Share this article on:

Influence of post-surgery time after cardiac transplantation on exercise responses


Medicine & Science in Sports & Exercise: February 1996 - Volume 28 - Issue 2 - p 171-175
Clinical Studies: Clinical Investigations

To test the hypothesis that exercise response changes with time after cardiac transplantation, we investigated the cardiorespiratory responses of nine orthotopic heart transplant patients (52.4 ± 2 yr) during graded exercise tests (30 W·3 min-1) done at 1, 3, 6, 9, and 12 months post-surgery. At peak exercise, 1) oxygen uptake per kg of body weight(˙VO2), minute ventilation (˙VE) and oxygen pulse (O2 pulse) did not change significantly between 1 and 12 months post-surgery; 2) transplanted heart rate (HRt) and delta heart rate (peak exercise heart rate - resting heart rate) increased significantly over time (P < 0.01; P < 0.05) with a marked increase between 1 and 3 months(P < 0.05); and (3) a significant negative correlation existed between O2 pulse and HRt (r = -0.36, P < 0.05), whereas no correlation was found between delta heart rate and delta˙VO2 (peak exercise ˙VO2 - resting ˙VO2, 1·min-1). During submaximal exercise, HRt increased significantly over time (P < 0.001); ˙VO2, ˙VE, and O2 pulse showed no significant change; and the˙VO2-HRt relationship shifted toward higher values of HRt. We conclude that, in the absence of formal physical training, the exercise response of denervated transplanted heart increases in relation to post-surgery time but does not affect oxygen uptake at submaximal and peak levels of exercise.

Service d'Exploration de la Fonction Respiratoire; Service de Chirurgie Cardiovasculaire et Thoracique, Hôpital Arnaud de Villeneuve, 34295 Montpellier Cedex 5, FRANCE; and Laboratoire Sport, Santé et Développement, University of Montpellier I, 34090 Montpellier, FRANCE

Submitted for publication September 1994.

Accepted for publication April 1995.

This work was supported by an “Institut National de la Santé et de la Recherche Médicale” grant CRE 93 1102.

Address for correspondence: Jacques Mercier, M.D., Ph.D., Service d'Exploration de la Fonction Respiratoire, Hôpital Arnaud de Villeneuve, 34295 Montpellier Cedex 5, France.

Cardiac transplantation is the treatment of choice for individuals with end-stage heart disease (1,11). Fragomeni and Kaye (9) reported actuarial survival rates of 84.5% for the first 5 yr and 72.6% 10 yr post-surgery with the use of triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone). The high survival rates of patients after orthotopic heart transplantation have led many investigators to study the cardiorespiratory and metabolic responses to exercise in patients with orthotopic heart transplantation (OHT) (16,21,25,27). These studies reported that exercise capacity, although improved after heart transplantation, does not completely normalize. Cardiorespiratory and metabolic disorders such as low aerobic capacity, reduced O2 pulse, early activation of lactic metabolism, and reduced ventilatory efficiency persist in patients with OHT after cardiac transplantation.

Curiously, the influence of post-surgery time on the exercise responses of patients with OHT has been insufficiently investigated. To our knowledge, only Niset et al. (21) and Rudas et al.(26) compared cardiorespiratory and hemodynamic responses during exercise in patients with OHT 1-3 months and 12 months after surgery, but their patients with OHT were participating in a rehabilitation program. Consequently, it was difficult to differentiate between the effects of post-surgery time and training during rehabilitation on the exercise responses of these patients. Nevertheless, post-surgery time seems to be an important consideration. Indeed, it has been reported that β-adrenoceptors, which play a role in denervated heart rate regulation, change with time after cardiac transplantation (4,28,30,33). In relation to post-surgery time, immunosuppressive therapy may also influence cardiorespiratory and metabolic responses to exercise, because we recently reported a detrimental effect of cyclosporine on skeletal muscle mitochondria(14,20). The persistence of impaired pulmonary gas exchanges (3,22) as well as abnormalities of skeletal muscle (29) may also influence with time the exercise response of patients with OHT. Based on these findings we hypothesized that the cardiorespiratory and metabolic responses to exercise in patients with OHT might change with post-surgery time independently of training or rejection.

