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(Chest. 1999;116:332-339.)
© 1999 American College of Chest Physicians

Lung Function and Cardiopulmonary Exercise Performance After Heart Transplantation*

Influence of Cardiac Allograft Vasculopathy

Martin Schwaiblmair, MD; Wolfgang von Scheidt, MD; Peter Überfuhr, MD; Bruno Reichart, MD and Claus Vogelmeier, MD

* From the Klinikum Grobhadern (Drs. Schwaiblmair, von Scheidt, and Vogelmeier) and the Department of Internal Medicine I and Heart Surgery (Drs. Überfuhr and Reichart), University of Munich, Munich, Germany.

Correspondence to: Martin Schwaiblmair, MD, Medical Clinic I, Klinikum Grobhadern, University of Munich, Marchioninistr. 15, D - 81377 Munich, Germany; e-mail: mschwaib{at}med1.med.uni-muenchen.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: The reduced exercise capacity observed in most patients after heart transplantation may be due to treatment with immunosuppressive drugs, deconditioning, cardiac denervation, and graft rejection. Cardiac allograft vasculopathy (CAV) is presently the major factor limiting long-term survival after transplantation. Little information is available with regard to the relationship between CAV and functional impairment in these patients.

Design: Prospective.

Setting: A university hospital and a large transplant center.

Patients: About 37 ± 5 months (range, 2 to 137 months) after orthotopic heart transplantation, 120 patients underwent lung function testing, cardiopulmonary exercise testing, and right and left heart catheterization. Significant CAV was defined as a stenosis >= 70% or severe diffuse obliteration in any of the three main vessels. Group I (n = 28) had a significant CAV; group II (n = 92), without a remarkable CAV, was the control group.

Measurements and results: Overall, the maximum heart rate was 86 ± 2% of what was predicted, and the peak oxygen consumption was 18.8 ± 0.7 mL/kg/min (64% of that predicted). Groups I and II did not show significant differences with regard to anthropometric data, hemodynamic measurements, or number of rejection episodes. Group I exhibited significant differences in maximum heart rate (120 ± 5 vs 134 ± 3 beats/min; p < 0.01), work capacity (47 ± 5% vs 59 ± 3%; p < 0.05), peak oxygen uptake (16 ± 1 vs 20 ± 1 mL/min/kg; p < 0.01), and functional dead space ventilation (31 ± 2 vs 26 ± 1; p < 0.01). Pretransplant status, etiology of heart failure, ischemic time, and the number of rejection episodes did not correlate with any exercise parameter.

Conclusions: Following heart transplantation, patients with significant CAV show a diminished exercise capacity, a reduced oxygen uptake, and a ventilation-perfusion mismatch. Thus, CAV may be a major factor limiting exercise capacity in heart-transplant patients.

Key Words: cardiac allograft vasculopathy • cardiopulmonary exercise testing • gas exchange • heart transplantation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although earlier studies of hemodynamics during submaximal exercise in human heart transplant recipients appear to show normal resting and exercise values for cardiac output, subsequent studies clearly demonstrate a 30-to-40% reduction in maximum exercise capacity.1 2 3 4 5 The exercise capacity of an individual patient depends on the functional status of the lungs and the cardiovascular system, as well as the capacity of the blood to deliver oxygen. Diastolic dysfunction, which may be due to a combination of several factors, including rejection, hypertension, and ischemia from cardiac allograft vasculopathy (CAV), appears to add to the denervation-induced chronotropic and inotropic incompetence, ie, lack of intracardiac neuronal liberation of norepinephrine, with the result of a limited cardiac output response to exercise.6 With respect to morbidity and mortality, CAV is the most important long-term complication following heart transplantation.7 8 9 The incidence of CAV increases beyond the third year after transplantation and reaches 40 to 60% by the seventh year.10 11 Clinical noninvasive tests have been shown to be relatively insensitive for identifying patients with CAV. Few data are available regarding the effect of transplant vasculopathy on cardiopulmonary exercise testing (CPX), a noninvasive method for assessment of the exercise capacity. Therefore, this study was designed to examine the influence of CAV on CPX and gas exchange.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
The study population included 120 patients (13 women and 107 men) after orthotopic heart transplantation with a mean age of 50 ± 9 years old (range, 24 to 64). The patients were selected out of a population of 478 patients to generate groups according to their coronary status. Between August 1981 and June 1996, cardiac transplantation was performed in 478 patients at the Klinikum Grobhadern of the University of Munich. An exercise test was not performed during the follow-up in 358 patients for the following reasons: (1) death before evaluation (n = 178); (2) vascular, orthopedic, or neurologic problems of the lower extremities that precluded bicycle exercise (n = 48); (3) patients living far from the transplant center (n = 58); (4) patients refusing the test (n = 42); (5) heterotopic heart transplantation (n = 9); and (6) miscellaneous reasons, such as uncontrolled hypertension, severe COPD, or a history of recent rejection or intercurrent illness (n = 23). The protocol was approved by the Ethics Committee of the University of Munich. Written informed consent was obtained from all subjects.

