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(Circulation. 1997;96:232-237.)
© 1997 American Heart Association, Inc.

Articles

Long-term Sequential Changes in Exercise Capacity and Chronotropic Responsiveness After Cardiac Transplantation

Michael M. Givertz, MD; L. Howard Hartley, MD; ; Wilson S. Colucci, MD

From the Cardiomyopathy Programs and Cardiovascular Divisions, Brigham and Women's Hospital, and Boston Medical Center, Harvard Medical School and Boston University School of Medicine, Boston, Mass.

Correspondence to Wilson S. Colucci, MD, Cardiomyopathy Program, Boston Medical Center, 88 E Newton St, Boston, MA 02118.

	Abstract

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Background Peak exercise capacity improves early after orthotopic cardiac transplantation. However, the physiological response to exercise remains abnormal, with a reduced rate of heart rate (HR) rise and reductions in peak exercise HR and the increment in HR from rest to peak exercise. This chronotropic incompetence is due in large part to cardiac denervation. If reinnervation occurs after transplantation, it might result in an improvement in both chronotropic responsiveness and maximal exercise capacity. We therefore hypothesized that the chronotropic response to exercise and maximal exercise capacity would improve with time after transplantation.

Methods and Results Peak symptom-limited cardiopulmonary exercise tests performed in 57 clinically stable cardiac transplant recipients (mean age, 45±2 years) serially for up to 5 years after transplantation and in 33 control subjects without heart disease were analyzed retrospectively. Pretransplantation exercise tests were also performed in 41 patients an average of 4.7±0.6 months before transplantation. At 1 year after transplantation, peak oxygen consumption was 16.6±0.9 mL·kg^-1·min^-1, reflecting a 43% increase versus pretransplantation. Nevertheless, compared with control subjects, maximal exercise capacity and the HR response to exercise were subnormal in transplant recipients. There were no further increases in peak exercise capacity, peak exercise HR, or the peak increment in HR with exercise up to 5 years after transplantation.

Conclusions One year after cardiac transplantation, peak exercise capacity and chronotropic responsiveness are subnormal. There is no further improvement in peak exercise capacity or chronotropic responsiveness as late as 5 years after transplantation. These data indicate that with regard to chronotropic responsiveness, functionally significant cardiac reinnervation does not occur between the first and fifth years after transplantation.

Key Words: transplantation • heart rate • exercise • sinoatrial node

	Introduction

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In the first year after successful cardiac transplantation, exercise capacity is generally improved compared with pretransplantation exercise capacity but nevertheless continues to be subnormal compared with age-matched normal subjects.^{1 2 3 4 5} A characteristic of the impaired exercise response after transplantation is chronotropic incompetence, which manifests as reductions in the rate of HR rise, dHR, and peak HR achieved with exercise.^{1 2 3} In patients without clinical evidence of rejection, the predominant cause of the chronotropic incompetence and subnormal exercise capacity is believed to be surgical denervation.⁶ This thesis is supported by our previous finding³ that the HR response to exercise in patients in the first year after transplantation is attenuated despite a normal response to exogenous ß-adrenergic stimulation with infused isoproterenol, indicating that the cause of this abnormality is proximal to the ß-adrenergic receptor.

There is evidence that reinnervation of the heart occurs after transplantation in animals.^{7 8 9 10 11} Although histological studies on human myocardium obtained after transplantation have yielded conflicting results,^{12 13 14} there is growing evidence from clinical,¹⁵ physiological,^{16 17 18} and biochemical^{18 19 20 21 22} studies in humans that partial reinnervation may occur late, generally 1 year, after transplantation. The functional significance of such reinnervation is not known. However, it is possible that reinnervation would result in correction of the HR response to exercise and therefore an increase in peak exercise capacity. These changes would be expected to manifest themselves gradually over a time course consistent with reinnervation (ie, years after transplantation).