In an attempt to verify this hypothesis we investigated the exercise responses of patients with OHT not participating in formal exercise training and free of rejection during the year following cardiac transplantation. More specifically, we studied whether transplanted heart rate and oxygen uptake measured during submaximal exercise and at peak exercise changed with post-surgery time.

Back to Top | Article Outline



Nine patients with OHT (age = 52.4 ± 2 yr, weight = 65.7 ± 5.5 kg, height = 171 ± 2 cm) participated in this study. Their post-surgery admission to the study was between 1 and 6 months (1 month for 6 patients, 3 months for 2 patients, and 6 months for 1 patient). Before surgery, all subjects had been classified according to the New York Heart Association (NYHA) criteria as functional class IV, with etiology including ischemic or idiopathic cardiomyopathy. Average donor age was 30 ± 2.8 yr. Donor-recipient matches were appropriate, the recipient in all cases receiving a graft from a donor of similar or greater anthropometric characteristics. After surgery, all patients received standard triple-drug therapy for immunosuppression (cyclosporine, azathioprine, and prednisone). None received β-blockers. At the time of the study, all were functional class I according to NYHA criteria. All were determined to be free of acute rejection and systemic infection. Their physical activity was limited to the activities of daily living and none participated in a specific rehabilitation program or athletic training. The aim and protocol were explained and written informed consent was obtained from all patients with OHT.

Back to Top | Article Outline


The exercise tests were conducted on a cycle ergometer (818, Monark, Varberg, Sweden). Respiratory variables and gas exchanges were measured with a breath by breath automated exercise metabolic system (CPX, Medical Graphics, St. Paul, MN). Briefly, subjects breathed via a low-resistance breathing valve(2700, Hans Rudolph, Kansas City, MO). Expiratory airflow was measured with a pneumotachograph (Type 3,3800, Hans Rudolph) connected to a pressure transducer (DP 250-14, Validyne Engineering Corp., Northridge, CA). Expired gases were analyzed for O2 with a zirconia solid electrolyte O2 analyzer and for CO2 with an infrared analyzer. Before each test the volume was calibrated by five inspiratory strokes with a 3-1 pump; the gas analyzers, with two mixtures of gases of known oxygen and carbon dioxide concentration (20.9% O2, 0.03% CO2; 12% O2, 5% CO2). During exercise, oxygen saturation (SaO2) was followed with an ear oxymeter (Spacelabs, Redmond, WA) and a three-lead ECG (D2, V2, V5) was continuously monitored with a cardioscope (Q 3000, Quinton, Seattle, WA) for the measurement of denervated transplanted heart rate. Finally, systolic blood pressure (SBP) and diastolic blood pressure(DBP) were measured with a cuff blood pressure transducer (410, Quinton).

Back to Top | Article Outline


Exercise tests were done at 1, 3, 6, 9, and 12 months post-surgery. Each patient with OHT performed at least three exercise tests in the year after surgery, with the result that for each test (1 month, 3 months, etc.) there were always at least six patients who had performed the test.

The day of experimentation, the patients with OHT arrived at the laboratory at 9 a.m. and received standardized instructions as to the testing procedure. Patients with OHT underwent a complete physical examination and a resting electrocardiogram. Each patient the performed a graded symptom-limited exercise test in seated position. The exercise began with a 30-W workload that increased 30 W every 3 min. Oxygen uptake (˙VO2, ml·kg-1·min-1) was calculated every minute over the last 20 s from expired gases and minute ventilation (˙VE). Transplanted heart rate (HRt, beats·min-1) was calculated at the end of every minute over 10 complexes. From ˙VO2 and HRt we calculated oxygen pulse (O2 pulse, ml·kg-1·beat-1). SBP and DBP were measured every 3 min up to the end of exercise. Indications for halting the test before the appearance of a plateau ˙VO2 were as follows: 1) adverse symptoms(as the transplanted heart does not sense anginal pain): severe dyspnea, light-headedness and faintness, confusion, severe fatigue, inability to maintain the pedaling frequency (50 rpm); 2) adverse signs: facial pallor, heart rate or blood pressure drop, or failure of either to rise with increasing effort, rapid increase in systolic and/or diastolic blood pressure exceeding 210/115 mm Hg for a moderate intensity of exercise (30 or 60 W), decrease of over 4% in SaO2; and 3) adverse electrocardiographic changes: frequent complex ventricular extrasystoles, ventricular tachycardia, sustained supraventricular tachycardia, atrial fibrillation, second- or third-degree heart block, severe ST segment depression (horizontal or downsloping greater than 4 mm). During the 5 min of recovery we followed three-lead ECG, HRt, SBP, and DBP.

