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European Journal of Heart Failure 2007 9(3):310-316; doi:10.1016/j.ejheart.2006.07.001
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© 2007 European Society of Cardiology

Changes in exercise capacity, ventilation, and body weight following heart transplantation

Dirk Habedanka,*, Ralf Ewertb, Manfred Hummelb, Roland Wenselc, Roland Hetzerb and Stefan D. Ankera,d

a Division of Applied Cachexia Research, Department of Cardiology, Charité Campus Virchow-Klinikum Augustenburger Platz 1, D-13353, Berlin, Germany
b Department of Cardiothoracic and Vascular Surgery Deutsches Herzzentrum Berlin, Germany
c Department of Internal Medicine II University of Regensburg, Germany
d Clinical Cardiology, National Heart and Lung Institute Imperial College, London, UK

* Corresponding author. Tel.: +49 30 450 553625; fax: +49 30 450 553963. E-mail address: dirk.habedank{at}charite.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 
Aims: Peak oxygen uptake adjusted to body weight (peak VO2) and ventilatory efficiency (VE/VCO2-slope) are important prognostic parameters in chronic heart failure. Our study prospectively examined changes in these parameters over 24months following heart transplantation (HTx) and evaluated the potentially confounding effects of weight gain.

Methods and results: One hundred patients with chronic heart failure (16 female, mean age at HTx 53.9±9.6years) underwent cardiopulmonary exercise testing before and 3, 6, 12 and/or 24months after HTx. Twenty-five healthy individuals served as matched normals. VE/VCO2-slope during exercise improved significantly at 6 (–23.7%), 12 (–21.3%), and 24months (–32.3%; all p<0.002 vs. baseline). At 6months, VE/VCO2-slopes were similar to the matched normals (31.8±4.3), 46 of 78 patients achieved values within the 95% confidence interval of normal. Peak VO2 increased significantly after HTx at 6 (+31.8%), 12 (+36.2%), and 24months (+42.2%; all p<0.005). None of the patients reached values within the 95% CI of normal. Although VE/VCO2-slope and peak VO2 were correlated inversely at every time point (p<0.03), reduction in VE/VCO2-slope did not correlate with increase in peak VO2. Symptoms that limited exercise changed from dyspnoea before HTx to leg fatigue after HTx.

Conclusion: Following HTX, VE/VCO2-slope returns to normal values in the majority of patients; however, despite improvement, peak VO2 remains abnormal in all patients. Symptoms causing patients to stop exercising change from dyspnoea to leg fatigue.

Key Words: Heart transplantation • Peak VO2 • Ventilatory efficiency • VE/VCO2-slope • Body weight

Received November 10, 2005; Revised May 23, 2006; Accepted July 7, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 
Peak oxygen uptake adjusted to body weight (peak VO2) is the gold standard for prognosis in chronic heart failure [1-4]. Its prognostic importance is probably due to combined reflection of the severity of the primary cardiovascular disorder and secondary changes in peripheral blood flow, skeletal muscle composition and aerobic capacity [5]. After curing terminal heart failure by orthotopic heart transplantation (HTx), peak VO2 improves significantly, with a peak at 12 months after HTx, but still remains subnormal [6,7]. This continuing reduction in exercise tolerance is mainly due to a combination of graft diastolic dysfunction, chronotropic incompetence [8], and abnormal peripheral oxygen utilisation [9].

Impaired ventilatory efficiency, expressed as the slope of the linear regression line relating ventilation to carbon dioxide production (VE/VCO2-slope) is a different parameter in patients with CHF, and it is largely caused by increased physiological dead space ventilation [10], which may reflect impaired pulmonary ventilation/perfusion matching during exercise [11-13]. The VE/VCO2-slope is also strongly related to abnormal chemo- and ergoreceptor reflex activation [14,15]. Since VE/VCO2-slope combines changes in cardiac function, pulmonary vessels and skeletal musculature, it appears to be another important prognostic parameter in CHF [16-19].