If the early (ie, at 1 year) reduction in exercise capacity is due at least in part to denervation, and if reinnervation occurs late after transplant, both the chronotropic response to exercise and exercise capacity should improve late (ie, between 1 and 5 years) after transplantation. There is very little information available regarding the changes in exercise capacity or chronotropic responsiveness that may occur between 1 and 5 years after cardiac transplantation. The purpose of the present study, therefore, was to test the hypothesis that reinnervation late after transplantation results in improved chronotropic responsiveness and exercise capacity. Peak exercise capacity and HR responses obtained serially in 57 transplant recipients at 1, 2, 3, 4, and 5 years after transplantation were analyzed retrospectively.

	Methods

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Transplant Recipients
Fifty-seven orthotopic cardiac transplant recipients were included in this study. Data were collected as part of routine posttransplant management from patients who underwent cardiac transplantation at Brigham and Women's Hospital between May 1986 and November 1990 and returned at 12-month intervals for annual evaluation. Data were analyzed retrospectively in patients who completed cardiopulmonary exercise testing at 1, 2, and 3 years after transplantation. Of the 57 recipients, 48 had serial tests for up to 4 years, and 42 also had serial tests for up to 5 years after transplantation. Of the 57 recipients, 41 had an exercise test performed an average of 4.7±0.6 months before transplantation. Of the patients studied, 41 were male and 16 were female. The mean age at the time of transplantation was 45±2 years (range, 14 to 62 years), and the mean age of the donor hearts was 27±2 years. The underlying cause of heart failure was idiopathic dilated cardiomyopathy in 33 patients and ischemic cardiomyopathy in 17. Aortic stenosis, lupus endocarditis, corrected transposition of the great arteries, rheumatic heart disease, doxorubicin toxicity, hypertrophic cardiomyopathy, and glycogen storage disease accounted for 1 patient each. Fifty-four transplant recipients were receiving triple-drug immunosuppression with cyclosporine A, prednisone, and azathiaprine. Three patients were receiving maintenance immunosuppression with only cyclosporine A and prednisone. All patients were stable at the time of exercise testing and had no evidence of clinical rejection or severe graft atherosclerosis. Annual endomyocardial biopsies showed no evidence of significant rejection in any patient, with an International Society of Heart and Lung Transplantation grade 0 or IA in 81% of patients and grade II in 16%. There was insufficient tissue for diagnosis in 3%. In addition, coronary angiography 3 years after transplantation revealed no significant epicardial coronary artery stenoses in 55 (96%) of 57 patients; 2 patients had significant stenoses. Approximately half of the patients were receiving a ß-blocker, calcium channel blocker, or both during the posttransplant period. The use of ß-blockers tended to decrease and the use of calcium channel blockers tended to increase from year 1 to year 3, but neither trend was significant (see Table 3).

View this table: [in this window] [in a new window]   Table 3. Sequential Changes in Peak o2 and dHR in Transplant Recipients Receiving Calcium Channel Blockers, ß-Blockers, Both, or Neither

Control Subjects
The control group consisted of 33 healthy adult males without a history of significant cardiovascular disease. None were receiving cardiac medications except for 1 patient taking hydrochlorothiazide for borderline hypertension. The mean age of the control group was 41±2 years (range, 24 to 56 years), which did not differ significantly from the transplant recipients. All control subjects were sedentary and untrained and gave informed consent as required by the Committee for the Protection of Human Subjects From Research Risks of the Brigham and Women's Hospital.