Back to Top | Article Outline

Statistical Analyses

Values of all variables are expressed by the mean ± SE (mean standard error). A one-way analysis of variance (one-way ANOVA) was performed to assess the effect of post-surgery time on weight and cardiorespiratory variables measured at rest and at peak exercise. A two-way analysis of variance (two-way ANOVA) was applied to assess the effects of power during exercise, post-surgery time, and the interaction between power and post-surgery time (power × post-surgery time). When an ANOVAF-ratio was significant, a post-hoc analysis using the Tukey test was performed to identify the differences. For all analyses,P < 0.05 was accepted as significant.

Back to Top | Article Outline


During graded exercise testing, none of patients with OHT developed a decrease of over 4% in SaO2 or adverse electrocardiogram changes such as severe ST segment depression, tachycardia, or atrial fibrillation. All patients stopped the exercise test because of fatigue and pain in the lower limbs.

Mean values of weight, HRt, and blood pressure measured at rest in relation to post-surgery time are listed in Table 1. At rest, the patients with OHT presented a persistent tachycardia 1 month post-surgery (90 ± 7 beats·min-1), which increased on follow-up examination at 12 months (104 ± 5 beats·min-1). However, no significant change was noted for the resting variables in relation to post-surgery time.

At peak exercise (Fig. 1), ˙VO2 normalized by weight, ˙VE, and O2 pulse did not change significantly between 1 and 12 months post-surgery. HRt and delta heart rate (peak exercise heart rate - resting heart rate) increased significantly over time(F = 3.67, P < 0.01; F = 2.75, P< 0.05). For these last two variables, marked increases appeared especially between 1 and 3 months post-surgery (P < 0.05). From 3 months to subsequent times, the changes were not significant. A significant negative correlation was found between O2 pulse and HRt measured at peak exercise (r = -0.36, P < 0.05) whereas no correlation was noted between delta heart rate and delta ˙VO2 (peak exercise˙VO2 - resting ˙VO2, l·min-1). From 1 month to 12 months, peak ˙VO2 corresponded to 53 ± 6.4% of the predicted value (31). Peak HRt represented 58% of the theoretical maximal value at 1 month, 69% at 3 months, 72% at 6 months, 75% at 9 months, and 71% at 12 months.

˙VE, ˙VO2, HRt, and O2 pulse increased significantly from rest to peak exercise (P < 0.001). For the same step of graded exercise, only HRt increased significantly in relation to post-surgery time (F = 9.77, P < 0.001) whereas no significant change was found for ˙VE, ˙VO2, and O2 pulse. This result is clearly illustrated by Figure 2, which represents the relationship between submaximal ˙VO2 and HRt. Indeed, this figure shows that HRt measured at each submaximal level of exercise increased markedly with post-surgery time whereas˙VO2 values remained relatively stable. As a consequence, the˙VO2-HRt relationship shifts toward higher values of HRt in relation to post-surgery time.

Back to Top | Article Outline


This study shows that during graded exercise the denervated heart rate of patients with OHT increased markedly in relation to post-surgery time in the first year after transplantation, even in the absence of a rehabilitation program, but that this increase was not associated with changes in submaximal and peak oxygen uptakes.

