Both cardiac and peripheral factors may contribute to the reduced physical capacity of heart transplant recipients (HTR) (14,18). Longer ischemic times and more frequent rejection episodes do not appear to adversely affect exercise capacity. Resting pulmonary vascular resistance powerfully predicts exercise capacity, with higher pulmonary vascular resistance associated with decreased exercise capacity. Female and older HTR have a lower absolute exercise capacity, but achieve a higher proportion of their predicted capacity. Older donor age negatively affects exercise capacity, but the effect appears to be minimal (21). The absence of chronic corticosteroid administration is generally associated with an improved exercise capacity (21).
Decreased cardiac adaptation to exercise may occur as a result of denervation. A study by Schwaiblmaier et al. (23) documented that HTR with reinnervation have a greater capacity for exercise than those with denervation. Bengel et al. (2) stated that reinnervation is an independent determinant for improvement in exercise capacity. Peripheral factors may include decreased skeletal muscle function, impaired vasodilatation, and deconditioning (18). A major problem in HTR with respect to the achievable exercise performance is the state of heart failure before heart transplantation (HTX), which is often associated with abnormalities in skeletal muscle metabolism (16). Without proper exercise training these aberrations may persist after HTX. The causes of the modified skeletal muscle metabolism after HTX may persist in addition to lifelong immunosuppressant with cyclosporine, azathioprine, and corticosteroids (11). This modified skeletal muscle metabolism resulted from administration of prednisolone in humans (7) and of cyclosporine in animal models (6,15). Thus, the absence of chronic corticosteroid administration is associated with an improved exercise capacity (21).
The maximal rate of oxygen uptake (V̇O2) during exercise is markedly reduced (approx. 45–60%) in HTR, compared with peak aerobic performance of healthy sedentary controls (1,2,4,12,14,18). Badenhop (1) reported an improved performance in HTR, expressed in metabolic equivalents (MET) from 60% to approximately 70%, based on age-adjusted values. In a recent study, Schmid et al. (22) reported that controlled endurance training 3× wk−1 for 40 min at an intensity of 60% of the HR reserve resulted in an improvement in V̇O2max from 16.7 ± 1.6 to 19.5 ± 2.4 mL·kg−1·min−1. These and additional authors (19) also reported that endothelial function of conduit vessels and systemic responsiveness to nitric-oxide-synthase inhibition can be improved with regular aerobic training after HTX. Kavanagh et al. (8) studied HTR who exercised 24–32 km·wk−1. He found maximal power output of up to 170 W, and an improvement in V̇O2max of 11 mL·kg−1·min−1.
During the last decade, exercise has become the accepted treatment after HTX. Training therapy should be viewed as an essential part in postoperative management of HTR (9,10,14,26). Limited data on high volume and intensity of long-term exercise training in HTR is available. Our study hypothesis was that HTR would not achieve normal healthy exercise performance levels using a comparable training regimen. The aim of this study was to evaluate exercise performance levels in HTR performing high-volume and -intensity exercise training with those of HTR undergoing a regular rehabilitation program and with those of sedentary healthy controls.
We investigated four groups of male subjects of comparable age and height (Table 1). Three groups were asymptomatic, otherwise healthy HTR. Two of the HTR groups were engaged in a regular ambulatory and/or home-based rehabilitation-training program for at least 2 yr, consisting of 30–40 min exercise training at 50–60% of HR reserve performed 1–2 d·wk−1. Both groups were separated, with respect to the state of reinnervation to a denervated (HTR-D) and a reinnervated (HTR-R) group. The control group consisted of sedentary healthy subjects (SHS). Healthy subjects claimed to be medication free (Table 1). The criteria for assignment into group HTR-D and HTR-R were the HR increase from rest to maximal power output (Pmax) during the incremental cycle ergometer test (28) and the HR response during recovery (HTR-D = HR increase < 36 bpm and a HR increase during the postexercise phase; HTR-R = HR increase > 36 bpm and a decrease in HR immediately after exercise).