Exercise Protocol
Graded maximal exercise testing was performed on a cycle ergometer (Sensormedics or Medical Graphics) using a continuous ramp protocol of 10 W/min. Subjects sat on the ergometer for 4 minutes before pedaling at a rate of 60 rpm, starting at a workload of 10 to 30 W. Exercise workload was increased every 3 minutes in increments of 30 W until peak exercise was obtained, as defined by symptomatic fatigue and/or dyspnea such that a pedaling rate of 60 rpm could not be maintained. HR was monitored by continuous ECG recording, and blood pressure was measured with the use of a standard arm-cuff sphygmomanometer. HR and blood pressure were recorded at rest, at the end of each 3-minute workload, and at peak exercise. Subjects breathed through a three-way valve mouthpiece connected to a metabolic cart that allowed breath-by-breath gas analysis, including determination of inspired volumes and expired oxygen and carbon dioxide content. Oxygen consumption (O₂) was recorded at rest, at the end of each workload, and at peak exercise. The respiratory quotient at peak exercise had to be 1.0 for the test to be considered valid and included in the analysis. Peak oxygen pulse was calculated by dividing peak O₂ by peak HR; dHR was calculated by subtracting resting HR from peak HR; and dSBP was calculated by subtracting resting SBP from peak SBP.

Statistical Analysis
Multiple comparisons within a group over time were made by use of repeated measures ANOVA. Differences between groups were determined by two-tailed unpaired Student's t tests. Least-squares linear regression analysis was used to determine the relationship between the peak increment in HR at 1 and 3 years after transplantation. All data are presented as mean±SE, with a value of P<.05 considered statistically significant.

	Results

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Exercise Responses Before and After Transplantation
In the 41 patients who performed exercise tests before transplantation, exercise responses 1 year after transplantation were generally improved compared with pretransplantation (Table 1). At 1 year, exercise duration, resting SBP, peak SBP, dSBP, rate-pressure product, peak O₂, and peak oxygen pulse increased significantly compared with pretransplantation. However, resting HR, peak HR, and dHR were unchanged from pretransplantation.

View this table: [in this window] [in a new window]   Table 1. Exercise Responses Before and 1 Year After Cardiac Transplantation in 41 Patients

Serial Exercise Responses After Transplantation
In the 57 patients who completed serial cardiopulmonary exercise tests at 1, 2, and 3 years after transplantation, exercise capacity and the HR and blood pressure responses to exercise were unchanged between years 1, 2, and 3 after transplantation (Table 2).

View this table: [in this window] [in a new window]   Table 2. Sequential Exercise Responses in 57 Transplant Recipients at Years 1, 2, 3, 4, and 5 After Transplantation and in 33 Normal Control Subjects

Compared with control subjects, posttransplantation patients had a higher resting HR, exercised for a shorter period of time, reached a lower peak HR and SBP, had reduced peak increments in HR (Fig 1A) and SBP, reached a lower rate-pressure product, and achieved a lower peak O₂ (Fig 1B) and peak oxygen pulse. Three years after transplantation, the change in HR with exercise and peak O₂ were 62% and 34% lower, respectively, in transplant patients versus control subjects. The majority of patients also performed exercise tests at 4 and 5 years after transplantation. In these patients, there were no additional improvements in chronotropic responsiveness or maximal exercise capacity (Table 2). The lack of change in chronotropic responsiveness and peak exercise capacity with time after transplantation was not affected by the age or sex of the patient (data not shown).

View larger version (17K): [in this window] [in a new window]   Figure 1. dHR (A) and peak oxygen consumption (peak O2) (B) in 57 transplant recipients at years 1, 2, and 3 after transplantation and in 33 control subjects. *P<.001 vs control subjects.

Compared with patients receiving neither ß-blockers nor calcium channel blockers, the dHR response to exercise and peak O₂ were not different in patients receiving ß-blockers or calcium channel blockers and were not different between years 1, 2, and 3 (Table 3). Because the dHR and peak O₂ tended to be lower in the small percentage (5% to 7%) of patients receiving both ß-blockers and calcium channel blockers, we cannot exclude the possibility that there would have been a change over time in the absence of these drugs.

