 2 July 1998; accepted 20 August 1998

Abstract To clarify the different cardiorespiratory response to exercise in patients with congenital heart disease and patients with chronic congestive heart failure, we investigated the effect of a progressive exercise test in 30 patients aged 10 to 24 years, including 9 patients with cyanotic congenital heart disease (group A), 13 patients who had undergone a Fontan operation (group B), and 8 patients with reduced left ventricular function (group C), and 18 healthy controls (group D). There was no difference in peak oxygen uptake among patient groups and all group A, B, and C values were lower than those in group D (P,0.001). Although peak heart rate was lower in patient groups than in group D, heart rate at a given exercise intensity was highest in group C. The oxygen pulse (oxygen uptake divided by heart rate5stroke volume3arterial venous oxygen difference), as an indicator of stroke volume, was lower in patients groups, especially in group C, than in group D. There was no difference in tidal volume between groups A and D, but the respiratory rates at any given exercise intensity were higher in group A than in the other patient groups, thus minute ventilation and the ventilatory equivalent were highest in group A. The increased respiratory rate and low tidal volume in group C resulted in rapid and shallow respiration. There was no difference in exertional symptoms at peak exercise among the groups. In addition to impaired responses of stroke volume during exercise in patients with reduced exercise capacity, there was little limitation of increase in ventilation in group B and excessive ventilation in group A. The present results suggest that relationship between ventilatory and cardiac responses during exercise in patients with cyanotic congenital heart disease with and without a Fontan operation is different from the relationship in patients with chronic congestive heart failure; however, these pathological differences did not influence exertional symptoms.  1998 Published by Elsevier Science Ireland Ltd. All rights reserved. Keywords: Cyanotic congenital heart disease; Fontan operation; Congestive heart failure; Exercise cardiorespiratory response; Exertional symptom

1. Introduction Patients with chronic heart failure exhibit an abnormal cardiorespiratory response to exercise [1,2]. Patients with poor left ventricular function demonstrate an increased heart rate and respiratory rate in response to exercise. The relationship between these abnormal responses and exertional symptoms has *Corresponding author. Tel: 181-6-8335012; Fax: 181-6-8727486.

been studied [3]. Although an abnormal cardiorespiratory response to exercise has also been observed in patients with congenital heart disease [4–7], especially in patients with cyanotic congenital heart disease and who had undergone a Fontan operation, reduced left ventricular function is not always observed in pediatric patients. Therefore, different mechanisms must be related to reduced exercise capacity in such patients. The purpose of the present study is to clarify the differences in cardiorespiratory

0167-5273 / 98 / $ – see front matter  1998 Published by Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-5273( 98 )00249-6

H. Ohuchi et al. / International Journal of Cardiology 66 (1998) 241 – 251

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response to exercise between patients with cyanotic congenital heart disease with and without a Fontan operation and patients with congestive heart failure due to poor left ventricular function, and to investigate whether these different cardiorespiratory responses are related to exertional symptoms during exercise.

2. Materials and methods

2.1. Subjects We studied 30 cardiac patients with reduced exercise capacity, including 9 patients with cyanotic complex congenital heart disease aged 10 to 24 years (group A), 13 patients aged 13 to 22 years with congenital heart disease who had undergone a Fontan operation (group B), and 8 patients aged 11 to 27 years with reduced left ventricular function due to cardiomyopathy or myocardial infarction associated with Kawasaki disease (group C) (Table 1). We also studied 18 healthy control subjects who had a history of Kawasaki disease without significant stenotic coronary artery lesions. There were no significant differences in age, height, and weight among groups. Two patients were taking digoxin, three were taking diuretics, and two were taking antiplatelet agents in group A. Four patients were taking digoxin, five were taking diuretics, five were taking diuretics, five were taking antiplatelet agents, and one was taking antiarrhythmic agent in group B. Two were taking angiotensin-converting enzyme inhibitor, and one was

taking antiarrhythmic agent in group C. No patients were taking b-blocker in the study groups.

