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(Chest. 2000;118:1661-1670.)
© 2000 American College of Chest Physicians

Exercise Intolerance Following Heart Transplantation*

The Role of Pulmonary Diffusing Capacity Impairment

Omar A. Al-Rawas, PhD; Roger Carter, MSc; Robin D. Stevenson, MD; Sureen K. Naik, PhD and David J. Wheatley, MD

* From the Department of Respiratory Medicine (Drs. Al-Rawas and Stevenson, and Mr. Carter) and the University Department of Cardiac Surgery (Drs. Naik and Wheatley), Glasgow Royal Infirmary, Glasgow, Scotland, UK.

Correspondence to: Omar A. Al-Rawas, Department of Medicine, College of Medicine, Sultan Qaboos University, PO Box 35, Postal Code 123, Muscat, Sultanate of Oman; e-mail: orawas{at}squ.edu.om


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Although impairment of the diffusing capacity of the lung for carbon monoxide (DLCO) in heart transplant recipients is well-documented, there are limited data on its impact on exercise capacity in these patients. The aim of this study was to determine the effect of DLCO reduction on exercise capacity in heart transplant recipients.

Design: Descriptive cohort study.

Setting: A regional cardiopulmonary transplant center.

Participants: Twenty-six heart transplant recipients who were studied before and after transplantation compared with 26 healthy volunteers.

Measurements: Spirometry and static lung volumes were measured using body plethysmography, DLCO was measured using the single-breath technique, and progressive cardiopulmonary exercise was performed using a bicycle ergometer, continuous transcutaneous blood gas monitoring, and on-line analysis of minute ventilation, oxygen uptake (O2), and carbon dioxide production.

Results: Before transplantation, the mean percent predicted for hemoglobin-corrected DLCO was reduced in patients (73.2%) compared to healthy control subjects (98.8%; p < 0.001) and declined significantly after transplantation (60.1%; p < 0.05). Although the mean maximal symptom-limited O2 (O2max) increased after transplantation (increase, 41.3 to 48.6% of predicted; p < 0.05), it remained substantially lower than normal (92.9%; p < 0.001). There was a significant correlation between DLCO and O2max after transplantation (r = 0.61; p = 0.001), but not before transplantation (r = 0.09; p = 0.66). DLCO was also inversely correlated with other respiratory responses to exercise, including the following: the ventilatory response to exercise (r = -0.44; p < 0.05); dead space to tidal volume ratio (r = -43; p < 0.05); and the alveolar-arterial oxygen gradient (r = -0.45; p < 0.05), but there was no correlation between any of these variables and DLCO before transplantation.

Conclusion: DLCO reduction after heart transplantation appears to represent persistent gas exchange impairment and contributes to exercise limitation in heart transplant recipients.

Key Words: cardiopulmonary exercise testing • exercise capacity • heart transplantation • pulmonary diffusing capacity • pulmonary function • pulmonary gas exchange


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Heart transplantation is an established treatment for end-stage heart failure.1 In addition to increased life expectancy, heart transplant recipients report a remarkable improvement of symptoms and functional capacity.2 However, exercise performance following heart transplantation remains impaired, even in the absence of exertional symptoms.3 The maximal symptom-limited oxygen uptake (O2max) and the anaerobic threshold are in the range of 50 to 70% of predicted.4 These values are comparable to those of patients in stable condition with severe heart failure (left ventricular ejection fraction [LVEF], < 20%).5 The cause of exercise intolerance in heart transplant recipients is not clear, but there is increasing evidence that it is multifactorial and involves complex interactions among cardiac, neurohormonal, vascular, skeletal muscle, and pulmonary abnormalities.3 6 The denervated heart has a reduced heart rate (HR) reserve due to the elevated resting HR and its blunted response to exercise.6 Heart compliance also is reduced, resulting in a left ventricular diastolic dysfunction.3 Persistent peripheral abnormalities that have been proposed to contribute to exercise limitation in these patients include abnormal neurohormonal responses to exercise,7 deconditioning,8 and peripheral circulatory dysfunction.9

