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(Chest. 2000;117:968-975.)
© 2000 American College of Chest Physicians

Relationship Between Impaired Pulmonary Diffusion and Cardiopulmonary Exercise Capacity After Heart Transplantation*

Ralf Ewert, MD; Roland Wensel, MD; Leonhard Bruch, MD; Sven Mutze, MD; Ulrike Bauer, MD; Mathias Plauth, MD and Franz-Xaver Kleber, MD

* From the Deutsches Herzzentrum Berlin (Drs. Ewert, Wensel, and Bauer), Klinik für Innere Medizin (Drs. Bruch and Kleber), and Institut für Radiologie (Dr. Mutze), Unfallkrankenhaus Berlin, and IV. Medizinische Klinik (Dr. Plauth), Klinikum Charité, Humboldt Universität zu Berlin, Germany.

Correspondence to: Ralf Ewert, MD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13 353 Berlin, Germany; e-mail: rewert{at}dhzb.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Diffusion impairment and reduced performance in cardiopulmonary exercise testing (CPX) have been found in patients after heart transplantation. The pathogenesis of these abnormalities is unclear. In particular, the contribution of pulmonary interstitial changes has not yet been verified.

Design: We analyzed pulmonary function tests, high-resolution CT (HRCT), echocardiography, left heart catheterization, and CPX in transplanted patients.

Patients: Forty long-term survivors were studied at a median of 47 months (range, 12 to 89 months) after heart transplantation.

Results: Diffusion was impaired in 40% (transfer factor for carbon monoxide) or 82.5% (carbon monoxide transfer coefficient) of the patients. Diffusion impairment was caused by a decreased diffusing capacity of the alveolar capillary membrane in 89% and/or by a decreased blood volume of the alveolar capillaries in 46% of cases. In five patients (12.5%), CT revealed interstitial lung changes. These patients did not have different values of diffusion capacity. Maximal oxygen uptake and ventilatory efficiency during exercise (minute ventilation/carbon dioxide output slope) were impaired in 92% and 46% of the cases, respectively.

Conclusions: Our data show that the diffusion abnormalities are caused by an impaired diffusion status of the alveolar capillary membrane. Interstitial changes detectable in HRCT were found not to be involved in this process. The reduced performance in CPX in our long-term survivors is caused by pulmonary perfusion abnormalities and low tidal volume, which is due to the deconditioning of respiratory muscle, rather than by interstitial changes or diffusion abnormalities.

Key Words: cardiopulmonary exercise testing • heart transplantation • high-resolution CT • pulmonary function test


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In patients who had undergone orthotopic heart transplantation (OHT), abnormalities in the results of pulmonary function testing (PFT), mainly in diffusion capacity, have been found.1 2 3 4 The impairment of diffusion has been attributed to a thickening of the alveolar capillary membrane caused by infection by the human cytomegalovirus (HCMV) or the drug toxicity of cyclosporine.5 6 7 8 Furthermore, the exercise capacity of these patients is limited, which has been shown on cardiopulmonary exercise testing (CPX).9 10 11 12 13 Several factors, such as chronotropic failure, respiratory muscle weakness due to the use of corticosteroids and/or deconditioning, and impaired graft function have been suggested to contribute to this reduced exercise performance.11 12 14 15 Recent data demonstrate a lower exercise tolerance in transplanted patients with reduced pulmonary diffusion capacity when compared to those with a normal diffusion capacity.16

These observations give rise to several interesting questions: (1) Can these findings be confirmed in patients at a different institution? (2) Is the impairment in diffusion capacity associated with functional alterations at the level of the alveolocapillary membrane, as monitored by the diffusion capacity of the alveolar capillary membrane (DM) and/or alterations of the calculated blood volume of the alveolar capillaries (QC)? (3) Is the impairment in diffusion capacity associated with interstitial pathology as detected by high-resolution CT (HRCT)?


