Doi:10.1016/j.healun.2003.12.010

Time Course of Physical Reconditioning During Exercise
Rehabilitation Late After Heart Transplantation
Uwe Tegtbur, MD,a Martin W. Busse, MD,b Karsten Jung,a Klaus Pethig, MD,c and Axel Haverich, MDd Background:
Exercise rehabilitation improves physical capacity in heart transplant recipients. The time course ofphysical reconditioning and skeletal muscle adaptation late after transplantation are unknown.
Methods:
Twenty-one heart transplant recipients, at 5.2 Ϯ 2.1 years after transplantation, completed 1 year ofan individually tailored home ergometer-training program (2.1 Ϯ 0.7 sessions weekly with matchedheart rates, intensity at 10% below anaerobic threshold). We analyzed time course of physicalreconditioning data for each home-training session (n ϭ 2,396). Constant-load tests with consistentblood lactate concentrations were performed quarterly (n ϭ 105) to estimate the time course ofskeletal muscle adaptation. Nine heart transplant recipients served as a control group (CG).
Results:
After 12 months, exercise capacity for matched heart rates (112 Ϯ 11 beats/min; CG, 114 Ϯ 8beats/min) increased by 35% Ϯ 19% (from 43 Ϯ 14 to 58 Ϯ 18 W; p Ͻ 0.001; CG, 53 Ϯ 18 to 54 Ϯ 18 W); 24% of the increase was caused by improved skeletal muscle function and 11% by centralfunctioning. Physical reconditioning showed its greatest increase within the first 3 months (ϩ18%;p Ͻ 0.001); 50% of the increase consisted of better skeletal muscle or central functioning. Betweenthe 4th and 12th months, exercise capacity increased continuously (ϩ15%; p Ͻ 0.001), mainlybecause of better skeletal muscle functioning.
Conclusions:
The persistent improvement in exercise capacity along with consistent lactate concentrationsduring 12 months of training indicates that exercise training could counteract the negative sideeffects of immunosuppressive treatment on skeletal muscles. Even late after heart transplantation,physical training should be performed regularly to prevent the accelerated decrease in exercisecapacity and in skeletal muscle function. J Heart Lung Transplant 2005;24:270 – 4. Copyright 2005by the International Society for Heart and Lung Transplantation.
Although improved survival rates have been shown after Cyclosporine and corticosteroid administration after HTX heart transplantation (HTX), exercise tolerance still is induces skeletal muscle dysfunction in slow-twitch fibers, decreased long after HTX, even with normal function of correlated with increased blood lactate concentrations the graft. Limiting factors are decreased chronotropic during physical Negative side effects of immu- competence, endothelial dysfunction, and changes in nosuppressive therapy on skeletal muscle function and inactivity are thought to contribute to the significant maximum exercise capacity increases from 40% to 50% of decrease in exercise capacity late after HTX.
normal values after HTX to 60% at 2 years after Although recent trials are encouraging and demon- After the 2nd year after transplantation, peak oxygen strate improved physical endurance, peak oxygen con- consumption decreases at a mean rate of approximately sumption, and quality of life in the 1st months after 5% per whereas cross-sectional data in healthy HTX, little is known about the time course of improve- adults has shown a decrease of only 1.5% each ment in exercise capacity caused by physical train-It remains unclear whether a systematic, long-term training approach can partially reverse the From the aDepartments for Sports Medicine and dCardiovascular and accelerated decrease in exercise capacity and the skel- Thoracic Surgery, Medical School of Hannover, bInstitute of Sports etal muscle dysfunction late after HTX.
Medicine, University of Leipzig; and cDepartment of Internal Medi- Therefore, in this study, we assessed the time course cine, Cardiology, Friedrich Schiller University Jena, Germany.
of physical reconditioning and skeletal muscle adapta- Submitted September 17, 2003; revised December 3, 2003; ac- tion during 12 months of controlled exercise training at Reprint requests: Uwe Tegtbur, MD, Medizinische Hochschule 5 years after heart transplantation.
