Carter R, Al-Rawas OA, Stevenson A, Mcdonagh T*, Stevenson RD
Department of Respiratory Medicine, Scottish Cardiopulmonary Transplant Unit*
Glasgow Royal Infirmary
Address for Correspondence: Dr R Carter, Clinical Respiratory Scientist, Department of Respiratory Medicine, Queen Elizabeth Building, Royal Infirmary, Alexandra Parade, Glasgow G31 2ER
SMJ 2006 51(3): 6-14
Heart transplantation is an established treatment for end stage heart failure. In addition to increased life expectancy, heart transplant recipients report a remarkable improvement in symptoms and functional capacity. Exercise performance following heart transplantation, however, remains impaired even in the absence of exertional symptoms. We have assessed the response to exercise in 47 patients with cardiac failure prior to and then at yearly intervals to five years post transplantation. All patients performed incremental symptom limited exercise tests during which minute ventilation (V’E), oxygen consumption (V’O2) and carbon dioxide production (V’CO2) and heart rate (HR) were measured. Ventiltory response (V’E/V’CO2), anaerobic threshold (V’O2 AT %predicted) and heart rate response (HR/VO2) were calculated. The dead space to tidal volume ratio (VD/VT) and alveolar-arterial oxygen gradient (A-aO2) were computed from transcutaneous monitoring. Despite substantial improvement in subjective functional capacity, heart transplant recipients continue to have limited exercise performance [Maximal V’O2% predicted pre-transplant 41.3 (2.2); 1 year 48.6 (1.7), p <0.001: V’O2 AT% 31.5 (1.1); 1 year 35.6 (1.0); respectively p<0.05]. The maximal oxygen uptake continued to improve at two years post-transplant but, thereafter, there was no further significant change at up to 5 years post transplant [50.9 (1.5)]. At one year post-transplantation peak HR [65.2 (0.9) vs 79.1(1.4)] and the HR/VO2 response [24.0(1.8) vs 79.6(4.2)] were significantly reduced compared to pre-transplant values. The heart rate response remained lower compared to predicted at 5 years post-transplant although there was a significant increase compared to one year post-transplant (32.9 vs 24.0mls/bt). There was a weak but significant relationship between maximal VO2 and peak HR (0.39, p<0.05) and HR/VO2 (r= 0.37, p<0.05) at one year post-transplant. Prior to transplantation the ventilatory response to exercise was elevated [V’E/V’CO2 45.6 (2.5)] and decreased significantly following transplantation [1 yr 34.1 (1.3), respectively p<0.001]. In addition, despite significant improvement in VD/VT after transplantation, it remained higher than normal [Pre VD/VT at maximum exercise 0.35 (0.02); 1 yr 0.31 (0.02); p<0.05]. There was a further fall in the VE/VCO2 and VD/VT at two years post-transplantation with no further change at up to 5 years post transplantation [VE/VCO2 32.0 (1.0); VD/VT 0.29 (0.01)]. Although cardiac output is markedly improved after transplantation, due to chronotropic incompetence associated with denervation, its response remains subnormal and this may explain the residual abnormalities of ventilatory and gas exchange responses to exercise following transplantation.
Heart failure is a serious condition with significant morbidity and high mortality. The reported mortality rates in patients with heart failure range from 24 to 35%, reaching greater than 50% in patients with NYHA functional class IV.1 Although drug therapy with angiotensin converting enzyme (ACE) inhibitors and vasodilators has been shown to improve survival in heart failure, patients with NYHA class IV and some patients with class III NYHA continue to have very poor life expectancy.1 In addition, these patients remain severely limited by dyspnoea and fatigue even when on maximal medical therapy.2 For these patients, heart transplantation has become the treatment of choice.3
Since the introduction of cyclosporin immunosuppressive therapy, the reported survival rate has reached 80 to 90% at one year and 60 to 70% at five years after heart transplantation.4,5,6,7 In addition to increased life expectancy, heart transplant recipients report an improvement in symptoms and functional capacity. 7,8
Exercise performance following heart transplantation, however, remains impaired even in the absence of exertional symptoms. 7,9,10,11,12,13 The maximum symptom-limited oxygen uptake and the ventilatory anaerobic threshold are in the range of 50% to 70% of predicted. 12,13
The cause of exercise intolerance in heart transplant recipients is not clear, but there is increasing evidence that it is multifactorial and is related to cardiac, neurohumoral, vascular muscle and pulmonary changes. 11,13 In a longitudinal study of 57 patients by Givertz et al, 13 it was demonstrated that at one year post transplantation, transplant recipients have a subnormal maximal exercise capacity that was associated with a blunted heart rate response and reduced peak heart rate (chronotropic incompetence) on cardiopulmonary exercise testing. This group also showed that the heart rate response to exercise was attenuated despite a normal response to exogenous beta-adrenergic stimulation with infused isoproterenol, indicating that the cause of the abnormality is proximal to the beta–adrenergic receptor. During the subsequent four years there was no further improvement in either, exercise capacity or the heart rate rise and peak heart rate achieved on exertion. The authors suggest that these findings support the hypothesis that the chronotropic incompetence is due to surgical denervation of the heart and that no re-inervation occurs within the first five years following transplantation.