The clinical data of the patients are shown in Table 1 . The reason for transplantation was dilated cardiomyopathy in 65% of patients and ischemic heart disease in the remaining 35%. None of the patients had undergone a structured postoperative rehabilitation program. All patients were clinically stable, with no history of recent rejection or intercurrent illness.


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  		Table 1. Patient Characteristics*

 
Medication
All patients were receiving maintenance immunosuppression with cyclosporine in combination with azathioprine (43%) and prednisolone (77%). Immunosuppression was continued throughout. At the time of testing, no individual was treated with ß-blockers. Cardioactive medication, used primarily for BP control, included angiotensin-converting enzyme inhibitors in 76%, calcium channel blockers in 60%, and diuretics in 55% of patients.

Pulmonary Function Tests
Pulmonary function tests included spirometry (FVC, FEV1, total lung capacity [TLC], and maximum expiratory flow at 50% of vital capacity [MEF50]) and determination of residual volume by body plethysmography. In addition, single-breath diffusing capacity of the lung for carbon monoxide (DLCO) was analyzed (Body Test equipment; Jaeger; Würzburg, Germany). Quality control procedures and reference values followed the standards of the European Community for Coal and Steel.12 A minimum of three measurements were taken, and the best values were used. Blood gases were analyzed (model ABL520; Radiometer; Copenhagen, Denmark) at rest and during maximum work capacity using capillary ear lobe blood. The patients breathed room air.

Hemodynamic Assessment
Right and left heart catheterization was performed as part of routine annual monitoring. A balloon-tipped, flow-directed thermodilution pulmonary artery catheter (model 9520A; Baxter Healthcare Corp, Edwards Laboratory; Santa Ana, CA) was introduced under local anesthesia via the femoral vein and floated under constant-pressure wave monitoring into a pulmonary artery for measurements of mean pulmonary artery pressure (PAPm). Pulmonary pressures were measured using transducers (Statham P50; Gould; Cleveland, OH) connected to a bedside hemodynamic and ECG monitoring system (Sirecust 404; Siemens; Erlangen, Germany). Pressure transducers were adjusted to the level of the right atrium. Actual and mean pressure measurements were taken at midpoint of the respiratory cycle to minimize the effects of inspiration and expiration. Cardiac output was quantified by the thermodilution method, three to five measurements being averaged. Cardiac index (CI) and pulmonary vascular resistance (PVR) were calculated with standard formulas.13

The femoral artery was cannulated with a 6F sheath. A pigtail catheter was introduced for systemic pressure recording and ventriculography. End-diastolic and end-systolic volumes were determined using the area-length method, and the ejection fraction (EF) was calculated. Stroke volume index (SVI) was calculated according to the standard formula.13 Coronary arteriograms were performed with Judkins catheters using multiple projections of both the right and the left coronary artery after nitroglycerin premedication. The final interpretation was based on a consensus of two investigators. Patients with at least one focal stenosis >= 70% in one of the three main coronary arteries (left anterior descending artery, ramus circumflexus, and right coronary artery) or diffuse severe distal obliterative changes were considered to suffer from significant CAV. Group I (n = 28) had significant CAV; group II (n = 92) had no significant CAV.