Hannover, Sportmedizin, Carl-Neuberg-Str. 1, 30625 Hannover, Ger-many. Telephone: ϩ49511-5325499. Fax: ϩ49511-5328199. E-mail: Patients
Copyright 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ tion), observed consecutively between December 1999 The Journal of Heart and Lung Transplantation and March 2000 in the Hannover HTX outpatient with a 6-minute warm-up, a 20-minute constant-load program, were asked to participate in the study. They were not performing regular physical training and were training intensity was set at 10% less than the anaerobic not particularly motivated in exercise training. Exclu- threshold. The patients were asked to exercise every sion criteria were graft dysfunction (ejection fraction Ͻ other day on the home ergometer. The smart card 50%, significant allograft vasculopathy with luminal down-regulated the training intensity when the heart obstruction Ͼ 50%, or ongoing rejection), peripheral rate exceeded the prescribed training heart rate (80%– arterial disease, and any musculoskeletal disorders.
90% of maximum heart rate). The individual training Twenty-one of 25 HTX recipients, enrolled in the heart rate did not change during the 12 months, and the training group (TG) and completed 12 months of respecitve training intensities were readjusted monthly.
exercise training and testing (TG, n ϭ 21; 5.2 Ϯ 2.1years after transplantation; aged 54 Ϯ 7 years; weight, Time Course of Physical Reconditioning
85 Ϯ 9 kg; height, 175 Ϯ 9 cm; 19 men and 2 women).
Improved exercise capacity for a given heart rate Nine of 15 HTX recipients, who were assigned prospec- reflects the increase in central adaptations (decreased tively to the control group (CG), completed all exercise catecholamines, decreased cardiac beta-adrenoreceptor testing protocols (CG, n ϭ 9; 4.2 Ϯ 2.3 years after sensitivity, increased stroke volume, etc.) and in skele- transplantation; aged 55 Ϯ 8 years; weight, 91 Ϯ 13 kg; height, 177 Ϯ 10 cm; 8 men and 1 women). They formed the home ergometer training with matched performed usual daily physical activities without partic- heart rates. Mean training heart rate, mean training ipating in regular training. We excluded 4 patients workload, and rate of perceived exertion in each home- because of medical limitations unrelated to the training training session (n ϭ 2,396) were stored on the smart program (TG, n ϭ 2; CG, n ϭ 2), and 6 refused further card. The smart cards were read monthly, and the time participation after initial exercise testing (TG, n ϭ 2; course of increase in exercise capacity for the individ- CG, n ϭ 4). Underlying diseases of the TG (CG) were ually matched heart rate was calculated. The control ischemic heart disease in 6 patients (2), dilated cardio- group performed constant-exercise tests with matched myopathy in 14 (6), and right ventricular dysplasia in heart rates before and after the control period.
one (1). Pharmacologic treatment consisted of double-or triple-immunosuppression with cyclosporine (TG, n Time Course of Skeletal Muscle Adaptation
ϭ 20; CG, n ϭ 8), tacrolimus (TG, n ϭ 1; CG, n ϭ 1), Improved exercise capacity with consistent lactate con-prednisolone (TG, n ϭ 21; CG, n ϭ 9), and azathioprine centration reflects increased skeletal muscle functioning (TG, n ϭ 10; CG, n ϭ 5). All patients received (perfusion, oxidative capacity, muscle fiber I and fiber II lipid-decreasing therapy and anti-hypertensive medica- structure, Therefore, patients performed 28- tion. Treatment did not change during the trial. All minute constant-load tests with electrocardiographic mon- subjects agreed in written consent, according to the itoring at the 1st, 3rd, 6th, 9th, and 12th months in the protocol approved by the ethics committee of the outpatient transplant center. We measured blood lactate concentration every 5 minutes. We derived the individualtest intensity from actual home-training workload to pro- Cardiopulmonary Exercise Testing
duce consistent blood lactate concentrations in the re- At baseline and after the training or after the control tests. The patients in the CG underwent the same testing period, patients underwent incremental exercise tests before and after the control period.
on a cycle ergometer (ergoline 900, Ergoline; Bitz,Germany), starting at a power output of 20 W and Statistical Analysis
increasing by 10 W every minute. We measured blood Data are presented as mean Ϯ SD. We compared lactate concentration (Lactate-Analyser Ebio, Eppen- differences between the TG and the CG using an dorf; Berlin, Germany) to determine the anaerobic unpaired, 2-sided t-test. We used a paired, 2-sided t-test to determine differences within the groups before and electrocardiography. Respiratory gas exchange was after 12 months. Serial responses of home- training and measured on a breath-by-breath basis (Oxygen Delta of constant-load test data were compared using a 1-way System, Jaeger; Wuerzburg, Germany).