Heart compliance is also reduced resulting in left ventricular dysfunction with relatively preserved systolic function.11 Several factors have been identified as contributing to myocardial stiffness following heart transplantation including: diastolic dysfunction from myocardial ischaemia due to prolonged donor heart ischaemic time and ischaemia sustained during the operation, ischaemia from cardiac allograft vasculopathy, cyclosporin-induced systemic hypertension, cyclosporin myocardial toxicity and recurrent minor episodes of rejection. 9,11,12,14
Efficient pulmonary gas exchange is an essential part of the complex process of exercise. 15,16 Pulmonary dysfunction following heart transplantation is therefore a potential cause of exercise intolerance in heart transplant recipients.14 Although central haemodynamic and peripheral circulatory changes have been extensively evaluated in heart transplant recipients,11 there is little information on the possible effects of lung dysfunction on exercise performance.17,18,19
We have recently developed the transcutaneous monitoring of arterial blood gases for the non-invasive measurement of indices of gas exchange at rest and during exercise testing.20 We have used this system to directly assess the impact of gas exchange abnormality on exercise capacity in heart transplant recipients.
A prospective longitudinal study consisting of heart transplant patients who were transplanted between January 1992 and June 2001 at the Scottish Cardio-Pulmonary Transplantation Unit (SCPTU) based at the Glasgow Royal Infirmary, North Glasgow University Hospitals Trust.
All transplant patients conforming to SCPTU inclusion criteria performed pulmonary function and cardio-pulmonary exercise tests according to the testing protocol. Pulmonary function tests and cardio-pulmonary exercise tests were performed during the assessment for heart transplantation and serially after transplantation. Lung volumes, forced ventilatory flows (Body Plethysmography Sensormedics V6200) and the single breath transfer factor for carbon monoxide (TLCO)(Transflow, Morgan Medical) were performed during each visit and included forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), residual volume (RV) and total lung capacity (TLC).
Predicted normal values were determined using the European Community for Steel and Coal equations for all variables. 21
Measured TLCO was corrected for actual haemoglobin concentration using the equation of Dinakara and associates. 22
Haemoglobin-corrected
TLCO = Observed TLCO / (0.06965 5 Hb);
Where Hb is the patient’s actual haemoglobin and 0.06965 is a correction factor to a standard haemoglobin concentration of 14.4 g.dL-1.
Symptom-limited exercise tests were performed using an electrically braked bicycle ergometer. Throughout each test, minute ventilation (V’E), oxygen consumption (V’O2) and carbon dioxide (V’CO2) were measured breath by breath by on-line ventilation and expired gas analysis (MedGraphics CPX-D). The ventilatory anaerobic threshold on exertion was calculated by the curve fitting method using a plot of V’O2 against V’CO2.23 The dead space to tidal volume ratio (VD/VT) and alveolar-arterial oxygen gradient (A-aO2) were computed from transcutaneous monitoring following an in-vivo calibration using a single arterialised ear lobe capillary sample. 20 A standard 12-lead electrocardiogram was displayed throughout the procedure.
Between January 1992 and June 2000, 289 patients were assessed for transplantation, of these, 142 underwent orthotopic heart transplantation at the Scottish Cardio-Pulmonary Transplantation Unit.