In preparation for the Ninth European Heart and Lung Transplant Games in Klagenfurt, Austria, 2002, 14 interested HTR volunteered to take part in training for the games, starting in 1999. Of the 14 HTR participants, 4 were denervated and 10 were reinnervated. The reason for heart transplantation for these participants was acute intervention. One patient had developed acute complications resulting from aortic valve reconstruction, and the other from PTCA. Waiting time for transplantation for all other CHF patients was 2–4 yr. The etiology of the CHF was an infectious myocarditis.
At the end of this investigation (July 2003), all endurance-trained heart transplant recipients (HTR-ET) were reinnervated. During the final 2 yr, two patients dropped out due to lack of available time for training. Two HTR participants had been heavily involved in athletics earlier in life. All other participants in the endurance-training program were not regularly involved in physical activity or exercise before the transplantation. All patients who exercised aggressively responded with excellent improvement in fitness.
Within this training study, the third HTR (HTR-ET) group supervised performed high-volume and -intensity endurance exercise training for at least 2 yr. Weekly net running or cycle-training time was in the range of 7–10 h·wk−1 (except two subjects with 15–20 h·wk−1) at an intensity slightly below (approx. 5%) the respiratory compensation point. Training intensity was controlled by heart-rate monitoring (Sporttester Vantage NV, Polar Electro, Finland). In this cross-sectional study, the HTR-ET group was compared with the denervated heart (HTR-D) and reinnervated heart (HTR-R) groups, and with sedentary healthy subjects (SHS).
Anthropometric data of the patients, time after transplantation, echocardiographic measurement of left ventricular ejection fraction at rest (LVEF), and the number of participants undergoing transplantation because of ischemic cardiomyopathy or nonischemic cardiomyopathy are depicted in Table 1. None of the participants had an acute rejection, clinically significant transplant vasculopathy, or allograft dysfunction, as determined by clinical evaluation, echocardiography, coronary angiography, and endomyocardial biopsy before enrollment. At the time of the study, participants received appropriate and not all-inclusive maintenance immunosuppressive therapy with cyclosporin A, prednisolone, azathioprine, tacrolimus, and mycophenolatmofetil. None of the participants in the group of HTR-ET received chronic corticosteroids. Concomitant individual medical treatment in all patients consisted of angiotensin-converting enzyme inhibitors, calcium channel blockers, alpha-blockers, beta-blockers, angiotensin II blockers, and diuretics.
Each participant performed an incremental exercise test on a cycle ergometer in an upright position to the limit of tolerance. The exercise test started at an initial level of 20 W followed by 10-, 15-, or 20-W increments (adjusted for individual capability) every minute until exhaustion. The ECG was monitored continuously, and a 12-lead ECG was recorded at rest, during the last 10 s of each increment, at the end of the exercise test and during recovery. HR was recorded continuously in 5-s intervals using Polar Vantage NV telemetry (Polar Electro). HR at Pmax (HRmax) and peak HR (HRpeak) were determined. Blood pressure was measured by the auscultation method at rest, at the end of each exercise stage, and during recovery.
Respiratory gas exchange measures were analyzed continuously during all tests in breath-by-breath mode (SensorMedics 2900, Yorba Linda, CA). Carbon dioxide production (CO2) and oxygen uptake (O2) were measured using rapid gas analyzers, while a turbine analyzed the ventilatory flow. CO2 was analyzed paramagnetically, while O2 was analyzed by infrared absorption. All instruments were calibrated before each test, and the necessary environmental adjustments were made according to manufacturer’s guidelines.
Capillary blood samples for blood lactate concentration (LA) analysis were collected from the hyperemic ear lobe at rest, during the last 10 s of each increment, at the end of the exercise test, and every min of a 6-min recovery. LA was measured by a fully enzymatic amperometric method in whole blood using the Eppendorf automatic analyzer (EBIO 6666, Eppendorf, Germany).
As in previous studies, respiratory gas exchange variables (24) and LA performance curves (5,20) were used to determine three phases of energy supply according to Skinner and McLellan (25). The lowest ventilatory equivalent for oxygen (V̇E/V̇O2) and the lowest ventilatory equivalent of carbon dioxide (V̇E/V̇CO2) were determined to describe the three phases of energy supply (24,25).