Our results are in agreement with those of Niset et al.(21), who reported a significant increase in HRt measured at peak exercise and delta heart rate from 1 to 12 months. However, the greater values observed at 12 months post-surgery by these authors could be the effects of the rehabilitation program, which allowed their patients to reach greater peak power during exercise. The mechanism for change in HRt in relation to post-surgery time is currently unknown. A reinnervation of the transplanted heart has been observed in animals(19,23) but in humans the existence of an anatomic reinnervation is controversial and few investigators believe it is likely(8,32). The most probable mechanism for the increased heart rate with time after cardiac transplantation in humans may be humoral because the data of the literature suggest an increased sensitivity to circulating catecholamines after cardiac transplantation(2,4,7,10,13,30).

Between 1 and 12 months post-surgery, ˙VO2 peak remained relatively stable at approximately 53 ± 6.4% of the predicted value(31). This value of ˙VO2 peak is in agreement with the results of the literature, which report that ˙VO2 peak following cardiac transplantation is between 45 and 70% of that measured in normal subjects (5,15,16,21,27). These results indicate that a functional limitation to exercise persists after cardiac transplantation, at least in the absence of physical training. This limitation has been attributed mainly to cardiac denervation and the resulting effects on exercise heart rate(15,16,24,27). Indeed, high resting heart rates and low peak exercise heart rates in patients with OHT, resulting in a small increment in heart rate from rest to peak exercise, probably have a profound effect on the cardiac hemodynamic adjustment to exercise(15). However, in our study we observed a stability of˙VO2 at peak exercise in relation to post-surgery time whereas HRt increased and O2 pulse tended to decrease, with a shift in the ˙VO2-HRt relationship toward higher values of heart rate at submaximal level of exercise. These data together with the results of Jensen et al. (15), who found no significant difference in the relation of cardiac output to ˙VO2 between patients with OHT and normal subjects, indicate that factors other than the limited and sluggish increase in denervated heart rate play a role in the exercise limitation of patients with OHT. Impaired O2 utilization by muscle may contribute to this exercise limitation because a significantly lower O2 arteriovenous difference versus O2 uptake difference has been reported in transplant patients than is found in normal subjects (15). Furthermore, Stratton et al. (29) found by magnetic resonance spectroscopy that skeletal muscle abnormalities persist in patients after cardiac transplantation. They mainly explained these abnormalities as a consequence of immunosuppressive therapy, including cyclosporine, corticosteroids, and azathioprine. We believe that the main effect may be attributed to the cyclosporine because: 1) we recently reported a decrease of mitochondrial skeletal muscle respiration by cyclosporine(14,20); 2) Stratton et al.(29) found muscle abnormalities even in patients who were not treated by steroids; and 3) to our knowledge, azathioprine has not been described as causing skeletal muscle toxicity. Also, an alteration in pulmonary diffusing capacity may participate because this parameter was found to be abnormal after cardiac transplantation(3,12,22) and the decrease in diffusing pulmonary capacity correlates with the level of cyclosporine(12).

Contrary to our results, Niset et al. (21), Kavanagh et al. (16), and Keteyian et al.(17) observed an increase in HRt associated with an improvement in ˙VO2 peak. A possible explanation for this difference is that their patients with OHT were participating in a rehabilitation program in hospital and at home. Therefore, we hypothesize that the increase in HRt in relation to post-surgery time mainly reflects the spontaneous adaptation of denervated transplanted heart, whereas the increase in ˙VO2peak is the result of an improvement in peripheral factors. One of the most important factors accounting for the increase in˙VO2 with training might be an increase in mitochondrial mass(6,18), which would counter the detraining effects induced by end-stage heart failure (29) and the detrimental effects of cyclosporine on mitochondrial skeletal muscle respiration (14,20). Indeed, in the absence of training, all of our patients with OHT stopped the graded exercise test because of fatigue and pain in lower limbs, which was probably the result of an early shift toward glycolytic metabolism(16,25,27) due to a low oxidative capacity of skeletal muscle or a reduced phosphocreatine and adenosine triphosphate resynthesis (29).

In conclusion, even in the absence of formal physical training, the exercise response of the denervated transplanted heart changes in relation to post-surgery time. However, the increase in denervated transplanted heart rate with time does not significantly affect oxygen uptake at submaximal and peak levels of exercise, probably because of peripheral skeletal muscle limitation, but this needs further investigation.