A cohort of the patients who had full pre-operative pulmonary function and cardiopulmonary exercise data (47 patients) also performed resting pulmonary function tests and cardio-pulmonary exercise tests at 1,2,3,4 and 5 years post transplantation. Assessment was performed in stable patients who had not suffered from any respiratory illness during the preceding two 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 standard triple immunosupression (cyclosporin, azathioprine and prednisolone).
The findings in cardiac failure patients were compared with data from 30 normal subjects recruited as volunteers from the general population in whom there was no evidence of cardio-pulmonary disease.
Unless stated otherwise, values are expressed as mean +/- one standard error of the mean (SEM). Lung function and cardio-pulmonary exercise data in heart transplant recipients were compared to those of normal subjects using the one way analysis of variance (ANOVA). The relationship between exercise parameters was assessed using the Pearson correlation and linear regression analysis. A p value of <0.05 was considered significant.
Subject characteristics are summarised in Table I. All groups had similar age and sex distribution. All patients were either life-long non-smokers or former smokers. After transplantation, there was a significant improvement in both left ventricular ejection fraction (LVEF) and the NYHA functional status
Table II compares the resting pulmonary function results in the study groups. TLC, VC, FEV1 and FEV1/VC were slightly reduced in heart transplant recipients compared to normal subjects. Although the RV was greater in recipients compared to normal controls this did not reach statistical significance. In contrast TLCO and KCO (before and after correction for haemoglobin) were significantly lower in recipients compared to the normal subjects).
Table III displays the cardio-respiratory response to symptom limited exercise in heart transplant recipients compared with normal controls. Maximum symptom-limited oxygen uptake (VO2) as a percentage of predicted was significantly lower in the transplant recipients compared to normal controls (39.5% vs. 92.9% of predicted, p< 0.001). The ventilatory anaerobic threshold was markedly reduced in recipients compared to controls. The ventilatory and gas exchange responses to exercise (VE/VCO2, VD/VT,) were all higher in recipients compared to normal controls although there was no significant difference between the A-aO2 gradient at maximum exercise in the transplant recipients compared to normal controls. The heart rate response was markedly elevated in the cardiac transplant recipients prior to transplantation compared with normal controls. The oxygen pulse at maximum symptom limited exercise was significantly lower than in the normal controls.
Of the 142 patients who underwent cardiac transplantation 1 and 5 year survival rates were 83 and 69%, respectively. Figure 1 shows the functional status of patients based on the NYHA classification prior to and at one year post transplantation. This shows substantial improvement of subjective functional capacity.
Table IV compares the lung function results in the transplant recipients prior to and at one year post transplantation. Prior to transplantation, FEV1, VC and TLC were significantly reduced compared to normal predicted values. Although above 80% of predicted, they were all significantly lower than the values in normal controls (P <0.05). Residual Volume (RV) was slightly elevated, but this was not significantly different from that of normal controls. The greatest impairment, however, was in TLCO and KCO, which were markedly reduced, compared to normal controls.
Mean TLCO declined significantly following transplantation (from 79.8% to 59.2% of predicted, p< 0.001), with a similar decline in KCO from 78.8% to 54.0% of predicted (p<0.001).
Table V shows the maximum symptom-limited exercise responses in heart transplant recipients before and after transplantation. Exercise responses were generally improved at 1 year compared with pre-transplantation. Maximum oxygen uptake corrected for body weight and percent predicted maximal VO2 was significantly improved compared with before the procedure. The mean maximal oxygen uptake corrected for body weight was 15.55 (SEM 0.44) mls.kg-1min-1. This represented a percentage-predicted maximum of 49.3 (1.3), matched for age gender and body surface area compared with 12.5 mls.kg-1min-1; 39.5% predicted (p< 0.05) prior to transplantation, however both were substantially lower than normal controls (28.9 mls.kg-1min-1; 92.9% predicted; p< 0.001). The ventilatory anaerobic threshold was significantly higher post transplantation compared to pre transplant values but was still reduced compared to normal controls. At one year post-transplant, peak heart rate, and the heart rate response (HR/VO2) were significantly reduced compared to pre-transplant and control values.