analysis of variance for repeated measures. If the anal-ysis of variance showed significant differences between 12-Month Exercise Training Program
the mean values, we determined the level of signifi- Patients performed exercise training at home on a cance by contrast. For all tests, a probability value of p smart card– guided cycle ergometer. In accordance Ͻ 0.05 was considered significant. We performed sta- with previously published training recommendations tistical analysis using a computer-assisted software for HTX recipients, the smart cards were programmed The Journal of Heart and Lung Transplantation Table 1. Cardiopulmonary Exercise Testing
Mean Ϯ SD. *p Ͻ 0.05; **p Ͻ 0.01 (significant differences within the groups before vs after exercise training or the control period). The changes in maximumworkload significantly differed between the groups (p Ͻ 0.01). CG, control group; HR, heart rate; RPE, rate of perceived exertion (Borg scale). TG, training group;VO maximum workload in the incremental tests. The over- Compliance
all increase in exercise capacity at 1 year was 35% Ϯ A total of 2,396 home-training sessions, 105 trimonthly 19% (43 Ϯ 14 vs 58 Ϯ 18 W, p Ͻ 0.001). The mean constant-load exercise tests, and 42 symptom- limited matched-training heart rate was 112 Ϯ 11 beats/min, incremental tests before and after the 12 months were representing 84% Ϯ 5% of maximum heart rate in the completed without adverse events. Compliance to pre- incremental tests. In the CG, exercise capacity for scribed home training was 2.1 Ϯ 0.7 sessions per week matched heart rates (114 Ϯ 8 vs 114 Ϯ 7 beats/min, of 3.5 sessions (63% Ϯ 17%). Patients missed 19% of the respectively) remained unchanged (53 Ϯ 18 vs 54 Ϯ 18 sessions because of vacation, 13% because of temporary W, not significant, p Ͻ 0.01 for differences between the illness, and 5% because of personal reasons.
Cardiopulmonary Exercise Testing
Time Course of Skeletal Muscle Adaptation
shows the mean values of exercise-related variables in the incremental tests at baseline and after constant-load intensity for consistent blood lactate con- 12 months. All patients ended the maximum, incremen- centrations. In the TG, the mean blood lactate remained tal exercise tests because of leg fatigue or dyspnea.
unchanged (2.5 Ϯ 0.7 mmol/liter), and the overallincrease in exercise capacity for consistent blood lac- Time Course of Physical Reconditioning
tate concentrations in 1 year was 24% Ϯ 16% (48 Ϯ 18 displays the time course of exercise capacity vs 59 Ϯ 18 W, p Ͻ 0.001). In the CG, exercise capacity for matched heart rates in the TG. Home-training work- for consistent mean blood lactate concentrations (1.8 Ϯ load in the 1st month corresponded to 42% Ϯ 6% of 0.6 vs 1.8 Ϯ 0.4 mmol/liter) were 53 Ϯ 18 W before and48 Ϯ 12 W after the control period, respectively, (notsignificant; p Ͻ 0.01 for differences between the TGand the CG).
DISCUSSION
We assessed the time course of physical reconditioningand skeletal muscle adaptation during 12 months ofexercise training in patients at 5 years after hearttransplantation. The main results of the study were that1) the 12-month increase in endurance exercise capac-ity was 35% (24% because of increased peripheralmuscle functioning and 11% because of increased cen-tral functioning); 2) physical reconditioning showed itsgreatest increase within the first 3 months (ϩ18%), 50%of the increase consisting of better skeletal muscle Figure 1. Time course of physical reconditioning. Mean values Ϯ SE
functioning, whereas the other 50% reflected changes per month of endurance exercise intensity and heart rate in 2,396 in central response; 3) during the last 9 months, the home-training sessions (114 Ϯ 11 per patient) in 21 heart transplant endurance capacity increased continuously (ϩ15%), recipients are displayed. The percentage increase in exercise intensity mainly because of better skeletal muscle functioning every 3 months is calculated. Patient perceived exertion (Borg scale,12 Ϯ 4 units) and heart rate (112 Ϯ 11 beats/min) did not change (ϩ15%); and 4) even late after heart transplantation, regular exercise training should be performed to pre- The Journal of Heart and Lung Transplantation skeletal muscle and on central functioning. In the first 3months of training, endurance exercise workload formatched heart rates showed the greatest increase by18%. In the following 9 months, we observed a furthersignificant increase by 17%. Changes in endurancecapacity for matched heart rates may be caused by 1 ormore of the following: decreased concentrations ofcirculating cardiac beta-adrenocep-tor increased stroke volume be-cause of increased blood increased parasym-pathetic and improved skeletal musclemetabolism.