2.2. Pulmonary function tests All patients underwent pulmonary function tests during which the following parameters were measured: vital capacity, the forced expired volume in 1.0 s (FEV1 ) (Spirosift, SP-600, Fukuda Denshi, Tokyo), and functional residual capacity, residual volume, and total lung capacity (Ellopse-1000 System, Fukuda Denshi, Tokyo). Residual volume to total lung capacity ratio (%) was calculated and the value of vital capacity was also expressed as a sex-matched percent of the normal value predicted from body height (% vital capacity).

2.3. Cardiac catheterization Cardiac catheterization was performed in all patients in groups A and D, 10 patients in group B, and 7 patients in group C under light sedation after an overnight fast to determined the arterial blood oxygen saturation (%), the volume of the left ventricle (%), the ejection fraction of the left ventricle, the enddiastolic pressure of the left ventricle, central venous pressure, and the cardiac index (l / min / m 2 ). Cineventriculography was performed in the anteroposterior and lateral projections with a film speed of 60 frames / s. The volume of the morphological right and left ventricle was calculated using Simpson’s rule. Adjustment of volume occupied by papillary muscles within the morphologic left ventricle was made according to Graham et al., as follows. Measured

Table 1 Subject characteristics

n Diagnosis (n) Age(yr) Height (cm) Weight (kg)

A

B

C

D

9 UVH (4), DORV (3) TOF (1), TGA (1) 1864 161613 4869

13 UVH (6), TA (3) DORV (3), PA (1) 1763 16066 5267

8 DCM (3), HCM* (2) KD** (2), Aortitis (1) 1765 15569 4369

18 KD (18) 1763 165611 5267

Abbreviations: DCM5dilated cardiomyopathy; DORV5double outlet right ventricle, HCM5hypertrophic cardiomyopathy; KD5history of Kawasaki disease; PA5pulmonary atresia; TA5tricuspid atresia; TGA5transposition of the great arteries; TOF5tetralogy of Fallot; UVH5univentricular heart. Group A5patients with congenital heart disease without definitive operation; group B5patients who had a Fontan operation; group C5patients with congestive heart failure; and group D5control subjects. *, Dilated phase. **, post operative state after aortocoronary bypass. Values are mean6SD.

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volumes of left ventricle less than 15 ml were adjusted to left ventricular volume (Vc )50.613 (calculated volume)10.36 (ml), and for left ventricular volume greater than 15 ml, Vc 50.963(calculated volume) – 3.3 (ml). Similarly, the right ventricular volumes were adjusted to Vc 50.6493(calculated volume). Because the outflow tract of the left ventricle in patients with double inlet left ventricle is usually the morphologic right ventricle, Simpson’s rule was applied to calculate its volume. Thus, the systemic end-diastolic volume in groups A and B, which is the largest volume during a cardiac cycle, was the total of the morphologic right and left ventricles in patients with tetralogy of Fallot, double outlet right ventricle, transposition of the great arteries, and double inlet left ventricle. Ejection fraction of the systemic ventricle was calculated as a ratio of stroke volume to end-diastolic volume (%). Cardiac output was measured by the Fick principle, and in patients who had undergone a total cavopulmonary connection or a atriopulmonary connection with a Glenn anastomosis, it was estimated by the Fick principle with an assumption that right and left pulmonary arterial saturations were equal.

2.4. Exercise protocol Subjects performed a ramp-like progressive exercise test on a treadmill (Q-5000 system, Quinton, Seattle, USA). We previously demonstrated a high correlation between ventilatory anaerobic threshold and the lactate threshold using this treadmill test and established its clinical usefulness for determining the ventilatory anaerobic threshold and evaluating cardiorespiratory tolerance in patients with congenital heart disease [8]. The exercise intensity was increased by 0.7 metabolic units every 30 s with completion of the incremental part of the exercise test in about 10 min. When selecting a slope of the oxygen uptake as a function of work rate, a value of 3.5 ml / kg / min (51.0 metabolic unit) was used because of the difficulty determining this metabolic unit in children. After a 4 min rest, the patients performed a 3 min warm-up walk at a speed of 1.5 km / h and then exercised with progressive intensity until exhausted. At the end of each exercise test, to determination of exertional symptoms at peak exercise, the patients were asked to identify the primary

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reason for stopping at the end of each exercise test as dyspnea, leg fatigue, dyspnea and leg fatigue, general fatigue, or other.