The aim of our study was to examine changes in these two important variables (peak VO2 and VE/VCO2-slope) over a 24-month period in post cardiac transplant patients and to evaluate how they relate to normal values.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Summary
 References
 
2.1. Study population
Between September 1997 and January 2002, we prospectively examined 100 patients before and 3, 6, 12 and/or 24 months after HTx, at the German Heart Institute, Berlin. Exercise data before transplantation were obtained during regular outpatient visits to our department (mean time to HTx 5.5±1.1 months). After successful HTx, all patients underwent a postoperative rehabilitation program of 3 to 4 weeks duration. At the time of post-transplant exercise testing, patients had to be clinically stable, with no history of recent graft rejection or infection. We aimed to perform exercise tests within a window of ±2 weeks of the pre-determined time-points. In the 99 patients surviving 24 months, at least 2 follow-up tests were available. The main reasons for not performing a test at a given time-point were lack of clinical stability (n=27), and withdrawal of consent for the particular test (on 15 occasions). One patient died 24 months after transplantation due to severe pneumonia.

For comparison with normal values, we also studied 25 healthy individuals matched in a ratio of 1:4 for age and sex. All healthy volunteers underwent the exercise protocol as described above.

2.2. Medication
In early postoperative treatment, all patients received triple drug immunosuppression with cyclosporine A (monitored by plasma levels), prednisolone, and azathioprine (according to leukocyte count or T-cell-differentiation). During the first 60 days, prednisolone treatment followed a decreasing dose scheme adjusted according to body weight following an asymptotic series from 10 mg/kg body weight in the 1st week to 0.3 mg/kg in the 9th week after HTx. The dose of prednisolone did not fall below 0.3 mg/kg body weight during the first year or 0.1 mg/kg during the second year. During follow-up, cyclosporine A was replaced with tacrolimus in 8 patients due to side effects, and azathioprine was replaced with mycophenolate mofetil in 14 patients. No patients were permanently withdrawn from prednisolone during the first 2 years. Additional cardioactive medication was primarily necessary for blood pressure control and included ACE-inhibitors or AT1-receptor antagonists (in 99% of patients), calcium channel blockers (93%), diuretics (92%), central alpha-blockers (17%) and/or beta-blockers (12%).

2.3. Exercise testing
A symptom-limited cardiopulmonary exercise test was performed on a treadmill according to the modified Naughton protocol. Expired gas was sampled through a Rudolph mask, conveyed to a spirometer and to oxygen and carbon dioxide detectors (Oxycon Alpha, Jaeger, Wurzburg, Germany). VO2 and VCO2, end-tidal expiratory gas concentrations pETO2 and pETCO2, and ventilation per minute VE were measured breath-by-breath. To avoid the problem of artificially elevated values (for example, due to cough) the average of 5 out of 7 breaths was calculated automatically.

All patients were monitored with a continuous 12-lead electrocardiogram and non-invasive blood pressure measurement at rest, at every stage of exercise and during recovery. Data at rest and forced expiratory volume in the first second (FEV1) were determined after 3 min of quiet standing and breathing into the mask. Exercise time was recorded and symptoms at peak exercise were documented. All patients exercised until limited by symptoms; so that for peak VO2, peak VCO2 and peak VE the highest readings of each parameter in the final minute of exercise were used. Respiratory exchange ratio (RER) as a marker of exhaustion was calculated from peak VCO2 and peak VO2. Ventilatory efficiency during exercise was measured by plotting VE against VCO2, values due to hyperventilation (acidosis) in the last minutes of exercise were removed, and the slope of the revealed linear relationship was calculated [21,22].

2.4. Expiratory and capillary gases at rest
In a subgroup of 41 patients, capillary blood gas analysis was performed immediately before exercise testing for assessment of ventilation-perfusion-disturbances in the lung at rest. Capillary blood gas analysis was performed using Radiometer Copenhagen (ABL 750) to assess partial pressure of carbon dioxide pcCO2 (in mm Hg). The difference of arterial and end-tidal expiratory partial pressure of CO2 (paCO2–pETCO2) can be used as evidence of increased alveolar dead space or uneven ventilation/perfusion in the lung [23]. To avoid more invasive techniques, we used capillary blood samples instead of arterial ones, and the difference pcCO2–pETCO2 was taken as representative of ventilation-perfusion mismatch at rest.

The study was approved by the institution's Ethics Committee, and informed consent was obtained from all subjects.