Efficient pulmonary gas exchange is an essential part of the complex process of exercise.10 Pulmonary dysfunction following heart transplantation is, therefore, a potential cause of exercise intolerance in heart transplant recipients.6 Severe chronic heart failure, the primary indication for heart transplantation, is associated with a variety of pulmonary function abnormalities including reduced lung volumes, airway obstruction, reduced diffusing capacity of the lung for carbon monoxide (DLCO), increased physiological dead space ventilation (VD/VT), and increased ventilatory response to exercise (ie, the ratio of minute ventilation [E] to carbon dioxide output [CO2]).11 12 Heart transplantation has been shown to restore lung volumes, airway function, and pulmonary hemodynamics toward normal.13 14 In contrast, DLCO has been persistently shown either to deteriorate or to remain subnormal following heart transplantation.15 16 Although DLCO reduction in heart transplant recipients is well-documented, there is little information on the role of this reduction on exercise performance in these patients.17 18 19 In a study of 11 patients evaluated before and after transplantation, at similar workloads, arterial blood gas levels and pH were significantly lower in recipients with DLCOs < 70% of predicted compared to those with higher DLCOs.17 In another posttransplant study, DLCO per unit of alveolar volume (KCO) was found to be significantly correlated with HR, oxygenation, and lactate levels at maximum exercise.18 However, both studies had important limitations. The first was limited by the small number of patients, and the second by the lack of pretransplant data. In addition, the O2max and its relationship to DLCO were not reported. More recently, Ville and coworkers19 reported a strong correlation between KCO and O2max (r = 0.81; p < 0.01) in 17 heart transplant recipients. They also showed that O2max, E, and oxygen pulse were significantly lower in recipients (nine patients) with KCO values < 80% of predicted (mean KCO, 52%) compared to those (eight patients) with higher values (mean KCO, 87%), but there were no control subjects or any comparisons with pretransplant data. The aim of this study, therefore, was to determine the impact of DLCO impairment on exercise performance in a larger group of heart transplant recipients with comparisons before and after heart transplantation.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The study population consisted of the following two groups: 53 heart transplant recipients (26 of whom were studied before and after transplantation) and 26 healthy volunteers.

Heart Transplant Recipients: Between January 1992 and January 1995, 67 patients underwent orthotopic heart transplantation at the Scottish Cardiopulmonary Transplantation Unit. As part of routine posttransplantation assessment, 53 of these patients performed resting pulmonary function tests and cardiopulmonary exercise tests at 6 to 12 months following transplantation. Twenty-six of 53 patients also had performed these tests as part of their pretransplant assessment, and they constitute the main study group with comparisons before and after transplantation. Table 1 shows that these 26 patients are representative of our cohort of heart transplant patients as they have baseline characteristics that are similar to those of the remaining 27 recipients for whom there were only posttransplant data available.


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  		Table 1.. Baseline Characteristics of the 26 Heart Transplant Recipients With Full Data Before and After Transplantation Compared to the Remaining 27 Recipients With Incomplete Data*

 
Before transplantation, all the 26 patients were complaining of breathlessness on exertion due to severe chronic heart failure. Anti-heart failure medication consisted of diuretics (all patients), angiotensin-converting enzyme inhibitors (20 patients), digoxin (14 patients), and other vasodilators (10 patients), and no patient was receiving ß-blockers or amiodarone. All patients were in stable condition at the time of pretransplant assessment, and none had any history of primary lung disease. After transplantation, an assessment was performed when patients were in stable condition and had been free from any respiratory illness during the preceding 2 weeks. Patients who received treatment for rejection or systemic infection were not tested until at least 2 weeks after completing treatment. All patients were on regimens of standard triple immunosuppression therapy (cyclosporine, azathioprine, and prednisolone).

Healthy Subjects: The findings in heart transplant recipients were compared with data from 26 healthy subjects (women, 5 subjects; mean age, 42.1 years; age range, 19 to 61 years; mean height, 169.4 cm [SD, 1.7 cm]; and weight, 76.5 kg [SD, 2.9 kg]; ex-smokers, 10 subjects; nonsmokers, 16 subjects) who were recruited as volunteers from the general population in whom there was no evidence of cardiopulmonary disease.