2.5. Heart rate, blood pressure measurements Twelve standard electrocardiogram leads were placed to monitor heart rate, and systolic blood pressure was measured every 2 min during exercise testing. Because it is difficult to measure blood pressure with a mercury sphygmomanometer during dynamic exercise, especially in younger patients, we measured systolic blood pressure by the palpation method. In our preliminary study, systolic blood pressure obtained by this method in 12 patients with cardiac disease during treadmill exercise testing was correlated with measurements with a mercury sphygmomanometer (r50.98, P,0.0001, Ohuchi et al., unpublished data, 1996).

2.6. Gas exchange measurements Ventilation and gas exchange were measured by the breath-by-breath method. Subjects breathed through a mask connected to a hot-wire anemometer (Riko A5500, Minato Medical Science, Osaka, Japan) in order to measure inspired and expired volume continuously. A mass spectrometer (MG-300, Perkin Elmer, St. Louis, USA) was used for continuous measurements of O 2 and CO 2 partial pressures. Two sizes of masks were used: one for children between 120 cm and 150 cm tall, which had a dead space of 80 mL, and another for children taller than 150 cm, which had a dead space of 100 ml. In the breath-bybreath protocol, derived respiratory parameters, including the respiratory rate, tidal volume, minute ventilation, ventilatory equivalents for oxygen and carbon dioxide, and the respiratory gas exchange ratio, were computed in real time and displayed with heart rate and oxygen uptake on a monitor. A personal computer (PC-980 1, NEC, Tokyo, Japan) was used for data acquisition and storage. Breath-bybreath data were averaged to provide 1 data point for each 30 s period. The delay times and response characteristics of the O 2 and CO 2 analyzers were carefully checked before each exercise test. The metabolic rate above which anaerobic metabolism supplements the production of aerobic energy

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production and leads to lactic acidosis corresponds to the ventilatory anaerobic threshold [9]. This threshold was defined as the oxygen uptake at which the ventilatory equivalent for oxygen and the end-tidal pressure for O 2 increased without increases in the ventilatory equivalent for carbon dioxide and endtidal pressure for CO 2 , alternatively determined by the V-slope method [10]. Informed consent was obtained from all subjects and / or their parents. This protocol was approved by the Ethics Committee of the National Cardiovascular Center.

defined as the ratio of minute ventilation at peak exercise to maximal voluntary ventilation.

2.8. Statistical analysis Simple regression analysis was used to determine correlations between pulmonary function and cardiorespiratory variables. Differences in proportions of exertional symptoms at peak exercise among study groups were analyzed with Fisher’s exact test. Differences in cardiopulmonary function at rest were evaluated using factorial one-way ANOVA and differences in mean cardiorespiratory values during exercise were assessed by two-way ANOVA. If differences were significant, individual comparisons were made using Scheffe’s procedure. Data are expressed as the mean6SE. P values ,0.05 was considered statistically significant.

2.7. Calculations The oxygen pulse (ml / min / beats) was calculated by dividing the oxygen uptake by heart rate and is equal to the product of the stroke volume and the arterial–venous O 2 difference. Therefore, this value relates to stroke volume and oxygen extraction and because the magnitude of oxygen extraction at peak exercise varies little in patients and normal subjects, the oxygen pulse at peak exercise reflects the individual stroke volume at peak exercise [11]. Maximal voluntary ventilation was estimated by the FEV1 340 [12]. The exercise breathing reserve was