Figure 1-Mean values of heart rate, oxygen uptake (˙VO2), delta heart rate (peak exercise heart rate - resting heart rate), and oxygen pulse measured at peak exercise in relation to post-surgery time. Individual data are represented by different symbols; dashed lines represent the mean.

Figure 1-Mean values of heart rate, oxygen uptake (˙VO2), delta heart rate (peak exercise heart rate - resting heart rate), and oxygen pulse measured at peak exercise in relation to post-surgery time. Individual data are represented by different symbols; dashed lines represent the mean.

Figure 2-Relationship between oxygen uptake (˙VO2) and denervated heart rate (HRt) during submaximal exercise in relation to post-surgery time. For each level of submaximal exercise, ˙VO2 values remain relatively stable with time after surgery whereas HRt increases markedly.

Figure 2-Relationship between oxygen uptake (˙VO2) and denervated heart rate (HRt) during submaximal exercise in relation to post-surgery time. For each level of submaximal exercise, ˙VO2 values remain relatively stable with time after surgery whereas HRt increases markedly.

Back to Top | Article Outline


1. Baumgartner, W., S. Augustine, A. Borkon, T. Gardner, and B. Reitz. Present expectations in cardiac transplantation. Ann. Thorac. Surg. 43:585-590, 1987.
2. Borow, K., A. Neumann, F. Arensman, and M. Yacoub. Clinical evidence for differential sensitivity of alpha and beta adrenergic receptors after cardiac transplantation. Circulation 72(Suppl. 3): 111-129, 1985.
3. Braith, R., M. Limacher, R. Mills, S. Leggett, M. Pollock, and E. Staples. Exercise-induced hypoxemia in heart transplant recipients.J. Am. Coll. Cardiol. 22:768-776, 1993.
4. Brodde, O., M. Kahamssi, and H. Zerkowski. Beta adrenoceptors in the transplanted human heart: unaltered beta adrenoceptor density, but increased proportion of beta 2 adrenoceptors with increasing post-transplant time. Naunyn Schmiedebergs Arch. Pharmacol. 344:430-436, 1991.
5. Cerretelli, P., B. Grassi, A. Colombini, B. Caru, and C. Marconi. Gas exchange and metabolic transients in heart transplant recipients.Respir. Physiol. 74:355-371, 1988.
6. Davies, K., L. Packer, and G. Brooks. Biochemical adaptation of mitochondria, muscle and whole-animal respiration to endurance training. Arch. Biochem. Biophys. 209:539-554, 1981.
7. Dempsey, P. J. and T. Cooper. Supersensitivity of the chronically denervated feline heart. Am. J. Physiol. 215:1245-1249, 1968.
8. Fallen, E., M. Kamath, D. Ghista, and D. Fitchett. Spectral analysis of heart rate variability following human heart transplantation: evidence for functional reinnervation. J. Auton. Nerv. Syst. 23:199-206, 1988.
9. Fragomeni, L. S. and M. P. Kaye. The registry of the International Society for Heart Transplantation fifth official report.J. Heart Transplant. 7:249-253, 1988.
10. Gilbert, E., C. Eiswirth, P. Mealey, P. Larrabee, and C. Herrick. Beta-adrenergic supersensitivity of the transplanted human heart is presynaptic in origin. Circulation 79:344-349, 1989.
11. Goodwin, J. F. Cardiac transplantation.Circulation 74:913-916, 1986.
12. Groen, H., J. Bogaard, A. Balk, S. Kho, W. Hop, and C. Hilvering. Diffusion capacity in heart transplant recipients. Chest 102:456-460, 1992.
13. Hammond, H., D. Roth, C. Ford, G. Stammas, M. Ziegler, and C. Ennis. Myocardial adrenergic denervation supersensitivity depends on a postreceptor mechanism not linked with increased cAMP production.Circulation 85:666-669, 1992.
14. Hokanson, J., J. Mercier, and G. Brooks. Cyclosporine A decreases rat skeletal muscle mitochondrial respiration in vitro. Am. J. Respir. Crit. Care Med. 151:1848-1851, 1995.