Procedures
For each participant, all tests were performed on the same day starting with spirometry and lung volume measurements, followed by DLCO measurement, and finally exercise testing.

Resting Pulmonary Function Tests: Standard spirometry and lung volumes were measured using a body plethysmograph (PK Morgan Ltd; Kent, UK). Measured variables included FVC, FEV1, and total lung capacity (TLC). DLCO and KCO were determined using the single-breath method (Transflow Test Model 540; PK Morgan Ltd). DLCO values in patients were corrected for actual hemoglobin concentration determined on the same day using the equation described by Cotes et al.20 Healthy subjects were assumed to have normal hemoglobin concentrations (ie, 14.6 g/dL).20 Quality control and procedures of lung function testing were performed according to the European Respiratory Society guidelines.20 21 Predicted normal values were determined using the equations of the European Community for Steel and Coal for all resting pulmonary function parameters.20 21

Cardiopulmonary Exercise Testing: Symptom-limited exercise tests were performed using an electrically braked bicycle ergometer with the patient breathing through a low dead space, low-resistance valve box. The valve box incorporates a flexible pneumotachograph placed on the limb used for the measurement of inspired E (Flexiflow; PK Morgan Ltd). The limb on which measurements of expiration are made is fed through a mixing chamber from which samples of expired air are analyzed for the fractional concentrations of carbon dioxide and oxygen by an infrared spectrometer and zirconium cell analyzer, respectively (Benchmark System; PK Morgan Ltd). Gas analyzers were calibrated with certified gas mixtures, and the pneumatograph system was calibrated and verified using a 3-L calibration syringe before each exercise test. Arterial blood gas values were monitored throughout exercise testing using a transcutaneous system (TCM3; Radiometer Ltd; Copenhagen, Denmark) heated to 45°C with the electrode attached to the flexor aspect of the forearm.12 The use of the transcutaneous system during exercise in patients with dyspnea due to various cardiopulmonary disorders has been validated previously in our laboratory.22 23

Before each test, subjects were seated in a comfortable chair and a brief history was taken to identify any recent respiratory illnesses or cardiac decompensation and to estimate the subject’s functional status using the New York Heart Association (NYHA) classification at the time of assessment. After explanation of the procedure, a transcutaneous electrode was attached to the flexor surface of the forearm and standard continuous 12-lead ECG monitoring was started. Following a period of in vivo calibration using a sample of arterialized ear lobe capillary blood, subjects were initially monitored for 2 min at rest while seated on the bicycle ergometer with a nose clip in place. They were then instructed to cycle with no additional load for 2 min. Then the workload was automatically increased by increments of 25 W every 2 min until a symptom-limited maximum workload and the primary symptom-limiting exercise were recorded. BP was measured using a standard cuff sphygmomanometer at the end of each stage. The criteria for terminating the exercise before patients reached a maximum symptom-limited point were the following: ischemic changes on ECG; ventricular arrhythmia; hypotension (ie, resting systolic BP < 90 mm Hg or falling BP during exercise); or severe systemic hypertension (systolic BP > 220 mm Hg).

Throughout each test, E, oxygen uptake (O2), and CO2 were measured by online ventilation and expired gas analysis (PK Morgan Ltd) using standard equations.24 The ventilatory anaerobic threshold on exertion was estimated by the curve-fitting method, using a plot of O2 against CO2,25 and are presented as the percent of predicted O2max. The values of transcutaneous oxygen and carbon dioxide tensions were used to estimate the alveolar-arterial oxygen pressure difference (P[A–a]O2) and VD/VT ratio using standard equations.24 The following cardiorespiratory responses to exercise also were derived26 : maximum voluntary ventilation, 37 times the FEV1; ventilatory response at maximum exercise (E/CO2); the change (from resting to maximal exercise value) in E ({Delta}E) divided by the change in CO2 ({Delta}O2); HR response (beats per liter) is the change in HR ({Delta}HR) divided by {Delta}O2 in liters; and oxygen pulse (mL/beats) at maximum exercise is O2 in milliliters at maximum exercise divided by the maximal HR. Maximal exercise values were compared to the predicted normal values of Jones and Campbell.26