Second, the HTX recipients performed sub-maximum constant-load exercise tests after every 3 months. In the Figure 2. Time course of skeletal muscle adaptation. Mean blood
1st quarter, exercise capacity for consistent blood lactate concentration and intensity during 28-minute constant-load lactate concentrations increased significantly by 9%. In tests in 21 heart transplant recipients Ϯ SE are displayed. The the 2nd, 3rd, and 4th quarters, exercise endurance percentage increase in exercise intensity every 3 months is calculated.
capacity significantly increased by 15%. Improved en- Mean blood lactate concentrations (between 2.4 and 2.6 mmol/liter) durance capacity with consistent lactate concentrations showed effects primarily on skeletal muscle function-ing. Among HTX recipients, exercise training could vent the accelerated decrease in exercise capacity increase perfusion, mitochondrial density and oxidative caused by immunosuppressive treatment and inactivity.
capacity of slow muscle fibers, resulting in smaller Peak oxygen consumption before introducing the train- ing program corresponded to the mean value calculated When we compared the results of matched heart rate from 1,200 HTX recipients (19.0 ml/min/kg), published and consistent blood lactate testing, 50% of the exercise by Ferretti et The magnitude of improvement in peak capacity increase during the first 3 months was because of oxygen consumption (ϩ9%) after 12 months of exercise better skeletal muscle functioning, whereas the other 50% training supports previous results (between ϩ8% and reflected changes in central response. During the follow- ϩ19%) gathered from long-term exercise-training studies ing 9 months, endurance capacity further increased con-initiated in the 1st year after Because the maxi- tinuously, mainly because of better skeletal muscle func- mum heart rate remained constant in our study and tioning. Results of previously published studies with because stroke volume has not been shown to improve healthy adults support this early central response and the after training in HTX recipients, the increase in peak continuously increased peripheral adaptation. Week-by- oxygen uptake can be established predominantly with week measurements of catecholamine response to exer- cise training in healthy adults has shown that the most oxygen consumption truly can be valued as a therapeutic rapid decrease occurs in the first 3 weeks of an endurance success because maximum exercise capacity decreases at training program. No further significant decrease in cate- an approximate rate of 5% per year late after heart cholamine concentration occurred in the following Otherwise, concentrations of the skeletal mus- Recent studies have shown that constant-load-testing cle enzymes of aerobic metabolism, the oxidative poten- protocols were more specific when used in assessing tial of muscle fibers, and the capacity peripheral muscle exercise-training effects in patients with chronic heart capillaries improved persistently during 24 months of failure and that they were more closely related to daily-life requirements than is peak oxygen consump- Cyclosporine inhibits the transformation of myosin Furthermore, advantages of sub-maximum con- heavy chains and oxidative enzymes from fast-to-slow stant testing are that it is non-exhaustive, safe, easy to muscle fiber types, but not from slow-to-fast fiber repeat, and has greater patient compliance.
Furthermore, long-term treatment with cor- To investigate the time course of exercise training ticosteroids induces skeletal muscle atrophy, mitochon- effects, we used 2 different endurance constant-test drial dysfunction, and oxidative damage, resulting in protocols in this study. First, we analyzed the data of greater blood lactate concentrations during exercise each home ergometer-training session (114 Ϯ 11 ses- The increase in blood lactate concentration correlates sions per patient per year). The monthly increase in positively with corticosteroid doses administered.
endurance exercise intensity with matched heart rates These results are supported by our finding that the reflects the time course of the summarized effects on constant-load exercise intensity with consistent lactate The Journal of Heart and Lung Transplantation concentrations decreased by 10% in the CG. In the TG, Functional endurance capacity in long-term treatment the significant and continuous increase in exercise after heart transplantation. Cardiology 2003;99:171–6.
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