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Between March 1994 and March 1995, 47 consecutive patients who attended our transplant clinic were screened and 40 were enrolled in the study. Five patients were unwilling to participate, and in two patients, the follow-up period was < 12 months. Demographic data are given in Table 1 . Four patients had previous open-heart surgery (three aortocoronary bypasses and one surgical repair of a congenital lesion). Pulmonary catheterization was done in 38 of the 40 patients at a median of 4.1 months (range, 0 to 26 months; mean ± SD, 6.4 ± 5.6 months) prior to OHT. Mean pulmonary pressure was normal (< 25 mm Hg) at rest in 15 of the 38 patients. Standard chest radiographs before transplantation available in 34 patients gave no evidence of pulmonary interstitial disease in any case, and radiologic signs of chronic heart failure (CHF) were present in 12 cases. Additional pleural thickening and/or effusions were documented in 3 of 34 cases.


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  		Table 1. Demographic Data*

 
At the time of this study, IgM or IgG antibodies directed against HCMV were detectable in 1 of 26 and 16 of 26 patients, respectively. In the first year following transplantation, HCMV infection was diagnosed in 10 of 40 patients. In 3 of 10 patients, there was clinical evidence of interstitial pneumonia. Episodes of graft rejection were diagnosed in 24 of the 40 patients. During the 12 months prior to this study, cyclosporine, azathioprine, and corticosteroids were used for immunosuppression in 19 of the 40 patients, while 21 of the 40 patients were receiving only cyclosporine and azathioprine. Of the 12 patients who had been smoking, 6 patients did stop smoking at the time of transplantation, while the remaining 6 patients continued to smoke at the time of the study.

At the time of the study, all patients were ambulatory, in stable condition, and without any evidence of infection, rejection, or relevant drug toxicity. They gave informed consent to participate in this study, which conformed to the guidelines of the 1975 declaration of Helsinki.

PFT
We performed constant volume bodyplethysmography (Master Lab; Jäger; Würzburg, Germany). Measurements of vital capacity (VC), FVC, FEV1, the FEV1/FVC ratio, total lung capacity (TLC), residual volume (RV), and the RV/TLC ratio were selected for final analysis. For the measurement of diffusion capacity, the single-breath technique, which uses carbon monoxide, was employed (Transferscreen; Jäger). For final analysis, the lung transfer factor for carbon monoxide (TLCO) and the transfer coefficient for carbon monoxide (KCO; as TLCO/alveolar volume) in mmol/min per kPa (1 kPa = 7.502 mm Hg) were selected. Although the majority of patients had hemoglobin (Hb) values in the normal range, we chose to use corrected values (Table 2 ) according to Hilpert.17 In this approach, Hb values of 13.5 g/dL (female patients) and 14.6 g/dL (male patients) were used as a reference. TLCO and KCO values corrected for Hb are identified as TLCOc and KCOc. According to values of TLCOc and KCOc, as a percentage of predicted impairment of diffusion capacity, changes were classified as mild (60 to 79%), moderate (40 to 59%) and severe (< 40%). For the calculation of DM and QC according to Roughton and Forster,18 19 two measurements of TLCO were performed: first, while breathing room air (20% oxygen = 15 kPa) with 0.3% carbon monoxide; and secondly, after a 3-min flush-out period of pure oxygen breathing that resulted in an alveolar oxygen concentration of approximately 92% (80 kPa). Confounding effects of smoking in our six smokers (between 5 and 10 cigarettes per day) have not been corrected for. However, they had discontinued smoking at least 12 h prior to PFT.


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  		Table 2. Adjustment of Diffusion Parameters For Hb Concentration*

 
Blood gas analyses (AVL Omni; AVL Medical Instruments; Bad Homburg, Germany) were made from arterialized capillary blood in all patients.

All measurements were done according to the guidelines of the European Respiratory Society and are expressed in percent of the predicted values.20

CT
Lung structure was assessed by HRCT (Somatom Plus; Siemens; Erlangen, Germany). The scan time was 2 x 1 s, and 2-mm slices were selected by the use of a 526 x 526 image matrix and a window frame of between - 450 and 1,400 Hounsfield units. Whenever there was diminished transparency, a second series of scans was taken with the patient in the prone position in order to differentiate the true structural lesions from the readily reversible changes that are due to hypostatic or ventilatory effects. Images were evaluated independently by two separate investigators by the use of a simple rating system, which was comparable to those used by other investigators.21 22 Lesions were categorized according to their presence or absence, their location (ventrobasal or dorsobasal, apical, or subpleural), their morphologic appearance (reticular, nodular, linear, band-type, or ground-glass), and their classification on a 4-grade scale (1 to 4). In addition, the evaluation included a rating as to whether the lesions were unilateral or bilateral, and whether there was a presence or absence of hilar/mediastinal lymphadenopathy (> 10 mm), traction bronchiectasia, cysts, emphysema, honeycombing, pleural involvement, or volume reduction.