3. Results

3.1. Hemodynamic data Arterial oxygen saturation at rest was lowest in group A (Table 2). Central venous pressure was

Table 2 Cardiopulmonary function at rest n

A 9

B 13

C 8

D 18

Pulmonary function VC(ml) Pred-VC(%) %FEV1.0(%) FRC(ml) RV/ TLC

31876246 8363 8763 17396190 2662

30686149* 8262 9261 1609698 2762

2354697* 7365 8764 13746140* 2863

39386206 9762 9061 21116144 2461

Cardiac function CVP(mmHg) SVvolume(ml) SVEF(%) SVEDP(mmHg) Qs index (l / min / m 2 ) SaO 2 at rest(%)

761* 270637* 5364 761 2.860.3 8761*

1161* 112611 5965 861 2.660.2 9561

662 177619 3266* 2465* 3.060.4 9861

361 13367 6462 961 3.660.2 9861

Abbreviations: CVP5central venous pressure; FEV 1.05forced expired volume in 1 second; FRC5functional residual capacity; Qs index5systemic flow index (5cardiac index in groups B, C, and D); RV5residual volume SaO 2 5arterial oxygen saturation; SV5systemic ventricle; SVEF5ejection fraction of the systemic ventricle; SVEDP5end-diastolic pressure of the systemic ventricle; TLC5total lung capacity; VC5vital capacity; Pred-VC5predicted VC value; RV/ TLC5residual volume to total lung capacity ratio. Values are mean6SE. *, P,0.05 vs group D. Groups A, B, C, and D are the same in Table 1.

H. Ohuchi et al. / International Journal of Cardiology 66 (1998) 241 – 251

higher in groups A and B than in group D. The systemic (left) ventricular ejection fraction was significantly lower and the end-diastolic pressure of the systemic (left) ventricle was significantly higher in group C compared with the other groups. Systemic cardiac flow index (cardiac index) tended to be lower in group B than in group D.

3.2. Pulmonary function at rest No significant obstructive ventilatory impairment was observed in any group. The vital capacity was lowest in group C. On the other hand, although the vital capacity was lower in groups A and B than in

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group D, the severity of restrictive impairment was relatively mild.

3.3. Exercise capacity Because there was no difference in peak gas exchange ratio among the groups and the values were enough high in all groups, we believed that maximal exercise level was achieved in all groups. Although there was no significant difference in endurance time, oxygen uptake at the ventilatory anaerobic threshold, or peak oxygen uptake among groups A, B, and C, these values were significantly lower in patients with decreased exercise capacity than in group D (Table 3).

Table 3 Cardiorespiratory variables at rest and peak exercise during progressive exercise testing Parameters

A

B

C

D

Endurance time (min) Appearance of VT (min) HR (rest; beats / min) HR (VT; beats / min) HR (peak; beats / min) SBP (rest; mmHg) SBP(peak; mmHg) VO 2 (rest; ml / kg / mm) VO 2 (VT; ml / kg / min) VO 2 (peak; ml / kg / min) Oxygen pulse (rest; ml / mm / beats) Oxygen pulse (VT; ml / mm / beats) Oxygen pulse (peak; ml / mm / beats) RR (rest; breath / min) RR (VT; breath / min) RR (peak; breath / min) TV (rest; ml) TV (VT; ml) TV (peak; ml) VE (rest; l / min) VE (VT; l / min) VE (peak; l / min) VE / VCO 2 (rest) VE / VCO 2 (VT) VE / VCO 2 (peak) R (rest) R (VT) R (peak) Peak VE / MVV

6.560.5* 2.660.2* 8763 11664 16063* 10564 16167 5.1603 16.461.2* 23.161.6* 2.860.2 6.760.5* 7.060.7* 2061 2962 4363 633619 1037699 14566122* 12.760.5* 29.461.8 61.965.8* 5863* 4864* 5266* 0.8760.02 0.8660.01 1.1260.03 0.5860.06

7.860.4* 3.060.2 8663 11263 16264* 11063 15065* 4.460.2 15.660.6* 24.96 1.2* 2.760.2 7.560.4* 7.960.4* 2061 2861 4662 579633 1045660 1356661* 11.160.5 28.461.6 62.3645* 5562* 4062* 4266 0.9060.01 0.8760.02 1.1860.02 0.5660.03