Individual Changes in Chronotropic Responsiveness
Between years 1 and 3, dHR was, on average, unchanged (mean change, 1±2 beats; range, -42 to +53 beats). The increment in HR increased by >20 bpm in four patients and decreased by >20 bpm in three. For the group as a whole, there was a strong correlation between dHR at 1 and 3 years after transplant (r=.68, P<.0001) (Fig 2). To determine if chronotropic responsiveness improved with time after transplant in a subgroup of patients, we compared patients with peak dHRs above and below the median at 3 years after transplant (median dHR, 36 beats; range, 10 to 82 beats). Group 1 (dHR >36 beats at 3 years after transplant, n=28) and group 2 (dHR 36 beats at 3 years after transplant, n=29) did not differ with regard to pretransplant peak O₂, sex, age at transplant, donor heart age, duration of ischemic time, duration of bypass time, need for pressor or inotropic support, use of immunosuppression, or use of ß-blockers or calcium channel blockers. At 1 year after transplantation, dHR and peak O₂ were 52% and 32% higher, respectively, in group 1 than in group 2 (Fig 3A and 3B and Table 4). However, there were no changes within either group in any resting or exercise responses between years 1, 2, and 3.

View larger version (16K): [in this window] [in a new window]   Figure 2. Correlation between dHR at years 1 and 3 after transplantation in 57 transplant recipients.

View larger version (32K): [in this window] [in a new window]   Figure 3. dHR (A) and peak oxygen consumption (peak O2) (B) at years 1, 2, and 3 after transplantation in patients with dHR above (group 1, solid bars) or below (group 2, shaded bars) the median at year 3 after transplantation. *P<.01 vs group 1.

View this table: [in this window] [in a new window]   Table 4. Sequential Exercise Responses in Transplant Recipients With a dHR Above (Group 1; dHR >36 Beats; n=28) or Below (Group 2; dHR 36 Beats; n=29) the Median at Year 3 After Transplant

	Discussion

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Failure of Chronotropic Responses and Exercise Capacity to Improve Late After Transplantation
This study demonstrates that 1 year after transplantation, transplant recipients have a subnormal maximal exercise capacity that is associated with chronotropic incompetence, and that during the subsequent 4 years, there is no further improvement in either exercise capacity or chronotropic responsiveness. Several previous studies^{1 2 3 23 24 25 26 27 28 29 30} demonstrated that after transplantation, exercise capacity is subnormal and is associated with reductions in the rate of HR rise, dHR, and peak HR achieved. This chronotropic incompetence is generally believed to be the result of surgical cardiac denervation and appears to contribute to the subnormal exercise capacity in these patients.⁶ We³ previously found that transplant recipients had normal responses to exogenous ß-adrenergic stimulation, thus supporting the hypothesis that chronotropic incompetence is due to denervation of the heart and also suggesting that postsynaptic mechanisms were intact, at least with regard to the sinoatrial node.

Reinnervation After Transplantation
Although studies in dogs and monkeys have shown histological and functional evidence of reinnervation with time after cardiac transplantation,^{7 8 9 10 11} the evidence for reinnervation in humans after transplantation is conflicting. Histological studies in humans have failed to document reinnervation. For example, using electron microscopy, Rowan and Billingham¹² were unable to find evidence of nerve growth in endomyocardial biopsy specimens from 13 long-term heart transplant survivors as late as 12 years after transplantation. Likewise, Regitz et al¹³ found that catecholamines were undetectable in endomyocardial biopsy specimens from long-term transplant recipients.

In contrast to these histological studies, several clinical observations and functional or biochemical studies have suggested that reinnervation may occur late after transplant in humans. Ischemic chest pain,¹⁵ vasodepressor syncope,^{31 32} respiratory sinus arrhythmia,^{16 33} and the concordant beating of donor and recipient atria³⁴ have been observed in heart transplant patients and have been proposed as evidence of reinnervation. In further support of reinnervation, Wilson et al¹⁹ documented significant, albeit subnormal, cardiac release of norepinephrine in response to intravenous tyramine in 39 of 50 patients 1 year after transplant. These investigators further observed that intracoronary tyramine infusion causes an increase in left ventricular contractility and a transient decrease in coronary flow in some patients late after transplantation.²⁰ These findings are consistent with studies²² that used ¹²³I-labeled MIBG imaging to demonstrate cardiac reinnervation in patients 1 to 2 years after transplantation.