CPX
A symptom-limited cardiopulmonary exercise test was performed on a treadmill in accordance with the modified Naughton protocol.23 This is an exercise test of periods of 2 min, with increments in both the slope and the velocity of the treadmill in order to simulate an increment of about one metabolic equivalent ({approx} 3.5-mL oxygen x kg x min) per period (CPX/D; Medical Graphics; St Paul, MN). We used a mask (models M and L; Hans Rudolph; Kansas City, MO) for gas sampling. For each mask and tubing, dead space as specified by the manufacturer was corrected individually. The expiratory gas was collected and conveyed to a spirometer as well as to an oxygen and carbon dioxide detector. Oxygen consumption (O2), carbon dioxide output (CO2), instantaneous expiratory gas concentration throughout the respiratory cycle, and minute ventilation (E) were measured continuously breath by breath. In all patients, FEV1 was measured at rest and multiplied with the factor 41 to provide a maximal voluntary ventilation (MVV). The ratio of maximal minute ventilation during exercise (Emax) and MVV was used as a measure of end-exercise breathing reserve. Maximal oxygen uptake (O2max) was defined as the peak O2 measured. Peak O2 always occurred well above the anaerobic threshold. The O2 at the gas exchange anaerobic threshold (O2 AT) was detected by the V-slope method in conjunction with simultaneous readings of end-tidal gas concentrations. Ventilatory efficiency during exercise was measured by plotting E against CO2. After the onset of acidotic ventilation, this function is nonlinear, and therefore only data from the linear portion of the data were used for further analyses. Data were expressed as absolute as well as in percentage predicted values derived from age- and sex-matched healthy control subjects.24 Impairment of O2max was classified as mild (60 to 79% predicted), moderate (40 to 59% predicted), and severe (< 40% predicted).

Echocardiography
Percutaneous ultrasound M-mode examinations were made by the use of a 2.5-MHz probe (Toshiba SSH-140A; Toshiba; Tokyo, Japan). The presence of abnormal findings with regard to valvular or kinetic variables and a left ventricular ejection fraction (LVEF) of < 55% was recorded. Grade I valvular incompetence or paradoxic septal movements were not considered a pathologic finding. Overall results were expressed as categories normal or abnormal.25

Cardiac Catheterization
Left heart catheterization was performed for left ventricular and coronary angiography (Integris H; Philips Medical Systems; Hamburg, Germany). Assessment of regional and/or global kinetics were done, and special emphasis was put on the analysis of cardiac allograft vasculopathy. The results were classified as normal or abnormal.

Data Processing and Statistics
All analyses were performed using appropriate software (SPSS, version 7.5; SPSS; Chicago, IL). To test the differences between individual groups, the t test or the nonparametric Mann-Whitney test were applied. For the evaluation of nominally structured items, the {chi}2 test was used. For all evaluations, 5% was considered significant. Unless indicated otherwise, values are given as mean ± SD, median, and range.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
PFT
We observed a markedly decreased TLCOc (82 ± 13% predicted) and KCOc (70 ± 12% predicted), whereas the remaining variables of pulmonary function were in the normal range (Table 3 ).


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  		Table 3. Spirometric and Body Plethysmographic Findings

 
When a reduction in TLCOc < 80% predicted was used as a cut-off point, diffusion capacity was impaired in 16 patients (40%). The severity of these changes was classified as mild in 13 patients (32.5%) and moderate to severe in 3 patients (7.5%). Impaired diffusion capacity as indicated by KCOc < 80% predicted was observed in 33 patients (82.5%). The reduction in KCOc was mild in 24 patients (60%) and moderate to severe in 9 patients (22.5%). In 31 patients (88.6%), DM was abnormal (< 20 mmol/min/kPa). The calculated QC was reduced in 16 patients (45.7%) when a value >= 50 mL was considered normal. Blood gas analyses at rest from arterialized capillary blood were normal in all patients (data not shown).