6.260.7* 2.760.5* 9263* 13465* a b 17164* 10065 14065* 5.160.4 15.161.4* 23.462.7* 2.360.1* 4.860.4* a 5.860.6* 2061 2761 4163 464643 727636* 1028684* 8.960.5 19.761.2* a b 41.7634* 4962 4062* 3963 0.8660.02 0.8760.02 1.1660.04 0.5260.06

11.060.4 3.760.2 7863 12062 18962 11063 17264 4.960.2 20.960.7 43.661.6 3.360.2 9.460.5 12.060.6 1861 2561 4862 590629 1186668 1854692 10.060.4 28.160.9 87.464.2 4761 3161 3361 0.8960.01 0.8560.01 1.1860.01 0.6360.03

Abbreviations: HR5heart rate; R5gas exchange ratio; RR5respiratory rate; SBP5systolic blood pressure; TV5tidal volume; VE5minute ventilation; VO 2 5oxygen uptake; VT5ventilatory threshold; Oxygen pulse5VO 2 / HR; VE / VCO 2 5ventilatory equivalent for carbon dioxide, MVV5maximal voluntary ventilation. Values are mean6SE. *, P,0.05 vs group D. a , P,0.05 vs group A. b , P,0.05 vs group B. Groups A, B, C, and D are the same in Table 1.

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3.4. Cardiovascular response during exercise The heart rate at rest and during mild to moderate exercise, including at the ventilatory anaerobic threshold, was highest in group C (Fig. 1). The heart rate in groups A and B did not differ from that in group D. The peak heart rate in groups A, B, and C was significantly lower than in group D, suggesting that these patients had chronotropic incompetence. Systolic blood pressure during exercise was lower in group C than in the other groups, but the difference was not significant. The peak systolic blood pressure was not significantly different in groups A and B compared with group D, but was significantly lower in group C than in group D. There was no significant difference in the oxygen uptake at rest among groups, but the oxygen uptake from warm-up to moderate exercise, including at the ventilatory anaerobic threshold, was significantly lower in groups A, B, and C than in group D. The oxygen pulse at rest was significantly lower in group C than in group D (Fig. 2). As the exercise intensity increased, the increase in the oxygen pulse was severely inhibited in group C compared with the other groups. The oxygen pulse was significantly

Fig. 2. Relationship between exercise intensity and oxygen pulse during rest to 4 min after beginning ramp exercise. Vertical lines indicated the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

lower during moderate exercise in groups A and B compared with group D. The heart rate at a given oxygen uptake was highest in group C, and the slope of the heart rate– oxygen uptake relationship during the period from rest to 4 mm after beginning of ramp exercise was 0.12 (beats / mm), which was steeper in group C than in the other groups (0.08, 0.06, and 0.05 in groups A, B, and D, respectively, P,0.001). The heart rate at a given oxygen uptake was lowest and the slope was the least steep in group D.

3.5. Ventilatory response during exercise

Fig. 1. Relationship between exercise intensity and heart rate during before and up to 4 min of ramp exercise. Vertical lines indicate the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

There was no significant difference in the ratio of minute ventilation at peak exercise to maximum voluntary ventilation in any group, suggesting that ventilatory function with respect to minute ventilation did not limit exercise capacity. Although there was no difference in the respiratory rate at rest among groups, the respiratory rate at a given exercise intensity was significantly higher in patients with decreased exercise capacity, especially in group A, than in group D (Fig. 3). There was no

H. Ohuchi et al. / International Journal of Cardiology 66 (1998) 241 – 251

Fig. 3. Relationship between exercise intensity and respiratory rate during rest to 4 min after beginning ramp exercise. Vertical lines indicated the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

difference in the respiratory rate at peak exercise among groups. The tidal volume at a given exercise intensity was lowest in group C and did not differ between group A and D (Fig. 4). The tidal volume at peak exercise was lowest in group C and was significantly lower in group C than in groups A and B. The minute ventilation at any given exercise intensity was highest in group A (Fig. 5), although the minute ventilation during the period from rest to 1 min after beginning of ramp exercise was lower in group C than in group B. There were no significant differences in minute ventilation after 2 min of ramp exercise among groups B, C, and D. The relationship between tidal volume and the respiratory rate during the period from rest to 4 min after the beginning of ramp exercise was almost linear in all groups (Fig. 6). The slope of the relationship was steepest in group D, that is, the increase in minute ventilation during exercise was influenced more by the tidal volume than the respiratory rate. The slope was least steep in group C, that is, the minute ventilation was increased more by respiratory rate than by tidal volume during exercise, indicating that respiration was rapid and shallow.

