Cardiovascular responses of heart transplant recipients to graded exercise testing JONATHAN T. BARRY
EHRMAN, STEVEN KETEYIAN, LEVINE, AND ROBERT SHEPARD
FRANK
FEDEL,
KENNETH
RHOADS,
Henry Ford Heart and Vascular Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, Henry Ford Hospital, Detroit 48202; and Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan 48201 (VO,) when comparing EHRMAN, JONATHAN, STEVEN KETEYIAN, FRANK FEDEL, consumption KENNETHRHOADS,T. BARRYLEVINE,ANDROBERTSHEPARD. normal healthy subjects. Cardiovascular responses of heart transplant exercise testing. J. Appl. Physiol. 73(l):
recipients
to graded
260-264, 1992.-A group of orthotopic heart transplant (OHT, n = 28) and heart
surgery (n = 19) patients, with similar ejection fractions and left ventricular end-diastolic pressures, were exercised to symptom-limited maximum to describe differences in cardiovascular and gasexchange responses.Testing was performed at a mean of 3 and 6 mo after surgery, respectively (P < 0.05). OHT patients have a greater resting systolic and diastolic blood pressure(P < 0.01) and a significantly greater (P < 0.01) heart rate (HR) at rest in the supineand standingpositions and during minutes 2 through 7 of supine recovery. Peak treadmill time was significantly less(P < 0.01) in OHT patients. No significant differences were found for systolic blood pressure (SBP) during recovery, peak HR, ventilation, relative 0, uptake (VO,), body weight, ventilatory equivalents for 0, and CO,, 0, pulse, and HR-SBP product (peak HR X peak SBP). Peak pulsepressure,heart rate reserve, total vo2, and absolute VO, at ventilatory threshold were significantly lower (P c 0.01) in the OHT patients. We concluded that I) complete cardiac decentralization is evident, 2) the significantly reduced TO, at ventilatory threshold should be consideredwhen activities of daily living are prescribed,and 3) SBP responseis more appropriate than HR for assessingrecovery of the decentralized heart after maximal exercise. decentralization; ventilatory threshold
ORTHOTOPIC HEART TRANSPLANTATION (OHT) surgery
is established as an effective alternative for individuals with end-stage heart disease. Over 2,400 procedures were performed in 1989 with up to an 85% 1-yr and 81% 5-yr survival rate, depending on the immunosuppressive drug treatment utilized (10). The transplanted heart is severed from the central nervous system (decentralized) but performs adequately when stressed. Pope et al. (12) demonstrated that patients with a decentralized heart respond to exercise in a sequential and attenuated manner, with stroke volume increasing initially, followed by a subsequent increase in heart rate (HR). These responses increase at a slower rate during exercise than does an innervated heart. Peak HR is reported to be similar in both OHT and coronary artery bypass graft patients (5). In 1988, Kavanagh et al. (7) reported a significantly lower peak HR and oxygen 260
OHT patients with
The purpose of this investigation was to compare the cardiovascular and gas exchange responses of OHT and heart surgery (HS) patients at initial postoperative testing. Because little comparative data presently exist, the results of this study should facilitate the development of effective exercise prescriptions for heart transplant recipients. METHODS Subjects. The two study groups consisted of 28 OHT recipients and 19 consecutive HS patients (14 coronary artery bypass grafts, 4 mitral valve replacements, and 1 aortic valve replacement). Before surgery OHT patients demonstrated New York Heart Association functional class 3 or 4, with etiologies including ischemic cardiomyopathy, myocarditis, valvular heart disease, and idiopathic cardiomyopathy. All OHT patients were determined to be free of acute rejection and systemic infection. This study was approved by the hospital’s Human Subjects Committee, and informed consent was obtained from each patient. Patient characteristics are presented in Table 1. The HS patients were chosen as a comparison group because of their 1) innervated myocardium; 2) recent surgery requiring a sternotomy and extracorporeal circulation; and 3) similar exercise habits before and after surgery. All OHT patients were receiving standard triple-dose immunosuppressive therapy (cyclosporine, Imuran, and Prednisone), and beta-blocker medications were taken by two OHT and four HS patients. Calcium-channel blocker therapy was received by four OHT patients and one HS patient. Cardiac catherization results revealed a mean ejection fraction and left ventricular end-diastolic pressure of 69 t 2.0 and 14 t 1 (*SE) mmHg, respectively, for the OHT patients at 1 yr postoperative and 66 t 4 and 18 t 4, respectively, for the HS patients before surgery (n = 28 and 12, respectively). Neither of the variables were significantly different between the two groups. Testing procedures. A medical history and physical examination were performed by a cardiologist on each patient before testing. Before a graded exercise treadmill test, supine and standing 12-lead electrocardiograms (ECG) were obtained on each patient, from which HR
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EXERCISE TABLE
TESTING
AFTER
1. Subject characteristics
Group
n
Age, yr
OHT HS
28 19
45t1.9" 59k3.1
Height,
cm
HEART TABLE
Weight,
kg
261
TRANSPLANTATION
3. Heart rate and blood pressure values
Months Postoperative
Heart
Rate, min”
Resting
44.4t0.4 43.8t0.6
79.5t4.2 80.4t3.3
3.0t0.4* 6.0t1.7
Values are means + SE. OHT, orthotopic heart transplantation; heart surgery. * P zsi0.05, OHT vs. HS. TABLE Stage 1
2 3 4 5 6 7
HS,
3 6 9 12 15 18 21
Speed, mph
2.0 2.0 3.0 3.0 3.0 3.5 4.0
mmHg
Group
n
Supine
Standing
Peak
Systolic
Diastolic
OHT HS
28 19
93+2* 74t3
94t2* 83k4
132t4 14o_t5
164t4.9" 129k4.5
96.0t2.3* 78.2k2.1
Values are means t SE. For abbreviations, see Table 1. * P < 0.001, OHT vs. HS.