Data Presentation and Analysis
Unless stated otherwise, values are expressed as the mean ± SEM. Lung function and cardiopulmonary exercise data in heart transplant recipients were compared with those of the healthy subjects using the independent sample Student’s t test. Comparisons between pretransplant and posttransplant data in the 26 heart transplant recipients were performed using the paired samples Student’s t test. The relationship between resting lung function tests and exercise parameters was assessed using the Pearson coefficient of correlation. A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Resting Cardiopulmonary Parameters
Table 1 shows that heart transplantation was associated with significant improvement in both the NYHA functional class and the LVEF. In the 26 recipients studied before and after transplantation, NYHA functional status shifted from grades III and IV (35% and 65% of patients, respectively) before transplantation to grades I and II (31% and 69%, respectively) after transplantation. Similarly, the mean LVEF increased from 13.8% before transplantation to 42.7% (p < 0.001) afterward. However, the mean hemoglobin concentration decreased after transplantation (decrease, 13.9 to 12.1 g/dL; p < 0.001).

Table 2 compares the pulmonary function results and resting cardiopulmonary parameters in the 26 heart transplant recipients before and after transplantation with healthy control subjects. Although the mean FVC, FEV1, and FEV1/FVC ratio improved after transplantation, the changes were small and not statistically significant, and all of these parameters were lower than those of healthy control subjects both before and after transplantation (p < 0.05). TLC was reduced before transplantation and increased significantly after transplantation (p < 0.05) to become similar to that of healthy control subjects. In contrast, hemoglobin-corrected DLCO and KCO decreased significantly after transplantation (DLCO decrease, 73.2 to 60.1% of predicted; KCO decrease, 84.3 to 69.4% of predicted; p < 0.001), and both parameters were significantly lower than normal both before and after transplantation (p < 0.001).


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  		Table 2.. Pulmonary Function Results and Resting Cardiopulmonary Responses in Heart Transplant Patients Before and After Transplantation Compared to Healthy Control Subjects*

 
Before transplantation, the resting VD/VT ratio and P(A–a)O2 were significantly higher than normal (p < 0.05). After transplantation, P(A–a)O2 improved significantly (increase, 2.9 to 1.9 kPa; p < 0.05), but there was no significant change in resting O2 or VD/VT. However, the resting HR increased significantly after transplantation (p < 0.05).

Cardiopulmonary Responses to Exercise
Table 3 displays the cardiopulmonary responses to symptom-limited exercise in the 26 heart transplant recipients before and after transplantation compared to healthy control subjects. Although the mean O2max increased after transplantation (increase, 41.3 to 48.6% of predicted; p < 0.05), it remained substantially lower than normal (92.9%; p < 0.001). Similar significant improvement also was noted in the anaerobic threshold, the E/CO2 ratio, VD/VT, P(A–a)O2, and oxygen pulse, but all of those parameters remained significantly (p < 0.05) different from the normal control values. The markedly elevated pretransplant HR response decreased after transplantation to become significantly lower than that of healthy control subjects (p < 0.05).


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  		Table 3.. Cardiorespiratory Responses to Symptom-Limited Exercise in Heart Transplant Patients Before and After Transplantation Compared to Healthy Control Subjects*

 
The Relationship Between DLCO and Cardiopulmonary Responses to Exercise
Figure 1 is a scatter plot of the percent predicted of hemoglobin-corrected DLCO at rest against the percent predicted O2max in the 26 heart transplant recipients compared before and after transplantation. There was a significant positive correlation between the posttransplant DLCO and O2max (r = 0.61; p = 0.001), but there was no significant correlation between the pretransplant values (r = 0.09; p = 0.66). Similarly, Figure 2 shows that there was a significant positive correlation between DLCO and the anaerobic threshold after transplantation (r = 0.53; p = 0.006), but not before transplantation (r = 0.08; p = 0.71).