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Fig. 4. Relationship between exercise intensity and tidal volume during rest to 4 min after beginning ramp exercise. Vertical lines indicated the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

Fig. 5. Relationship between exercise intensity and minute ventilation during rest to 4 min after beginning ramp exercise. Vertical lines indicated the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

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H. Ohuchi et al. / International Journal of Cardiology 66 (1998) 241 – 251 Table 4 Exertional symptoms of the study groups

Dyspnea Leg fatigue Dyspnea1leg fatigue General fatigue Others or undermined

A

B

C

D

3 2 1 2 1

7 3 1 0 2

5 2 0 0 1

8 5 2 1 2

Groups A, B, C, and D are the same in Table 1.

Fig. 6. Relationship between tidal volume and respiratory rate during rest to 4 min after beginning ramp exercise. Vertical and horizontal lines showed standard error. WU5warm-up. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

Patients in groups A and B showed an intermediate respiratory pattern. Although the ventilatory efficiency improved in all groups as the exercise intensity increased, impaired

ventilatory efficiency was observed in groups with lower exercise capacity, especially in group A (Fig. 7). Exertional symptoms at peak exercise occurred in 42 of 48 patients, including dyspnea in 23 patients, leg fatigue in 12 patients, both dyspnea and leg fatigue in 4 patients, general fatigue in 3 patients. Exertional symptoms are summarized in Table 4. There was no significant difference in the distribution of symptoms among groups. Although the peak oxygen uptake (ml / kg / min) did not differ between patients with leg fatigue (3264) and patients with dyspnea (3062), the respiratory rate at peak exercise was significantly higher in patients with leg fatigue (5163) than in patients with dyspnea (4362) (P5 0.011). There was no difference in the tidal volume and minute ventilation at peak exercise between patients with leg fatigue and patients with dyspnea.

4. Discussion

Fig. 7. Relationship between exercise intensity and the ventilatory equivalent for carbon dioxide (VE / VCO 2 ) during rest to 4 min after beginning ramp exercise. Vertical lines indicated the standard error. WU5warm-up. *: P,0.05 vs group D. Solid circle, solid triangle, solid square, and open circle represent values for groups A, B, C, and D, respectively.

Because the response of oxygen uptake at the onset of exercise is reduced in patients with reduced left ventricular function [13], the magnitude of the increase in oxygen uptake at a given exercise intensity decreases as the severity of heart failure increases [14]. The magnitude of the decrease in the peak oxygen uptake was similar among patients with reduced exercise capacity in the present study. Because oxygen uptake is closely related to cardiac output [15,16], impaired response of cardiac output appeared to be the common striking feature among these patients. Exercise capacity did not differ among the patients groups, making it possible to evaluate the influence of pathological differences on the cardiorespiratory response during exercise. Chronotropic incompetence defined as a peak heart rate during exercise that is less than the age-predicted