Additionally, the first (LTP1) and the second lactate turn point (LTP2) were determined by means of linear regression break point analysis, as presented earlier (5,20). The study protocol was approved by the Institutional Ethics Committee of the University of Vienna, and a signed written informed consent was obtained from each participant.
Repeated measures analysis of variance (RM-ANOVA) was used to determine differences between groups at rest, at the turn points in respiratory gas exchange variables and blood lactate concentration and maximal power output (Pmax) for selected variables. Post hoc comparisons were made employing a Tukey HSD post hoc test for unpaired N. RM-ANOVA was used to determine significant differences between the respiratory gas exchange and lactate turn points. Post hoc comparisons were made employing the LSD post hoc test for paired N. The level of statistical significance was set at alpha P < 0.05.
There was no significant difference for age, height, LVEF, and time after HTX between groups. Body weight in HTR-R and HTR-D was significantly higher than in HTR-ET and SHS (Table 1). During the entire training period, no complications occurred that would lead to long-lasting training interruptions.
Power output, oxygen uptake, and HR response during cycle ergometer tests for all groups are depicted in Tables 2–4. No significant differences were found between the V̇E/V̇O2 and LTP1 and between the V̇E/V̇CO2 and LTP2 for P, V̇O2, HR, and LA at these turn points for all groups. Power output and oxygen uptake were significantly higher in HTR-ET compared with all other groups.
HRpeak in HTR-ET was significantly higher than in HTR-D and HTR-R, but not significantly different from SHS. HRmax of HTR-D and HTR-R were significantly different P < 0.05 (125 ± 16 bpm vs 142 ± 10 bpm). In HTR-D, HRmax (125 ± 16 bpm) was significantly lower than HRpeak in the postexercise period (135 ± 16 bpm). Furthermore, the HR increase of HTR-ET was significantly higher than in both HTR-D and HTR-R, and significantly lower than in SHS (Table 4).
Blood LA concentrations measured at rest and during the incremental cycle ergometer test are shown in Figure 1. There were significant differences in LAmax between HTR-ET (9.9 ± 2.2) and the other HTR groups (HTR-D = 5.5 ± 1.5; HTR-R = 5.1 ± 1.0). There was no significant difference in LA concentration between HTR-ET and SHS (9.2 ± 2.1). Percent Pmax at LTP2 and at lowest V̇E/V̇CO2 was not significantly different between all groups, and was found around 75% of Pmax, indicating similar exertion of subjects.
Contrary to our hypothesis, the results of this cross-sectional study suggest that controlled high-volume and -intensity training in HTR may yield results that are similar to or that even exceed levels of exercise performance of sedentary healthy subjects of similar age. None of our HTR-ET received corticosteroid therapy, and heart transplantation in these patients occurred as a result of nonischemic cardiomyopathy, which is a better precondition for improved exercise performance and training (21); however, this does not explain above-average performance of this patient population.
It is generally accepted that physical exercise after HTX significantly improves exercise performance of HTR, as documented in the literature (1,8–10,17,22). These authors reported an increase of 15–25% in exercise performance in HTR after training. In our study, the HTR-ET achieved double or even greater values for V̇O2max compared with the other HTR groups. The exceptionally high performance of our HTR-ET group may be attributed to a high weekly training volume of 7–20 h, which was 4 times higher than the other groups, and 2–8 times higher than published data (8).
Comparing our results with findings of other investigations (2,8,13,29), our HTR displayed a resting HR that was significantly higher than that of SHS. The HR response of HTR-D and HTR-R were comparable to those reported during submaximal and maximal performance by Wilson et al. (29). In contrast, our HTR-ET group showed a normal HR response during exercise, with HRmax comparable to healthy subjects. However, the HR increase in the HTR-ET group was significantly lower in contrast to SHS, which was likely due to a higher resting HR in the HTR-ET group. The HTR-R group showed a significantly higher HR increase in comparison with HTR-D group. However, the HR increase was still approximately 50% less than the HR increase of the HTR-ET group. In contrast to HTR-R, this manifestation of a physiological HR response in the HTR-ET group may be less due to more pronounced reinnervation alone than an improved performance of peripheral muscles that allows an improved cardiac functioning.