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  		Figure 1.. A scatter plot of the percent predicted DLCO against the percent predicted O2max in the 26 heart transplant recipients compared before and after heart transplantation.

 


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  		Figure 2.. A scatter plot of the percent predicted DLCO against the anaerobic threshold as a percentage of the predicted O2max in the 26 heart transplant recipients compared before and after heart transplantation.

 
Table 4 shows that the relationship between DLCO and O2max persisted even after correction for lung volumes (the correlation between KCO and O2max after transplantation was 0.50; p = 0.009). In contrast, there was no significant correlation between O2max and any of the remaining resting lung function parameters either before or after transplantation.


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  		Table 4.. The Relationship Between O2max and Resting Lung Function Parameters (as Percent of Predicted) in the 26 Heart Transplant Recipients Before and After Transplantation

 
Figures 3 to 5 show that DLCO was inversely related to the E/CO2 ratio (r = -0.44; p = 0.023), VD/VT (r = -0.43; p = 0.028), and P(A–a)O2 (r = -0.45; p = 0.022) after transplantation, but that there was no relationship between DLCO and any of these parameters before transplantation.



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  		Figure 3.. A scatter plot of the percent predicted DLCO against the ventilatory response to exercise (ie, E/CO2 ratio) in the 26 heart transplant recipients compared before and after heart transplantation.

 


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  		Figure 4.. A scatter plot of the percent predicted DLCO against the VD/VT ratio in the 26 heart transplant recipients compared before and after heart transplantation.

 


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  		Figure 5.. A scatter plot of the percent predicted DLCO against the P(A–a)O2 in the 26 heart transplant recipients compared before and after heart transplantation.

 
There was no significant correlation between DLCO and any of the indexes of cardiac function including LVEF, HR response, and oxygen pulse either before or after transplantation. Although hemoglobin levels were significantly lower in heart transplant recipients compared to candidates, there was no correlation between O2max and hemoglobin concentration either before or after transplantation.

The relationship between DLCO and the cardiopulmonary responses to exercise in the 26 heart transplant recipients was confirmed by repeating the analysis in the group within our cohort of heart transplant recipients who had complete posttransplant data (53 patients). Figure 6 shows that DLCO and O2max were significantly correlated (r = 0.62; p > 0.001). Similarly, DLCO was positively correlated with the anaerobic threshold (r = 0.54; p < 0.001) and was inversely related to E/CO2 ratio (r = -0.43; p < 0.001), VD/VT (r = -0.29; p < 0.05), and P(A–a)O2 (r = -0.38; p < 0.001).



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  		Figure 6.. A scatter plot of the percent predicted DLCO against the percent predicted O2max in the 53 heart transplant recipients.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrated three main findings. First, DLCO was reduced in heart transplant candidates and declined further after transplantation despite the improvement in all other indexes of resting cardiopulmonary function, and DLCO was significantly correlated with O2max and the anaerobic threshold after transplantation. Second, the ventilatory and pulmonary gas exchange responses to exercise (ie, E/CO2 ratio, VD/VT, and P[A–a]O2) were abnormal before transplantation, improved but did not completely normalize following transplantation, and were all inversely correlated with DLCO after transplantation. Third, there was no relationship between the remaining resting lung function tests (spirometry and lung volumes) and any of the cardiopulmonary responses to exercise either before or after transplantation.