H. Ohuchi et al. / International Journal of Cardiology 66 (1998) 241 – 251

maximum [17], has been observed in congenital heart disease [5–7]. Chronotropic incompetence affects exercise capacity in both pediatric and adult cardiac patients [18,19]. A number of factors are believed to contribute to chronotropic incompetence during exercise, including hypoxia in patients with cyanotic congenital heart disease [20], sinus node dysfunction following cardiac surgery [21], and preoperative hypoxia in patients with tetrology of Fallot, transposition of the great arteries, and a functional single ventricle. However, the cause of chronotropic incompetence is unclear in the present study. Although the peak heart rate was lower in groups A and B than in the control group, the slope of heart rate–oxygen uptake relationship was steeper than in the control group. Thus, impaired cardiac output was responsible for the smaller stroke volume in groups A and B and was compensated for, to some extent, by an accelerated heart rate. The acceleration of the heart rate response was, however, less in groups A and B than in group C. Because cardiac function of the systemic ventricle was relatively well maintained in groups A and B compared with group C, the magnitude of this heart rate acceleration may have corresponded to the degree of impairment of stroke volume during exercise. Alternatively, the heart rate response may have been blunted even though the slope of the heart rate–oxygen uptake relationship was steeper. Because the peak heart rate was significantly lower in groups A and B than in control group, the latter hypothesis is more likely. The heart rate response in groups A and B showed an intermediate pattern compared with the patterns in groups C and D. It is possible that although reduced left ventricular function resulted in inhibition of increase in the stroke volume in group C compared with groups A and B, the heart rate response was relatively well maintained in group C probably because of the absence of hypoxia or cardiac surgery. Clark et al, showed that a percentage of chronotropic incompetence which influences exercise capacity was relatively low in adult patients with congestive heart failure [22]. Therefore, it is suggested that blunted heart rate response could not compensate adequately for impaired response of stroke volume during exercise in patients with congenital heart disease with or without Fontan operation compared to patients of group C. The blunted heart rate response was also

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demonstrated at the ventilatory threshold exercise level, in which cardiorespiratory variables were not influenced by subject’s motivation. Thus, chronotropic incompetence is probably closely related to impairment of increase in cardiac output in patients with congenital heart disease with relatively maintained systemic ventricular function compared to adult patients with poor left ventricular function. Obviously, we need to consider that the increase in intracardiac shunt and subsequent decrease in systemic oxygen concentration results in reduced exercise capacity in patients of group A. Because systemic arterial oxygen saturation was not monitored during exercise test, it is not unclear that how much the magnitude of intracardiac shunt is related to decrease in exercise capacity in the present study. Impaired ventilation in response to hypoxia [23] and an accelerated ventilatory response at the beginning of exercise have been reported in patients with cyanotic congenital heart disease compared with healthy subjects [24]. The tidal volume was equivalent in groups A and D in the present study and the respiratory rate and minute ventilation were greatest in group A, thus the ventilatory equivalent for carbon dioxide output, which is an index of ventilatory efficiency, was also highest, indicating that the ventilatory efficiency was lowest in group A. Although the detailed mechanism of excessive ventilation is unknown, ventilatory stimulators of the central nervous system, such as H 1 ions, CO 2 , and hypoxia, have been suggested as contributors to excessive ventilation in patients with cyanotic congenital heart disease [24]. In the present study, the increase in respiratory rate, rather than the tidal volume, due to ventilatory stimulation appeared to be responsible for excessive ventilation during exercise in patients with cyanotic congenital heart disease. Abnormal cardiorespiratory response during exercise have been observed in adult patients with congestive heart failure [25]. Pump failure of the left ventricle due to myocardial damage results in low compliance and the low compliant lung leads to increase in dead space ventilation, resulting in excessive ventilation to maintain alveolar ventilation during exercise [25]. The response of cardiac output during exercise in these patients is impaired and the respiratory pattern is rapid and shallow [2,25]. In the present study, the respiratory and cardiovascular