The oxygen pulse at maximal exercise was significantly elevated compared to pre-transplantation values but remained lower than normal control subjects. The ventilatory response on exertion (VE/VCO2) and the degree of wasted ventilation (VD/VT) at maximum exercise were significantly reduced post transplant but remained raised compared to normal control subjects. The ventilatory reserve (VE/MVV) was similar in all the groups studied.
Maximal oxygen uptake and percent-predicted oxygen uptake increased at 24 months after cardiac transplantation compared with before the procedure but did not significantly change thereafter. Compared to pre-transplantation, post-transplantation patients reached a lower peak heart rate (79.1% against 65.2% predicted maximum) and had reduced heart rate response (79.6 against 24.0 mls/bt) at one year. This chronotropic response remained lower compared to predicted normal at 5 years post transplantation although there was a significant increase in the peak heart rate achieved and in the heart rate response compared to one-year post-transplant (32.9 against 24.0 mls/bt). At one year post-transplantation only 6% of patients who performed an exercise test were able to reach >or = 80% of age predicted maximum heart rate compared with 32% at 3 years (p<0.01) and 45% at 5 years post-transplant (p<0.01). There was a weak but significant relationship between the maximal oxygen uptake and peak heart rate achieved (r = 0.39, p<0.05) and the heart rate response (HR/VO2) on exertion (r= 0.37, p<0.05) at one year post-transplantation. At 5 years post-transplantation the correlation was improved between peak heart rate achieved and maximal oxygen uptake (r = 0.485, p< 0.001) (Figure 2) and the heart rate response on exertion (r = 0.477, p < 0.001) (Figure 3). The mean resting heart rate preceding the exercise test ranged from 98 to 100 beats/min at the time of the 1-, 3- and 5-year visit after cardiac transplantation.
The ventilatory response on exertion was significantly lower at one-year post transplantation compared to pre-transplant values but did not significantly change thereafter. The reduced ventilatory response on exercise was associated with a reduction in the degree of wasted ventilation with a significant fall in the VD/VT at one-year post-transplantation compared to pre-transplant values. There was a further fall in VD/VT at two years compared to one-year post-transplantation with no further change at up to 5 years post-transplant. Ventilatory reserve was also improved post- transplantation with a significant improvement in the VE/MVV at two years post- transplantation that was maintained at up to 5 years post-transplant.
This study has shown that despite normal or near normal values for lung function parameters and cardiac haemodynamics, the maximal oxygen uptake at one year post transplantation was significantly lower in heart transplant recipients than in normal controls. This abnormal physiological response to exercise was associated with a reduced heart rate response and reduction in peak heart rate post transplantation. This chronotropic incompetence on exertion is related to cardiac denervation.
In this longitudinal study of 47 patients post transplantation it was shown that the maximal oxygen uptake continued to improve at two years post transplant but, thereafter, there was no further significant change at up to 5 years post transplant.
The results of resting pulmonary tests in this study are in agreement with previous reports. 24, 25
Despite improvement in lung volumes, there was a persistently low transfer factor (TLCO) and transfer coefficient (KCO) after cardiac transplantation (59.2 % and 54.0% of predicted, respectively). This confirms the findings of previous studies. 9, 25, 26, 27, 28 The transfer factor may remain low due to irreversible changes caused by chronic pulmonary congestion, pulmonary oedema or interstitial damage from subclinical infections in immunocompromised patients. The influence of pre-transplant pulmonary function on post transplant lung function is well documented. In the study of Groen et al, 25 the percentage reduction in KCO after transplantation was greater in patients with respiratory crackles compared with those without crackles before transplantation. It was suggested that patients with clinical evidence of pulmonary oedema experience a greater reduction in KCO after transplantation. In the same study, the percentage change in KCO was positively correlated with pre-transplant KCO (patients with higher pre-transplant KCO had greater decreases in KCO after transplantation).
In another study of 22 heart transplant patients, Ohar et al28 found no relationship between the change in TLCO and the changes in static and dynamic lung volumes after heart transplantation.