Four patients (10.0%) exhibited restrictive abnormalities as defined by VC or TLC < 80% predicted. FVC was reduced (< 80% predicted) in four patients (10.0%), while FEV1 (< 80% predicted) or FEV1/FVC (< 75%) revealed obstruction in three or four (10.0% or 7.5%) patients, respectively. Nine patients (22.5%) had an abnormal increase in RV (> 120% predicted), but on average, transplanted patients had normal RV values both in absolute terms and relative to TLC.

CT
Bilateral interstitial changes were observed in five patients (12.5%), which were classified as grade 1 in three patients, grade 2 in one patient, and grade 3 in one patient. They were located in the dorsobasal/subpleural region of the lower lobes in all cases, and additional lesions in the subpleural region of the upper lobes were found in two cases. The changes were mainly linear or reticular in type. Honeycombing was found in one case. Additional findings included bronchiectasia in one patient (2.5%), pleural thickening in five patients (12.5%), emphysematous bullae in six patients (15.0%), and mediastinal or hilar lymphadenopathy in three patients (7.5%). No alteration in lung volume was visualized.

The frequency of interstitial lesions was higher in smokers compared to nonsmokers (p = 0.007), and in patients with HCMV infection during the early period after grafting (p = 0.013). There was no difference in diffusion capacity between the patients with or without interstitial changes. Also, the prevalence of interstitial changes was not significantly different between the group of transplant recipients with or without decreased diffusion capacity.

CPX
O2max, O2 AT, and ventilatory efficiency during exercise were markedly decreased in our patients (Table 4 ).


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  		Table 4. Findings in CPX

 
The O2max was impaired (< 80% predicted) in 36 patients (92%), and this limitation was severe (< 60% predicted) in 20 patients. Similarly, O2 AT was decreased (< 80% predicted) in 19 patients (50%) and reduced to a severe degree (< 60% predicted) in 11 patients. All patients were able to exercise beyond the anaerobic threshold. In all patients, the E/CO2 at rest was normal, but the E/CO2 slope on exercise was increased > 120% predicted in 18 patients (46.0%). The mean E/MVV ratio was rather low and was not > 70% in any of the patients. Also, there was no incidence of arterial oxygen desaturation as measured by percutaneous oximetry. Furthermore, chronotropic heart failure can be excluded on the grounds of an adequate rise of the heart rate during exercise.

With regard to exercise variables O2max, O2 AT, E/CO2 slope, and E/MVV ratio, patients with altered diffusion parameters TLCOc or QC were not different from patients with normal diffusion parameters. Patients with abnormal DM values had a significantly lower E/CO2 slope (p = 0.03) than patients with normal values, while there was no such difference with regard to O2max, O2 AT, or the E/MVV ratio. Univariate analyses showed that O2max was independent of any other variable tested (Table 5 ).


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  		Table 5. Univariate Analysis of Factors Influencing O2max

 
Cardiac Function
In echocardiography, the LVEF was 53.1 ± 7.6% (median, 50.2%; range, 35 to 71%) for our long-term survivors of OHT. Paradoxical septal movements were present in 15 patients (37.5%) patients, and global hypokinesia was observed in 1 patient. Evidence of minor tricuspid regurgitation was found in 28 patients (70.0%), and only 1 patient had significant tricuspid regurgitation. Mitral regurgitation was noted in five patients (12.5%) and was classified as minor in three patients and moderate in two patients. Taken together, 22 patients (55%) were classified as normal by means of echocardiographic findings.

On cardiac catheterization, hypokinetic segments were documented in six patients (15.0%), while coronary abnormalities were found in eight patients (20.0%). In total, findings were normal in 29 patients (72.5%).