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responses in group C were similar to those seen in adult patients with congestive heart failure. Because the tidal volume was lowest during exercise in group C, the minute ventilation was maintained by accelerated the respiratory rate. Abnormal pulmonary function at rest and an impaired cardiorespiratory response has been reported in patients with tetralogy of Fallot and a functional single ventricle who undergo a definitive operation [5,26]. Because patients with cyanotic congenital heart disease who underwent a Fontan operation in the present study had relatively good function of the systemic ventricle compared with patients in group C, the mildly inhibited increase in tidal volume in these patients appeared to be mainly due to reduced vital capacity caused by cardiac surgery rather than to low compliance of the lung secondary due to pulmonary congestion during exercise. The response of tidal volume to exercise in groups A and B, especially in group A, similar to that in control subjects. It is possible that lung compliance was relatively high in groups A and B because of a decreased pulmonary flow due to intracardiac shunting in group A and to lack of a pulmonic ventricle in group B. Although an increase in dead space ventilation during exercise has been observed in patients who had a Fontan operation, this dead space ventilation is not considered to be due to decreased lung compliance but to an increase in the high ventilation-perfusion space in the lung during exercise [4]. Although vital capacity was similar in groups A and B, the responses of the respiratory rate and the tidal volume were greater in group A than in group B. Therefore, another type of ventilatory stimulation, such as hypoxia and / or retention of CO 2 during exercise may have been present in group A. It is considered that chronotropic incompetence, impaired increase in stroke volume, and maybe magnitude of intracardiac shunt are responsible for reduced exercise capacity in group A, and that the lack of a ventricular pumping chamber for the pulmonary circulation in addition to the former two factors as demonstrated in group A contributes to the reduced exercise capacity in group B. Contrary, it is thought that the extremely impaired increase in stroke volume due to poor left ventricular function is a main limiting factor in decreasing exercise capacity in group C. Sullivan et al., have suggested that excessive

ventilation is related to exertional dyspnea [25]. In the present study, however, the respiratory rate at peak exercise were higher in patients with leg fatigue than in patients with dyspnea. Patients who complained of dyspnea may not have been able to utilize their ventilatory capacity because of the exertional dyspnea itself. Because no difference in the ratio of minute ventilation at peak exercise to maximal voluntary ventilation was noted, and each patient group has relatively-sufficient ventilatory reserve, it is not likely that the capacity of increase in minute ventilation may not be a limiting factor in determinating factor of exertional symptoms in these group patients. In addition, the fact that patients with leg fatigue had increased ventilation compared to patients with dyspnea may have been related to the link between working muscle and excessive ventilation in patients with heart failure [27]. If exertional symptoms do not reflect circulatory dysfunction [28], the respiratory pattern characterized by respiratory rate and tidal volume may have had little relation to exertional symptoms in these patients. Although 27% patients stopped because of leg fatigue, a study of peripheral factors such as size of working muscle might be needed together with conventional pulmonary function and cardiorespiratory variables. Despite of significant difference in ventilatory responses during exercise, there was no difference in exertional symptoms among study groups. Therefore, there may be common determinant factors originating from working muscle in such patients with reduced exercise capacity. In addition, subjective level of exertional symptoms was not analyzed because of difficulty in determinating such symptoms in relatively young patients with congenital heart disease. In our experience, it is difficult to evaluate a exertional symptom at peak exercise with a subjective scale rating the patient level of dyspnea or leg fatigue in pediatric cardiac patients. However, although a number of patients studied was small, we need to consider that reproducibility of exertional symptoms is not so high [29] and exertional symptoms may be depend on the type of exercise test performed [30]. In summary, the accelerated heart rate response during exercise, which compensates for decreased cardiac output, was more impaired in patients with congenital heart disease than in patients with reduced left ventricular function. Although the response of

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cardiac output was impaired, the ventilatory response was relatively well maintained in patients who had undergone a Fontan operation. Because ventilation during exercise in patients with cyanotic congenital heart disease was accelerated, other forms of ventilatory stimulation, such as hypoxia and / or retention of CO 2 during exercise, may have been involved. Because of the presence of pulmonary congestion, the magnitude of restrictive ventilatory impairment was considerable in patients with reduced left ventricular function as has been reported in adult patients. These data suggest that although exercise capacity is reduced, the relationship between ventilatory and cardiac responses during exercise in patients with cyanotic congenital heart disease or after a Fontan operation differs from that in patients with reduced left ventricular function but these pathological differences did not influence their exertional symptoms. Thus, we should take the different cardiorespiratory responses and indistinguishable exertional symptoms into consideration when evaluating the result after any intervention for such patients with cyanotic congenital heart disease.

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