2.5. Statistical analysis
All data are shown as mean±standard deviation. Paired t-test and repeated measure ANOVA-test were used as appropriate. The relation between peak VO2 and VE/VCO2-slope was calculated by linear and logarithmic regression. Mann-Whitney test was used to compare different symptoms at limit of exercise. A p-value<0.05 was considered statistically significant. All analysis was performed using StatView 5.0 (SAS Institute Inc., Cary, NC, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Summary
 References
 
The baseline characteristics of the 100 patients (16 female, 84 male) and 25 healthy normals (4 female, 21 male) are shown in Table 1 [20]. The mean age of the patients at transplantation was 53.9±9.6 years (range 26-66 years).The aetiology of chronic heart failure was dilated cardiomyopathy (n=66), ischaemic cardiomyopathy (n=30) and cardiomyopathy of other origin (n=4). The mean age of the healthy normals was 51.1±9.7 years, range 29-66 years.


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  		Table 1 Baseline characteristics

 
3.1. Exercise testing: ventilatory efficiency (VE/VCO2-slope)
Ventilatory efficiency during exercise steadily improved after HTx (Fig. 1), reaching high significance at 6 months (–18.5±4.6%), 12 months (–17.9±4.0%), and 24 months (–18.4±4.2%; all p<0.002), and missing significance only narrowly at 3 months (–14.6±6.1%; p=0.054, absolute values are shown in Fig. 1). VE/VCO2-slope remained at an improved level without significant changes during the follow-up period. When compared to matched healthy individuals, ventilatory efficiency was normal to slightly impaired. In detail, at 6 months (i.e., at best values of follow-up) the transplanted patients achieved a VE/VCO2-slope of 31.8±4.3, which was no longer different from matched normal (29.9±0.7; p=0.12 vs. normal). There remained a significant difference to normal values at 3, 12, and 24 months (all p≤0.01), although a substantial proportion of patients had values within the 95% confidence interval [CI] of normal (28.6 to 31.4): 24 of 72 patients at 3 months, 39 of 88 patients at 12 months, and 31 of 70 patients at 24 months. At 6 months, the majority of patients (46 of 78) had a VE/VCO2-slope within the 95% CI of normal.


Figure 01
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  		Fig. 1 VE/VCO2-slope at follow-up and vs. healthy individuals. Boxes: 75th percentile and median, lines: 90th percentile, n: number of patients with exercise test. Intra-individual changes in % appear in the text. *p<0.01 vs. pre HTx values; {dagger}p≤0.01 vs. matched normal; {ddagger}p=0.12 vs. matched normal.

 
3.2. Exercise testing: oxygen uptake (peak VO2)
Peak VO2 increased after HTx, and similar to VE/VCO2-slope this improvement in exercise capacity reached significance 6 months after transplantation: at 3 months +36.9±16.0% (p=0.07), at 6 months +44.4±14.0% (p=0.003), at 12 months +56.9±11.9% (p<0.001), and at 24 months +58.0±14.4% (p<0.001; see Fig. 2 for absolute values). In contrast with VE/VCO2-slope, peak VO2 values remained clearly below those of the matched healthy control subjects (p<0.0001 at all time-points of follow-up). During the entire follow-up period none of the patients reached normal values, i.e. values above the 95% CI (>31.2 ml/min/kg).


Figure 02
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  		Fig. 2 Peak VO2 at follow-up and vs. healthy individuals. Boxes: 75th percentile and median, lines: 90th percentile, n: number of patients as shown in Fig. 1. Intra-individual changes in % appear in the text. *p<0.01 vs. pre HTx values; {dagger}p<0.0001 vs. matched normal.

 
Body weight changed following HTx and since oxygen uptake is expressed adjusted to body weight, we compared weight changes in follow-up to changes in peak VO2. The patients showed a significant weight gain at 6 months (+1.3±0.8 kg), 12 (+4.5±1.0 kg) and 24 months (+0.3±1.3 kg; all p<0.05) after HTx. Since we could not differentiate between gains in fat or muscle, we tried to eliminate this potential influence of weight changes and also examined absolute values of peak VO2 (in ml/min). These absolute values of total oxygen consumption showed the same changes as oxygen uptake adjusted to weight, i.e. there was no significant increase at 3 months (+32.6±16.8%; p=0.12), and a significant improvement at 6 (+48.4±15.1%, p=0.003), at 12 (+70.6±17.1%, p>0.001), and at 24 months (+63.8±19.5%, p<0.001), and the absolute values were also different from normal values.

