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.
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.
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).
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.
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.
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.
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.
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