Our data suggest that with respect to chronotropic responsiveness and peak exercise capacity, functionally significant reinnervation does not occur during the first 5 years after transplantation. It is important to emphasize that we did not study reinnervation but rather the potential functional consequences of reinnervation of the sinoatrial node. These data therefore do not exclude the occurrence of cardiac reinnervation per se, which might occur to a greater extent in other areas of the heart (eg, the ventricular myocardium). This latter possibility is supported by the observation that the intracoronary infusion of tyramine can cause regional heterogeneity of cardiac norepinephrine release.²⁰ In this regard, it is also noteworthy that the HR response to exercise is similarly blunted in patients with and without evidence of myocardial reinnervation by ¹²³I-labeled MIBG uptake.²² Our findings are in contrast to those of Rudas et al,¹⁷ who found that the rates of HR acceleration and deceleration during and after exercise, respectively, were faster in patients 42 months versus 2 or 16 months after transplantation. However, that study compared different groups of patients for each time period and is thus subject to confounding factors that were eliminated by our use of sequential observations in the same patients.

Other Mechanisms of Reduced Exercise Capacity
The contribution of chronotropic incompetence to subnormal exercise capacity in transplant recipients is not known. It should be noted that subnormal exercise capacity after transplantation may be due to several factors in addition to chronotropic incompetence, including allograft rejection,²⁴ diastolic dysfunction,^{5 35 36} abnormal skeletal muscle metabolism or function,³⁷ and use of immunosuppressive and antihypertensive medications.³⁸ For example, the use of maintenance prednisone after transplantation was found to be associated with a lower exercise capacity as well as higher right-sided pressures and pulmonary vascular resistance.³⁹

Study Limitations
Certain limitations of this study should be noted. First, the subjects were selected on the basis of the completion of serial exercise tests at 1, 2, and 3 years after transplantation and thus constitute only about half of the patients transplanted at our institution during the study period. Because these patients, by definition, have a 3-year survival of 100%, they represent a relatively healthy cohort. Contrary to our findings, one might expect this group to bias the results in favor of improvement in exercise capacity with time. A second limitation to our study is the inability to control for medication use and, in particular, drugs that can affect chronotropic responsiveness, such as ß-blockers and calcium channel blockers. However, the observed limitations in exercise capacity and chronotropic responsiveness were not related to the use of these agents because they occurred to a similar degree in patients not receiving these agents. Third, our control group was not strictly matched by age or sex. However, the ages of the two groups were similar. More importantly, we found that the lack of improvement in chronotropic responsiveness after transplantation was unaffected by patient age or sex. Finally, our data do not control for participation in exercise programs.

In summary, 1 year after cardiac transplantation, peak exercise capacity and chronotropic responsiveness are subnormal, and neither exercise capacity nor chronotropic responsiveness improves further during the next 4 years. These data suggest that in most patients, functionally significant reinnervation of the sinoatrial node does not occur.

	Selected Abbreviations and Acronyms

 

dHR = peak increment in heart rate with exercise dSBP = peak increment in systolic blood pressure with exercise HR = heart rate MIBG = m-iodobenzylguanidine SBP = systolic blood pressure

	Acknowledgments

 
This work was supported in part by a training grant in cardiovascular research from the NIH (HL-07604). We wish to acknowledge the dedicated work and invaluable support provided by the physicians, nurses, and staff of the Cardiac Transplantation Program and the Exercise Laboratory at the Brigham and Women's Hospital.

Received October 14, 1996; revision received January 2, 1997; accepted January 4, 1997.

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