In patients with abnormal findings on echocardiography or cardiac catheterization, none of the exercise testing variables were different when compared to patients with normal cardiac function.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We demonstrated (in our patients’ measurements of TLCOc 82 ± 13 and KCOc 70 ± 12% predicted) that diffusion abnormalities are prevalent in the majority of long-term survivors of OHT. This phenomenon was also noted in survivors of 14 months (TLCO 57% predicted),6 36 months (TLCO 80% predicted),2 and 54 months (TLCO 79% predicted)5 after transplantation. In good agreement, other investigators found KCO values to be 75% predicted 24 months after transplantation.26 This was confirmed when we recently demonstrated in 642 patients that the abnormalities in diffusion capacity are a usual finding for up to 11 years after OHT.27 In the present study, we set out to clarify the cause of impaired diffusion capacity and found that the permeability of the alveolar capillary membrane plays a major role. We observed an abnormally low DM value in > 80% of our long-term survivors. This finding demonstrated a structural alteration in interstitium and/or vascular wall.

A potential additional factor for the alteration of diffusion capacity in transplanted patients is a reduced blood volume in the alveolar capillaries (calculated by QC). We found a reduction in QC in almost 50% of our patients. These data suggest that alveolar capillaries were potentially altered not only in quality (permeability of membrane) but also in quantity (measurement of blood volume as an indirect marker). Abnormal DM and/or QC values in combination with the absence of HRCT-detectable interstitial changes in the majority of patients suggests that a "low-grade pulmonary microvascular injury" may be the cause of diffusion abnormalities in transplanted patients. This hypothesis is based on the results in CHF patients, where serial determinations of diffusion over a limited time or a comparison of diffusion capacity in small patients groups early and late after OHT were undertaken.1 2 4 5 7 8 26 A recent report that analyzed lung biopsies in heart transplants promotes this concept.28 It is speculated that cyclosporine may be responsible for these findings by its vasopressor effect with or without intimal proliferation and medial hyperplasia,29 but the data of correlation between cyclosporine (and the plasma levels of drug) and the diffusion parameters are controversial in heart-transplanted patients.1 2 5 6 7 12 26 In 21 kidney transplant patients, it was found that after transplantation the serum levels of cyclosporine were within the therapeutic range, and no alterations in pulmonary diffusion capacity were documented at 3, 6, and 12 months after transplantation when compared with pretransplant values.30

Interstitial pulmonary changes need to be considered as another potential cause for abnormal diffusion capacity in patients after OHT. To our knowledge, in the present study, lung morphology for the first time was evaluated by HRCT for the detection of interstitial changes in asymptomatic transplanted patients. Currently, HRCT is the most powerful noninvasive technique for the evaluation of the presence and nature of pulmonary interstitial changes.22 31 Several studies have demonstrated that HRCT findings can predict the histologic patterns observed in samples obtained by lung biopsy.22 32 In clinical diagnostic strategies, lung biopsy has been increasingly replaced by CT, particularly in high-risk patients. Therefore, to perform a lung biopsy in survivors after organ transplantation where there are no clinical problems in order to elucidate the mechanisms of diffusion impairment or for research purposes would raise ethical questions. It is very important to know that a normal HRCT cannot exclude early and clinically significant interstitial lung changes.33 By the use of HRCT, we found interstitial lesions only in five of our patients (12.5%). In contrast to studies of patients with interstitial lung diseases, the presence of interstitial changes were not correlated with abnormalities in diffusion capacity.31 In our opinion, it is a consequence of low-grade and limited expansion of these interstitial lesions in our transplanted patients.

From our data, we found no evidence that supports the hypothesis that impaired diffusion capacity is responsible for reduced exercise performance, which was not different between patients with normal and abnormal TLCOc values. In contrast to a recent study,16 we also could not find a correlation between any variable of CPX and KCO (data not shown). During exercise limitations, none of our patients had shown oxygen desaturation in gas exchange, and this demonstrated that it is an unlikely cause of impaired exercise performance. Similarly, a reduction in arterial oxygen saturation has been described only in transplanted patients early after transplantation during a maximal34 and not a submaximal workload.35 Also, in patients with CHF, impaired diffusion is not the relevant factor that limits exercise performance.18 23 O2 and the ventilatory efficiency proved to be subnormal in 50% of our long-term survivors during exercise. This finding is in agreement with the observation that cardiopulmonary performance improves only during the first year after OHT and remains unchanged thereafter,11 14 while others have observed a further decrease in O2max with time after OHT.13