Marconi et al. (13) found that children after heart reinnervation (age 14 ± 4 yr) achieved a HRmax of 177 ± 16 bpm, which was significantly higher compared with that of children of the same age (age 14 ± 4 yr) with still denervated hearts (HRmax 151 ± 16 bpm), and similar to that of a healthy age-matched group (13 ± 1 yr; HRmax 180 ± 10 bpm). However, children with reinnervated hearts had a normal HR response during exercise, but still a lower V̇O2max compared with the healthy controls. Our findings are in agreement with Marconi’s interpretation of a muscular insufficiency, indicating that the maximal aerobic power of HTR is not only limited by pharmacological muscle deterioration, but may also be limited by a lack of adequate exercise training.
Previous studies have reported that heart transplant recipients with reinnervation have a greater capacity for exercise than those with denervation (2,23). However, Bengel et al. (3) found that sympathetic reinnervation after cardiac transplantation is not simply a function of time. Reinnervation is more likely to occur at a young age, after rapid und uncomplicated surgery, allowing for lower frequency of rejection. In a previous study, these authors (2) clearly identified an improved chronotropic and inotropic responsiveness to exercise in reinnervated recipients that is associated with higher exercise capacity and a trend toward improved activities of daily life. In our study, the HTR-R did not show any differences in performance compared with HTR-D. Our results do not disagree with the findings of Bengel et al. (2); however, our results differ from those of Bengel et al. (2) to the extent that we included only those HTR-R and HTR-D that performed only a comparable and moderate level of exercise training (1–2 h·wk−1). This suggests that the amount of training performed is responsible for the low exercise performance capacity in HTR.
Bengel et al. (3) documented that transplant recipients who had dilated nonischemic cardiomyopathy before surgery can expect to have a higher likelihood of future reinnervation. However, none of our HTR-ET had ischemic cardiomyopathy before surgery. Bengel et al. (3) reported that young heart transplant recipients are frequently candidates for reinnervation in comparison to older heart transplant patients. To reduce the influence of age on exercise performance, we studied only HTR of similar age. Based on this age of our HTR groups, we are not able to directly compare our results with those of Bengel et al. (3).
Squires et al. (27) showed that 1 yr after cardiac transplantation, approximately one third of the subjects had partial normalization of the HR response to graded exercise. However, these authors concluded that a higher peak exercise HR and a larger HR reserve did not result in better aerobic exercise capacity.
Remarkably, all of our HTR-ET performed well above average, and exhibited all the manifestations of reinnervated heart transplant recipients. Based on our data, it is not clear whether the exercise training alone is responsible for the improvement in reinnervation, or whether reinnervated HTR are better suited for training in comparison to other groups.
With respect to the markedly improved aerobic capacity of the HTR-ET in contrast to SHS and both other groups, the HTR-ET group showed a significant rightward shift of the lactate performance curve with similar maximal blood lactate concentration, compared with the healthy untrained subjects. The anaerobiosis of peripheral muscles in the HTR-ET group occurred at a much higher workload during an incremental exercise test, compared with all other groups in our study.
Patients with congestive heart failure have not only a centrally impaired O2 delivery, and therefore a limited capacity to produce energy aerobically, but also muscular impairment caused by chronic deconditioning (16). Although HTR-D and HTR-R performed a regular rehabilitation-training program, they had low blood LA levels. This corroborates the view of still degenerated skeletal muscles. Our results from HTR-ET suggest that higher-volume and -intensity training may override the peripheral metabolic aerobic incompetence that was reflected by a normal maximal blood lactate concentration similar to the healthy control group.
One limitation of the study was the cross-sectional approach, as exercise performance was not experimentally evaluated before or shortly after heart transplantation. Exercise performance in the HTR-ET group might not be an effect of training alone; it might also be influenced by a higher pretraining exercise performance level or by genetic potential. A second limitation of the study might have been the methods used to identify reinnervated patients. Independent of innervation status, both groups with regular rehabilitation-training regimens had lower exercise performance results.
Adequately adopted high-volume and -intensity designed endurance training can stimulate muscle development despite immunosuppressive therapy, and might greatly benefit the HTR to achieve a level of physical performance that is similar to or greater than that of healthy subjects.
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