The lack of any significant correlation between the change in TLCO and the pre-transplant static and dynamic lung volumes may be due to the fact that these were only mildly reduced before transplantation. Patients with severe lung function abnormalities and those with significant co-existing primary lung disease are usually excluded in the selection process of heart transplant candidates. This may also explain the absence of any relationship between pre-transplant lung function and outcome after heart transplantation as reported by Brussieres et al.29
The results of the cardio-pulmonary response to exercise in the 47 patients prior to transplantation are in agreement with previous findings which have shown that patients with chronic heart failure exhibit an excessive ventilatory response to exercise 30, 31, 32 The results of the present study in stable patients assessed prior to transplantation confirm that excessive ventilatory response to exercise is a characteristic of chronic heart failure. We have previously shown that the ventilatory response to progressive exercise testing and the maximal symptom-limited oxygen uptake as a percentage of predicted are inversely related in the heart transplant recipients.33 This study has also confirmed that patients with chronic heart failure have an increased degree of “wasted ventilation” as assessed by VD/VT at rest, and this persisted on exertion, confirming the findings of Metra et al 32 and Sullivan et al. 30 The relevance of these findings to the reduction in maximal oxygen uptake in patients with cardiac failure has been described previously. 33
The results of this study of 47 transplant recipients demonstrate a significant improvement in maximal oxygen uptake within one year of the cardiac transplantation. The maximal oxygen uptake then remains stable from 1 to 5 years after cardiac transplantation. The average maximal oxygen uptake one-year after cardiac transplantation was 15.55 mls min-1kg-1. This is slightly lower than the range of values reported in previous studies. 7, 9, 10, 13, 25, 34, 35, 36 One-year maximal oxygen uptake was 17.0-ml min-1 kg-1 in 60 patients in a study reported by Mandak et al34 whose mean age was 52 years. In a study by Osada et al7 the maximal oxygen uptake at one-year post transplant in 140 patients, whose mean age was 47 years, was 21 mls min-1kg-1. This compares with 15.5 mls min-1kg-1 in the 47 patients whose mean age was 50 years in the present study. This finding is similar to the study of Givertz et al 13 who showed a maximal oxygen uptake of 16.6 +/- 0.9 mls min-1kg-1 at one year post transplantation (57 patients, mean age 45 +/- 2 years). This reflected an improvement of 43% compared to pre-transplantation values.
In agreement with these previous reports, the results of this study show that despite substantial improvement of subjective functional capacity, heart transplant recipients continue to have limited exercise performance as assessed by incremental cardio-pulmonary exercise testing. In the present study although most patients had a significant increase in exercise capacity after cardiac transplantation, the average percent predicted maximal oxygen uptake at one-year post transplant was only 49% of predicted. The reasons why peak exercise capacity does not return to normal in most patients after cardiac transplantation are not well understood. Subnormal exercise capacity after transplantation may be due to several factors which include cardiac denervation, which may interfere with the ability to reach age-predicted maximum heart rate response (chronotropic incompetence),13 allograft rejection,35 diastolic dysfunction10 and immunosuppressive therapy, which may result in secondary loss of muscle mass from steroid induced myopathy, deconditioning and permanent skeletal muscle changes resulting from long standing heart failure prior to cardiac transplantation. 12, 14, 37, 38, 39, 40
Similar to previous studies, this study has demonstrated a resting tachycardia and attenuated maximum heart rate response to exercise in patients after transplantation. The maximal oxygen uptake is normally correlated with maximum heart rate, and it is unclear whether the reduced peak heart rate is a consequence of or the cause of the decreased exercise capacity in these patients. The denervated heart 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 exercise41,42 and hence reduces the exercise capacity. In heart transplant recipients with their diastolic dysfunction, the ability to augment stoke volume is limited providing a pathophysiological reason for their reduced exercise capacity.43 In the present study a weak but significant correlation was found between the improvement in maximal oxygen uptake at one year post transplantation and the peak heart rate achieved which supports the theory of a chronotropic incompetence due to a denervated heart contributing to continuing exercise limitation after transplantation. This confirms the findings of Osada et al7 who found a similar relationship between peak heart rate and maximal oxygen uptake at 6 months post transplant (r = 0.32; p = 0.04). The correlation between these parameters improved at 3 years post transplantation (r = 0.47; p= 0.0002). Givertz et al13 showed a 43% increase in maximal oxygen uptake at one year post transplantation but that compared with control subjects maximal exercise capacity was subnormal in transplant recipients. This group also showed that the physiological response to exercise remained abnormal in the transplant recipients with a reduced rate of heart rate rise and reductions in peak exercise heart rate. The authors suggested that this reduced exercise capacity compared to control subjects was associated with chronotropic incompetence that is due in large part to cardiac denervation.