15. Jensen, R., F. Yanowitz, and R. Crapo. Exercise hemodynamics and oxygen delivery measurements using rebreathing techniques in heart transplant patients. Am. J. Cardiol. 68:129-133, 1991.
16. Kavanagh, T., M. Yacoub, D. Mertens, J. Kennedy, and R. Campbell. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulation 77:162-171, 1988.
17. Keteyian, S., E. Jonathan, F. Fedel, and K. Rhoads. Exercise following cardiac transplantation: recommendations for rehabilitation. Sports Med. 8:251-259, 1989.
18. Kirkwood, S., L. Packer, and G. Brooks. Effect of endurance training on a mitochondrial reticulum in limb skeletal muscle.Arch. Biochem. Biophys. 255:80-88, 1987.
19. Kontos, H., M. Thames, and R. Lower. Responses to electrical and reflex autonomic stimulation in dogs with cardiac transplantation before and after reinnervation. J. Thorac. Cardiovasc. Surg. 59:382-392, 1970.
20. Mercier, J., J. Hokanson, and G. Brooks. Effects of cyclosporine on endurance exercise time and skeletal muscle mitochondrial respiration in rats. Am. J. Respir. Crit. Care Med. 151:1532-1536, 1995.
21. Niset, G., L. Hermans, and P. Depelchin. Exercise and heart transplantation: a review. Sports Med. 12:359-379, 1991.
22. Ohar, J., J. Osterloh, N. Ahmed, and L. Liller. Diffusing capacity decreases after heart transplantation. Chest 103:857-861, 1993.
23. Peiss, C., T. Cooper, V. Willian, and W. Randall. Circulatory responses to electrical and reflex activation of the nervous system after cardiac denervation. Circ. Res. 19:153-166, 1966.
24. Pflugfelder, P., F. McKenzie, and W. Kostuk. Hemodynamic profiles at rest and during supine exercise after othotopic cardiac transplantation. Am. J. Cardiol. 61:1328-1333, 1988.
25. Pope, S., E. Stinson, G. Daughters, J. Schroeder, N. Ingels, and E. Alderman. Exercise response of the denervated heart in longterm cardiac transplant recipients. Am. J. Cardiol. 46:213-218, 1980.
26. Rudas, L., P. Pflugfelder, F. McKenzie, A. Menkis, R. Novick, and W. Kostuk. Normalization of upright exercise hemodynamics and improved exercise capacity one year after orthotopic cardiac transplantation.Am. J. Cardiol. 69:1336-1339, 1992.
27. Savin, W., W. Haskell, J. Schroeder, and E. Shrison. Cardiorespiratory responses of cardiac transplant patients to graded, symptom-limited exercise. Circulation 62:55-60, 1980.
28. Steinfath, M., H. Von der Leyen, A. Hecht, K. Neumann, W. Schmitz, H. Scolz, A. Haverich, and B. Heublein. Decrease in beta 1 and increase in beta 2 adrenoceptors in long term follow up after orthotopic cardiac transplantation. J. Mol. Cell. Cardiol. 24:1189-1198, 1992.
29. Stratton, J., G. Kemp, R. Daly, M. Yacoub, and B. Rajagopalan. Effects of cardiac transplantation on bioenergetic abnormalities of skeletal muscle in congestive heart failure. Circulation 89:1624-1631, 1994.
30. Von Der Leyen, H., M. Steinfath, A. Hecht, et al. Changes in cardiac beta 1 and beta 2 adrenoceptor densities after human cardiac transplantation. Relation to transplant coronary vasculopathy and pretransplantation disease. Am. Heart J. 124:686-696, 1992.
31. Wasserman, K., J. Hansen, D. Sue, and B. Whipp.Principles of Exercise Testing and Interpretation. Philadelphia: Lea& Febiger, 1986, pp. 72-83.
32. Wilson, R., B. Christensen, M. Olivari, A. Simon, C. White, and D. Laxson. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans. Circulation 83:1210-1220, 1991.
33. Zerkowski, H., M. Kahamssi, and O. Brodde. Development of beta adrenoceptor number and subtype distribution in the transplanted human heart. Eur. Heart J. 12(Suppl. F):124-126, 1991.


©1996The American College of Sports Medicine