We have confirmed the inverse relationship between peak VO2 and VE/VCO2-slope before HTx and at follow-up (r2=0.30 to 0.40 and p<0.03; logarithmic regression). In contrast, longitudinal changes in VE/VCO2 slope within subjects did not correlate with changes in peak VO2 (p>0.05 at 3, 6, 12 and 24 months).

3.3. Ventilatory parameters: FEV1 and breathing reserve VE/MVV
FEV1 increased significantly at 6 (20.9±19.4%; p=0.02), at 12 (30.5±16.3%; p<0.01), and 24 months (16.2±15.8%; p=0.04). At each time point, forced ventilatory volume remained significantly worse than values for the normal volunteers (p<0.001). The patients' breathing reserve (expressed as the ratio of maximum exercise ventilation and maximal voluntary ventilation VE/MVV in percent) increased during follow up (38.5±15.1% pre HTx to 43.1±17.1% at 24 months), but this trend did not reach significance (p=0.3) and values were not different from those of healthy volunteers (35.0±16.9%).

3.4. Reasons for exhaustion
After exercise testing, we asked patients to specify the main reason(s) for stopping - more than one answer was possible. The reasons specified changed completely after HTx. Before HTx most of patients had to stop exercise due to dyspnoea (47% pre, 15% to 24% after HTx), whereas after HTx most patients stopped due to symptoms of leg fatigue and muscle exhaustion (13% pre vs. 65% to 78% after HTx). Chest pain and angina pectoris only occurred pre HTx (25%). Patients with dyspnoea and those with muscle exhaustion had a comparable peak VO2, VE/VCO2-slope and breathing reserve (all p>0.05 before HTx and in follow up).

3.5. Ventilation-perfusion mismatch at rest: capillary–alveolar difference
VE/VCO2 as an indicator of ventilation/perfusion-mismatch at rest was higher pre HTx (39.6±1.7) and significantly lower at all time points during follow up (35.3±0.6 at 3 months; 33.4±0.6 at 6 months; 35.6±0.7 at 12 months; and 34.8±0.6 at 24 months; all p<0.01). However, values were within the normal range [18,27]. The ventilation/perfusion-mismatch at rest can also be estimated by a metabolic parameter: the difference of capillary and end-tidal expiratory partial pressure of CO2 (pcCO2–pETCO2). Despite an increase in pETCO2 after HTx (30.2±0.7 mm Hg before HTx vs. 33.6±0.6 mm Hg at 6 months; p<0.01), the pcCO2 and the difference pcCO2–pETCO2 (4.8±1.6 vs. 2.1±0.5 mm Hg; p>0.05) remained unchanged.

3.6. Concomitant medication: steroid dosage
As discussed above, steroid treatment followed a decreasing dosage scheme and was by definition related to body weight; this scheme was altered only in case of rejection. Therefore, the main determinant for the cumulative dosage was whether or not rejection had occurred. The 72 patients with one episode of rejection within the first 6 months, had a cumulative dose of prednisone of 7.4 g±1.8 g, and there was neither a correlation of cumulative prednisone dose and peak VO2 (r=0.22; p=0.10) nor of cumulative prednisone dose and VE/VCO2-slope (r=0.14; p=0.38).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Summary
 References
 
Our study shows that heart transplantation has beneficial effects both on exercise capacity (peak VO2) and ventilatory efficiency (VE/VCO2-slope). However, these changes are qualitatively different, as VE/VCO2-slope becomes similar to normal values in the majority of patients, whereas peak VO2 remains abnormal in all patients. An improved VE/VCO2-slope is normally associated with a higher peak VO2, but in this population of heart transplanted patients this does not seem to be the case. Peak VO2 remained subnormal, consistent with the existence of confounding factors beyond the normalization of ventricular function. This is also illustrated by the pattern of symptoms causing patients to stop exercising - changing from dyspnoea pre HTx to leg fatigue post HTx. The influence of body weight increase after HTx on improved peak VO2 is of minor importance.