The temporal relationship in the ability to achieve age-predicted maximum heart rate was studied. The percentage of patients able to achieve > or = to 80% of age-predicted maximum increased from 6% at one year post transplantation to 32% at 3 years and 45% at 5 years. However the correlation between maximal oxygen uptake and peak heart rate or heart rate response on exertion, whilst significant, were weak both at one and 5 years post transplantation (highest correlation coefficient r = 0.48). These data indicate that the inability of cardiac transplant recipients to achieve normal exercise performance is not completely explained by a limitation of heart rate responsiveness.
Although studies in dogs and monkeys have shown histological and functional evidence of reinnervation with time after cardiac transplantation, 44, 45, 46, 47, 48, 49 the evidence for reinnervation in humans after transplantation is conflicting. Histological studies in humans have failed to document any evidence of reinnervation. For example, using electron microscopy, Rowan and Billingham50 were unable to find evidence of nerve growth in endomyocardial biopsies from 13 long-term heart transplant survivors as late as 12 years after transplantation. Similarly, Regitz et al51 found that catecholamines were undetectable in endomyocardial biopsies from long-term transplant recipients. In contrast to these histological studies, functional studies have suggested that reinnervation may occur late after transplant in humans. Lord et al 52 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 patients with partial reinnervation, causing a positive chronotropic and inotropic status, may be able to do more exercise. In the present study the data suggest that although there is a significant improvement in the number of patients achieving a higher peak heart rate and in the heart rate response at 5 years compared to one year post transplant the responsiveness is less than control subjects. This suggests that functionally significant reinnervation does not occur during the first 5 years post transplantation. This confirms the findings of Givertz et al 13 who also showed that at one year post transplantation, peak exercise capacity and chronotropic responsiveness are subnormal and that there was no further improvement in peak exercise capacity or chronotropic responsiveness as late as 5 years after transplantation.
The ventilatory response to exercise in our patients was similar to that reported in previous studies. 19,53 Before transplantation, VE/VCO2 was elevated and decreased significantly following transplantation, but remained higher than normal at one-year post transplantation. The ventilatory response remained stable, but higher, than normal up to 5 years post transplant. In addition, the present study showed that despite significant improvement in VD/VT after transplantation, it remained higher than normal. It is not known why ventilatory and gas exchange abnormalities on exercise fail to resolve completely after heart transplantation. One possible explanation is that long standing pre-transplant heart failure leads to irreversible structural damage. Alternatively, these abnormal pulmonary responses may be functional in origin, resulting from a sub-optimal cardiac output response to exercise. Heart failure is characterised by excessive ventilatory response to exercise (54). Patients with chronic heart failure also have increased “wasted ventilation” as assessed by VD/VT. 54 It has been shown in our previous studies that the ventilatory response and VD/VT in heart failure are positively correlated suggesting that they may be causally linked. The observation of a raised degree of “wasted ventilation” or increased VD/VT is of great importance. Elevated VD/VT values during exercise may be due to a reduction in pulmonary blood flow via a reduced cardiac output. This suggests that pathologically high ventilation/perfusion ratio mismatching occur in patients after transplantation without significantly low ventilation/perfusion mismatching (normal A-aO2 gradient post transplantation). This places the abnormality on the pulmonary circulation rather than the airway side of the gas exchange unit and suggests perfusion is reduced in well-ventilated lungs.55 It is therefore postulated that the failure to increase cardiac output to match ventilation during exercise increases the proportion of lung units with high ventilation/perfusion ratio thereby increasing the VD/VT and consequently leading to an excessive ventilatory response to exercise.54 Although cardiac output is markedly improved after heart transplantation, due to a chronotropic and inotropic incompetence associated with denervation, its response to exercise remains sub-normal44 and this may explain the residual abnormalities of ventilatory and gas exchange responses to exercise following transplantation.
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