Cardiopulmonary Responses to Exercise
In agreement with previous reports,3 the results of this study show that despite substantial improvement of the subjective functional capacity, heart transplant recipients continue to have limited exercise performance as assessed by incremental cardiopulmonary exercise testing. The ventilatory response to exercise (E/CO2 ratio) in our patients was similar to that reported by Marzo and associates.27 Before transplantation, the E/CO2 ratio was elevated, and it decreased significantly following transplantation but remained higher than normal. In addition, the present study showed that despite significant improvement in VD/VT after transplantation, it remained higher than normal. The cause of the lack of complete resolution of pretransplant ventilatory and gas exchange abnormalities during exercise is not known. It may indicate irreversible structural lung damage caused by the long-standing pretransplant heart failure. Alternatively, these abnormal pulmonary responses may be due to a suboptimal cardiac output response to exercise.12 28 Chronic heart failure is characterized by an excessive ventilatory response (E/CO2 ratio) to exercise and an increased degree of "wasted ventilation," as assessed by VD/VT.29 We and others have shown previously that the E/CO2 ratio and VD/VT in patients with heart failure were positively correlated and have suggested that they may be causally linked.12 28 It was suggested that the failure to increase cardiac output to match ventilation during exercise increases the proportion of lung units with high ventilation-perfusion ratios, thereby increasing VD/VT and, consequently, leading to an excessive ventilatory response to exercise.12 28 Although cardiac output is markedly improved after heart transplantation, its response to exercise remains subnormal,30 and this may explain the residual abnormalities of ventilatory and gas exchange responses to exercise following transplantation.

DLCO and Exercise Capacity
Exercise intolerance in heart transplant recipients is well-documented. Although its underlying pathophysiology is not fully understood, the complex nature of the exercise process favors multiple causes.3 Factors identified as contributory to exercise intolerance following transplantation include the following: inotropic and chronotropic incompetence of the denervated heart30 ; abnormal neurohormonal responses7 ; persistent skeletal muscle abnormalities8 ; abnormal peripheral circulation9 ; and pulmonary dysfunction.17 18 19

In this study, we identified DLCO impairment, which was very common in heart transplant recipients, to be associated with exercise intolerance. The correlation between DLCO and exercise performance persisted even after correction for lung volumes. The lack of any correlation between DLCO and exercise capacity before heart transplantation is consistent with previous reports that DLCO becomes a limiting factor to exercise performance only when its reduction is severe.31 In patients with COPD, DLCO values < 70% of predicted have been shown to be associated with frequent gas exchange abnormalities during exercise, whereas these abnormalities were uncommon when DLCO values were > 70% of predicted.31 In addition, DLCO impairment has been found to predict pulmonary gas exchange abnormalities and exercise intolerance in patients with mild to moderately severe heart failure.32 33 34 Unlike in these reports, there was no relationship found between O2max and DLCO in our patients before transplantation. The difference between our findings and those of others may be due to the severity of heart failure in heart transplant candidates. Heart transplant candidates would be expected to stop exercising due to their severe cardiac insufficiency before DLCO limitation becomes important.

The mechanism by which DLCO impairment causes exercise intolerance is not clear. Gas exchange in the lung depends on several interdependent processes. These include ventilation, perfusion, diffusion, and matching of ventilation and perfusion.35 The measured DLCO is affected by disturbance in any of these processes and, therefore, can be considered as a composite index of the integrity of the pulmonary gas exchanging unit rather than being specific to the process of diffusion.36 In addition, the isolated impairment of diffusion is very rare, and because of the large physiologic reserve, diffusion impairment is not considered to be an important limiting factor in the transfer of oxygen to the arterial blood even in patients with severe lung disease.36 The relationship between DLCO and exercise performance in heart transplant recipients is therefore likely to represent a general dysfunction of the pulmonary gas exchange rather than an isolated diffusion defect. This is supported by the lack of complete resolution of the ventilatory and pulmonary gas exchange responses to exercise (ie, E/CO2 ratio, VD/VT, and P[A–a]O2) in our patients, and by the significant relationship between DLCO and each of these parameters.

In conclusion, DLCO impairment in heart transplant recipients is associated with abnormal ventilatory and pulmonary gas exchange responses to exercise and appears to contribute to exercise intolerance in these patients.


   Footnotes
 
Abbreviations: DLCO = diffusing capacity of the lung for carbon monoxide; HR = heart rate; KCO = diffusing capacity of the lung for carbon monoxide per unit of alveolar volume; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; P(A–a)O2 = alveolar-arterial oxygen pressure difference; TLC = total lung capacity; CO2 = carbon dioxide output; VD/VT = physiological dead space ventilation; E = minute ventilation; O2 = oxygen uptake; O2max = maximum symptom-limited oxygen uptake

Received for publication July 22, 1999. Accepted for publication June 20, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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