CPX
An incrementally progressive, symptom-limited cardiopulmonary exercise test was performed. The individuals were tested at least 2 h after their last meal, using an electronically braked cycle ergometer (model ER900; Ergotest; Jaeger, Germany). The heart rate and rhythm were monitored by an ECG. The participants were connected to a two-way, low-resistance y-mouthpiece and a pneumotachograph while breathing room air. The expired air was collected continuously in a Douglas bag. Oxygen and carbon dioxide were analyzed every 15 s with an Ergopneumotest (EOS-Sprint; Jaeger, Germany). Before each test, pneumotachograph and gas analyzers were calibrated using a graduated syringe and test gases with known concentrations. Maximum workload (P) was defined as the highest work level reached and maintained for at least 1 min. The predicted value was derived from Löllgen et al.14 Similarly, for maximum heart rate, maximum oxygen uptake (O2max), peak respiratory ratio (RER), and maximum ventilation, the highest readings of each parameter were used. At rest and during maximum exercise, the physiologic dead space ventilation (VD/VT) and alveolar-arterial oxygen pressure difference (P[A-a]O2) were calculated based on the PaCO2. The VD/VT values were obtained using the standard formula. The P(A-a)O2 at the end-exercise point was determined based on direct measurement of arterial PaO2 and PaCO2 using the simplified alveolar gas equation. The anaerobic threshold (AT) was evaluated with the V-slope method. After 5 min of adaptation to the mouthpiece, P was increased in 30-W slopes every 3 min, up to the point of exhaustion (the inability to maintain a constant speed and/or the development of intolerable dyspnea). Reference values were derived from Wasserman et al.15

Statistical Analysis
All data are given as mean ± SEM. A two-sample t test was used to compare values between the two groups (with Bonferroni posttest correction where appropriate). A one-way analysis of variance of the lung function and exercise parameters using the coronary status as covariate was performed. Correlation coefficients were determined with the Pearson test. For correlation coefficients and t-test values, a p value < 0.05 was considered significant. The statistical computations were performed using appropriate computer software (SPSS/PC+; SPSS, Inc; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Pulmonary Function Tests
Pulmonary function test results and blood gas values are shown in Table 2 . DLCO, when corrected for hemoglobin (< 75% of predicted) was diminished in 28 patients (23%). A mild restrictive defect (TLC < 75% of predicted) was observed in 10 patients (8%), and 5 patients (4%) had significant airway obstruction (FEV1/FVC < 70%).


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  		Table 2. Pulmonary Function Test Results and Blood Gas Analysis*

 
When patients with and without CAV were compared, no significant differences in FVC, TLC, FEV1, MEF50, DLCO, and blood gases could be demonstrated. DLCO was slightly higher in the group of patients without CAV.

Hemodynamic Assessment
As shown in Table 3 , there were no significant differences between the two groups in all hemodynamic parameters studied. EF, CI, SVI, and PVR were in the normal range. PAPm (22.0 mm Hg in group I vs 21.5 mm Hg in group II) and left ventricular end-diastolic pressure (15.6 mm Hg in group I vs 15.5 mm Hg in group II) were slightly elevated in both groups. Six patients showed a reduced EF (< 60%). A diminished CI (< 2.0 L/min/m2) was observed in eight patients (7%).


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  		Table 3. Hemodynamic Parameters*

 
CPX
Cardiovascular and ventilatory data from graded maximum exercise testing are shown in Table 4 . Exercise capacity was reduced in all heart transplant patients. Similarly, O2max was lower in heart transplant patients than it was in normal subjects (18.8 ± 1.0 mL/min/kg = 63.9 ± 1.8% of predicted, matched for age, gender, and body weight). Peak O2max was < 50% of predicted in 13 patients (11%), between 50% and 70% in 68 patients (57%), and between 70% and 90% of predicted in 39 patients (32%); none of our patients reached >= 90% of peak predicted O2max. The average RER was 1.33 ± 0.03, showing adequate maximal effort. The maximum heart rate was 86 ± 2% of the predicted value. Mean AT, VD/VT, and P(A-a)O2 were in the normal range.


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  		Table 4. Results of Cardiopulmonary Exercise Testing*

 
Comparing the groups with and without CAV, significant differences could be demonstrated with respect to P, peak HR, RER, O2max, and VD/VT during maximum exercise. Maximum ventilation, tidal volume/FVC, breath frequency, and P(A-a)O2 were similar. Seventeen patients in group I (61%) had an increased VD/VT (> 28%). In contrast, a raised VD/VT was observed in only 19% of the patients in group II.

Correlation of Preoperative and Postoperative Variables to Postoperative Cardiopulmonary Exercise Parameters
The following failed to correlate with any of the exercise parameters: the heart disease making transplantation necessary; pre- and posttransplantation values for PAPm; the CI, EF, and PVR; the age of the donor; the ischemic time; the time of mechanical ventilation after transplantation; the type of immunosuppression; and the number of rejection episodes (Table 5 ). Only the diffusing capacity correlated significantly with P (r = 0.46; p < 0.001) and VD/VT (r = 0.45; p < 0.001).