VE/VCO2-slope decreased (i.e. improved) early after HTx and remained at a normal to slightly impaired level throughout the follow-up period. However; a proportion of patients (about 40%) still had an abnormal VE/VCO2-slope at each follow-up assessment, which may be due to irreversible changes in the pulmonary vessels caused by pulmonary hypertension and vascular remodelling [24,25] or the influence of non-cardiac factors on VE/VCO2-slope. These non-cardiac factors may include alterations of skeletal musculature [14], a fact that is supported by findings that exercise training after HTx can only marginally improve ventilatory efficiency [26].

In the treatment of heart failure, a similar reduction in VE/VO2-slope as an expression of reversible changes in lung ventilation and perfusion has been described following treatment with ACE-inhibitors [27] but not with beta-blockers [28]. In another small study, the VE/CO2-quotient was also decreased in 15 heart failure patients 1.4 years after HTx [29] (pre 52.1±7.9 vs. 38.8±3.8 post HTx), but values did not reach those of healthy controls. In our study and in a study recently published by Nanas et al. [30] (n=12) VE/VCO2-slope was used instead of the VE/CO2-quotient as used by Marzo et al [29]. We confirmed the VE/VCO2-slope values shown by Nanas et al (31.4±3.8), but these values were taken at a single time point and incorporate a wide range of values. To our knowledge, the study presented here is the first to examine patients over a longer follow-up period. Our values in healthy individuals (29.9±0.7) are very similar to those reported by Hansen et al. (29.1±1.4) [31], and can be taken as representative.

In contrast to the VE/VCO2-slope, the assessment of peak VO2 integrates cardiac function as well as skeletal, pulmonary and endothelial status. Peak VO2 is also weight-related. There have been many studies of peak VO2 following HTx, a summary of these studies dating from the late 1970s to the present day [6-9,29,30,32-35] is given in Table 2. Our data confirm that exercise capacity improves after HTx but remains subnormal. Nevertheless, aerobic exercise training can increase peak VO2 significantly [26], and near normal values can be achieved [36].


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  		Table 2 Studies of exercise capacity (peak VO2) after HTx reported in the literature

 
We also investigated whether the smaller than expected rise in exercise capacity could be explained by weight gain after HTx. Previous studies [37-39] have shown a significant weight gain after HTx. Our data confirmed this long-term weight gain; however, absolute values of oxygen uptake showed a similar increase after HTx as values adjusted to body weight. Therefore, weight gain may only contribute marginally to improvement in exercise capacity.

An inverse relation between peak VO2 and VE/VCO2-slope has been shown in both healthy individuals and heart failure patients [12,40], and our data confirmed this relationship at every time point of follow-up. In contrast, individual improvement in ventilatory efficiency (i.e. decline in VE/VCO2-slope) did not correlate with improvement in peak VO2. This supports our hypothesis that the two variables reflect different aspects of the syndrome of heart failure and are affected differently by heart transplantation. Moreover, peak VO2 is also influenced by numerous other factors, such as beta-adrenergic blockade [41], diastolic dysfunction [9], chronotropic incompetence [8], immunosuppression [7], duration of postoperative intensive care [34], mitochondrial content, and capillary/fiber ratio in skeletal muscles [42].

4.1. Limitations
We could not refer to the mortality data reported by other authors because our inclusion criteria required patients to have had one valid exercise test at 3 or 6 months (i.e. they had to be able to exercise for at least 1 min at this time point). This meant that the patients were more clinically stable than the average HTx patient. We also did not study the influence of diffusion impairments of the lung.


   5. Summary
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
References
 
Curing CHF by heart transplantation has beneficial effects both on exercise capacity (peak VO2) and on ventilatory efficiency (VE/VCO2-slope). Changes in these parameters are qualitatively different, as VE/VCO2-slope returns to near normal values in the majority of patients, whereas peak VO2 remains abnormal in all patients. We conclude that normal cardiac output is not accompanied by normalisation of exercise capacity. Confounding factors beyond ventricular or pulmonary function require further investigation. This is also reflected in the pattern of symptoms limiting exercise, which changed from dyspnoea before HTx to leg fatigue and muscle exhaustion after HTx. Changes in body weight after HTx are not related to changes in peak VO2.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Summary
 References
 

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