Are there any other factors that might be responsible for the decrease in exercise capacity? It is well known that ventilation may be compromised in transplanted patients and lead to poor exercise test results. In our patients, we observed a linear correlation between maximal E (Emax) or the Emax/MVV ratio and O2max (data not shown), although this correlation is known to lose power when used in interindividual rather than intraindividual comparison. In this view, the Emax proved to be a significant determinant of O2max. Accordingly, O2max and Emax were shown to improve in patients after OHT and following the appropriate physiotherapy.36 Due to methodologic variations, no meaningful comparison was made with maximal ventilation in the various studies.37 Therefore, the concept of "excessive ventilatory response" needs to be considered cautiously due to the limiting influence of reduced inspiration volume. Indeed, weakness of respiratory muscles has the potential to limit tidal volume. This line of thought raises several methodologic questions, such as the use of standard formulae for calculation of MVV by multiplication of FEV1 by the empirically derived factor.38 It is not unlikely that this extrapolation, based on short-term ventilation performance, may lead to erroneous estimates of MVV.

Another reason for reduced exercise capacity may be reduced cardiac function. It is well known that reduced exercise performance can be attributed to chronotropic failure, which predominantly takes place in the first year after OHT. In our long-term transplanted patients, a chronotropic failure did not occur. Although 45% of our patients had reduced left ventricular function at rest, we analyzed the influence of this fact on their exercise capacity. We found no association between cardiac function and exercise parameters in our long-term survivors. This is in agreement with studies carried out in patients with CHF that show LVEF to be a poor predictor of exercise performance.

In summary, from our data we observed that an altered diffusion capacity is a common finding in long-term heart transplanted patients. Only very rarely are interstitial pulmonary changes detected by HRCT in these patients. Reduced CPX performance, however, did not seem to be caused by pulmonary diffusion abnormalities, but rather by pulmonary perfusion abnormalities, low tidal volumes, and weakness of respiratory muscle under condition of exercise. Because the vasoconstrictive side effect of cyclosporine can interfere with the autonomic vasodilation in small renal vessels in response to exercise,39 the potential effect of cyclosporine on capillary blood volume at rest and during exercise should be explored. Furthermore, cyclosporine-induced mitochondrial myopathy40 41 may be associated with an abnormal peripheral oxygen utilization, which in turn may lead to a reduction in the maximum aerobic capacity.


   Acknowledgements
 
We are indebted to Tonie Derwent for assistance with this article.


   Footnotes
 
Abbreviations: CHF = chronic heart failure; CPX = cardiopulmonary exercise testing; DM = diffusion capacity of the alveolar capillary membrane; Hb = hemoglobin; HCMV = human cytomegalovirus; HRCT = high-resolution CT; KCO = transfer coefficient for carbon monoxide; KCOC = transfer coefficient for carbon monoxide corrected for hemoglobin concentration; LVEF = left ventricular ejection fraction; MVV = maximal voluntary ventilation; OHT = orthotopic heart transplantation; PFT = pulmonary function testing; QC = blood volume of the alveolar capillaries; RV = residual volume; TLC = total lung capacity; TLCO = lung transfer factor for carbon monoxide; TLCOc = lung transfer factor for carbon monoxide corrected for hemoglobin concentration; VC = vital capacity; CO2 = carbon dioxide output; E = minute ventilation; Emax = maximal minute ventilation during exercise; O2 = oxygen consumption; O2max = maximal oxygen uptake; O2 AT = oxygen consumption at the gas exchange anaerobic threshold

Received for publication March 12, 1999. Accepted for publication September 14, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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R. Ewert, C. Opitz, R. Wensel, M. Dandel, S. Mutze, and P. Reinke
Abnormalities of Pulmonary Diffusion Capacity in Long-term Survivors After Kidney Transplantation*
Chest, August 1, 2002; 122(2): 639 - 644.
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