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  		Table 5. Correlation Coefficients*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, CPX was performed in patients following heart transplantation. In spite of normal or near-normal values for lung function parameters and cardiac hemodynamics, O2max was significantly lower in heart transplant patients than it was in normal subjects. Two patient groups were established depending on their CAV status. In comparison to patients without CAV, patients with CAV showed significant changes in maximum heart rate, O2max, and VD/VT. The pretransplant status, the etiology of heart failure, the ischemic time, and the number of rejection episodes did not correlate with any of the exercise parameters.

Despite improvement in lung volume, we and others observed a persistently low DLCO after cardiac transplantation (83.8 ± 2.7% of predicted).16 17 18 19 20 DLCO may remain low due to irreversible changes caused by chronic pulmonary congestion, interstitial damage from subclinical respiratory infections in immunocompromised patients, and cyclosporine toxicity.17 DLCO not only depends on the area and thickness of the blood-gas barrier, but also on the blood volume in the pulmonary capillaries. Therefore, alterations in the pulmonary circulation, caused by cardiac denervation, could be of importance.21 Comparing the two study groups, we found that patients with CAV had somewhat lower FVC (-7.5%), TLC (-3.1%), FEV1 (-4.6%), and DLCO (-9.6%). Therefore, we cannot exclude a possible influence of the diminished lung function values on the CPX parameters. Nevertheless, the relative extent of the differences is significantly greater for the CPX parameters, eg, P (-20.6%), O2max (-9.2%), and VD/VT (+16.1%). In addition, we did not observe an increase in P(A-a)O2 during exercise, suggesting that lung function is not the major cause for the reduced aerobic capacity in patients with CAV.

Maximum oxygen consumption is considered to be one of the most reliable indexes for exercise tolerance. The supply of oxygen needed to meet the oxygen requirement for muscle mitochondrial high-energy phosphate generation during exercise is a critical function of the circulation. Thus, the adequacy of cardiovascular function can be estimated from the pattern of oxygen uptake in response to an exercise stimulus. Similar to other reports,21 22 the average peak exercise O2max after cardiac transplantation in our study was 18.8 mL/min/kg, indicating a low aerobic capacity of transplant recipients. Consistent with prior observations, a low AT was also present.2 The AT occurred at approximately 56% of O2max in both groups, suggesting that all patients reached their exertion limit. The decreased oxygen uptake and AT in transplant recipients indicate that the oxygen delivery to tissues is reduced in comparison to normal individuals.

The hemodynamic profile of heart-transplanted patients was comparable to that seen in other studies.4 22 25 26 The cardiac function was slightly impaired in terms of elevated filling pressures. Similar values for resting left ventricular EF in both groups make it unlikely that ischemic cardiomyopathy influenced the results of CPX. In this context, it is important to notice that in patients with CAV, time since transplantation was, on average, > 1 year longer than in patients without CAV. This is not surprising, as the prevalence of critical coronary stenoses >= 75% increases beyond the fourth year after transplantation. Thus, this factor may have influenced our study results.9

On the other hand, patients with significant CAV have a lower exercise tolerance. Vanhess et al27 showed that exercise capacity, determined by a graded exercise test until exhaustion, is an independent predictor for subsequent all-cause and cardiovascular mortality in patients with coronary artery disease. The diminished oxygen uptake in patients with CAV probably results from subnormal EF and cardiac output augmentation in response to exercise, as well as an exaggerated increase in intracardiac filling pressure during exercise. Elevated intracardiac filling pressure implies that the ventricles are less compliant than normal. Our study results suggest that CAV is of major importance for exercise capacity and O2max after transplantation. Nevertheless, CAV is not considered to be the sole reason for these findings. Potential contributing factors include graft rejection and cardiac denervation, which may interfere with the ability to reach the age-predicted maximum heart rate and stroke-volume response. Also, immunosuppressive therapy, which may result in secondary loss of muscle mass from steroid-induced myopathy, deconditioning, and permanent skeletal muscle changes following long-standing heart failure before cardiac transplantation, may contribute.2 4 28 29 30 With regard to the absence of pretransplant CPX values, we cannot exclude the possible influence of a limited exercise capacity before transplantation on our study results.

Furthermore, the increase in VD/VT in patients with CAV is an observation of great importance.31 Elevated VD/VT values during exercise may be due to a reduction in pulmonary blood flow via reduced cardiac output. This suggests that pathologically high ventilation/perfusion ratio (/) mismatching occurs in patients with significant CAV without significantly low / mismatching (normal P[A-a]O2). This places the abnormality on the pulmonary circulation rather than the airway side of the gas exchange unit; ie, perfusion is reduced in well-ventilated lungs.32 33

The predictive value of CPX as a marker of CAV (using coronary arteriography as the gold standard) in transplant patients needs to be defined. Regions of the myocardium with reduced ability to increase blood flow may develop an imbalance of oxygen delivery and oxygen requirements. In these regions of the left ventricle, the rate of adenosine triphosphate production will be inadequate to sustain contraction.15 Thus, these areas become hypokinetic or akinetic. Stroke volume will therefore decrease at the work levels at which hypokinesia or akinesia becomes apparent. The results of our study suggest that CPX may provide a good estimate of the functional consequences of CAV. Klainman et al34 showed that patients with silent or symptomatic ischemia during exercise testing had lower values of maximal oxygen consumption compared to control patients. In patients with ischemic heart disease, the abnormal heart response to exercise is probably due to the disturbed oxygen supply-demand relationship in the myocardium, which causes a diminished blood flow through the arterial circulation and an imbalance between tissue oxygen demand and supply. To define the precise role of CPX in the noninvasive monitoring of heart-transplanted patients, it needs to be studied in comparison to exercise or dipyridamole thallium scintigraphy and dobutamine stress echocardiography.35 36 37 38 39

Similar to prior studies, we demonstrated a resting tachycardia and attenuated maximum heart rate response to exercise in patients after transplantation. O2max is normally correlated with maximum heart rate, and it is unclear whether the reduced peak heart rate is the consequence or the cause of the decreased exercise capacity in these patients. The denervated heart, indicated as intramyocardial by an absent neuronal epinephrine release and uptake, causes a chronotropic and inotropic incompetence. The limited ability to increase the heart rate, in combination with a subnormal increase of stroke volume, diminishes the cardiac output response to exercise40 41 and consequently reduces the exercise capacity. In heart transplant recipients with their diastolic dysfunction, the ability to augment stroke volume is limited, providing a pathophysiologic background for their reduced exercise capacity.42 There is evidence that reinnervation occurs in some patients after orthotopic heart transplantation. Lord et al43 showed that functional sympathetic efferent reinnervation of the sinus node was associated with improved heart rate response during exercise and with recovery after exercise. It is therefore possible that the patients with partial reinnervation, causing a positive chronotropic and inotropic status, may be able to do more exercise. This reinnervation could mask the reduced oxygen uptake, because the reinnervation and CAV is a time-dependent process and both occur in the long-term follow-up after heart transplantation.

In summary, our study shows that, contrary to cardiopulmonary exercise parameters, the lung function of most patients with heart failure is normal after cardiac transplantation. Only diffusing capacity remains reduced after transplantation. Considerable exercise limitation, however, remains in most recipients as measured by O2max and P. Heart transplant recipients with significant CAV show a significantly reduced work capacity and decreased oxygen uptake with additional indications for a / mismatch. Although there is no apparent ischemic cardiomyopathy at rest, exercise-induced myocardial ischemia, leading to diastolic and systolic dysfunction, is the most likely explanation for the reduced oxygen uptake in heart transplant recipients with significant CAV, compared to those with a normal angiogram. Further studies are needed to clarify whether CPX leads to the detection of early forms of CAV and therefore may serve as a screening method in the monitoring of heart-transplanted patients.


   Footnotes
 
Abbreviations: AT = anaerobic threshold; CAV = cardiac allograft vasculopathy; CI = cardiac index; CPX =cardiopulmonary exercise testing; DLCO = single-breath diffusing capacity of the lung for carbon monoxide; EF = ejection fraction; MEF50 = maximum expiratory flow at 50% of vital capacity; P = maximum workload; P(A-a)O2 = alveolar-arterial oxygen pressure difference; PAPm = mean pulmonary artery pressure; PVR = pulmonary vascular resistance; RER = peak respiratory ratio; SVI = stroke volume index; TLC = total lung capacity; VD/VT = physiologic dead space ventilation; O2max = maximum oxygen uptake; / = ventilation/perfusion ratio

Received for publication August 4, 1998. Accepted for publication March 3, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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