2. Graded exercise protocol used for testing Cumulative Duration, min
Resting Blood Pressure,
Grade,
0 7.0 7.5 12.5 17.5 16.0 18.0
%
TABLE
4. Respiratory responsesduring peak exercise VE,
h,
Group
n
l/min
ml kg-’
OHT HS
16 9
75.Ok5.0 78.9t8.7
l
&ifE, l
min-’
17.5kO.9 20.4tl.l
l/min
RER
51.3k4.0 45.6t3.1
1.25*0.01* 1.13kO.03
Values are means + SE. VE, ventilation; OO,, 0, consumption; ventilatory equivalent for 0,; RER, respiratory exchange ratio. For other abbreviations, see Table 1. * P I 0.05, OHT vs. HS. O$E,
was determined. An appropriately sized blood pressure ordinate, respectively. The vo2 (l/min) at which each re(BP) cuff was attached to a mercury sphygmomanometer viewer determined a patient’s VT to have occurred (VTand applied to the right arm of each patient. A 12-lead VO,) was calculated, and a mean VT-VO, was computed continuous monitoring ECG stress system was used for each patient. Mean VT-VO, was also expressed for (model 3000, Quinton Instruments, Seattle, WA), and a each patient as a percentage of peak VO, [VT% = demonstration of walking on the treadmill was presented (VT - \jo,lpeak 00,) X 1001. Mean values were then to each patient. Depending on availability of the neces- calculated for both study groups. sary equipment, patients from each group also underStatistical analysis. All variables were analyzed with went gas exchange analysis (n = 16 for OHT and n = 9 the use of the Student’s two-sample t test, and Bonfor HS). Mean postoperative time was significantly dif- ferroni’s multiple comparison adjustment was applied to ferent for the entire group of patients; however, there recovery HR. Systolic BP during recovery was analyzed was no significant difference between the OHT (n = 9) with univariate repeated-measures y analysis of variance and HS (n = 15) patients who underwent gas exchange group effect. Interreviewer agreement was determined analysis (3.2 t 1.8 vs. 2.7 t 3.2, P = 0.71). A Horizon II with the intraclass correlation coefficient. metabolic system (Sensormedics, Anaheim, CA) was utilized and calibrated according to manufacturer’s recomRESULTS mendations before each test. This system provided continuous measurement of expired gases and reported an Resting supine and standing HR were significantly greater (P < 0.01) for the OHT patients. Resting systolic average value every 15 s. and diastolic BP were also significantly higher for the The treadmill protocol and metabolic cart were simultaneously started after it was felt that the patient was OHT patients (P < 0.01). Peak HR was not significantly different between the two groups, and the mean increase walking comfortably without using handrail support. in HR from rest to peak exercise (HR reserve) for HS The exercise protocol was modified from Savin et al. (I4 and is shown in Table 2. The test was performed to and OHT patients was 68 and 40 min-‘, respectively (P zz symptom-limited maximum exertion. BP, HR, and an 0.01). HR results are given in Table 3. Total exercise treadmill time (TT) was significantly ECG were recorded at the end of each 3-min stage. At the greater (P < 0.01) for the HS than for the OHT patients end of the test the treadmill was stopped, and the patient greater was placed in the supine position. BP, HR, and ECG were (7.9 vs. 10.0 min). Peak RER was significantly (P < 0.01) for OHT patients, with all but one patient monitored throughout an 8-min recovery period. VO, (l/min and ml. kg-l. min-l), ventilatory equivaachieving a peak value of ~1.00. For the remaining gas lent for oxygen (O&5, l/l), ventilatory equivalent for exchange measurements, no significant differences were noted between groups except absolute VO, (Urnin), which c!rbon dioxide (COJE, l/l), expired carbon dioxide (VCO,, Urnin), respiratory exchange ratio (RER), and was 14.2% greater in the HS patients (P < 0.01). Comventilation (VE, l/min) were recorded throughout the plete results can be found in Tables 4 and 5. test and used to determine ventilatory threshold (VT). The HS patients demonstrated a more rapid decline in HR during recovery than did the OHT patients (Fig. 1). Methods described by Beaver et al. (1) and Wasserman RHR at minutes 2, 3, 5, and 7 were significantly greater et al. (20) were used as guidelines by four independent and experienced reviewers, when evaluating the followin the OHT patients (P < 0.01). Both groups demoning four graphs: 1) TO, (x) and VCO, (y); 2) time (x) strated a significant decrease in systolic BP from minute and O$E and COJE (y); 3) time (x) and VE (y); and 4) 1 to minute 6 of recovery, and at each time point there time (x) and RER (y), where x and y are the abscissa and was no significant difference between groups (Fig. 2). Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on November 2, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
262 150T 140
EXERCISE
a
TESTING
AFTER
HEART TABLE
0 OHT 0 HS
TRANSPLANTATION
5. Ventilatory
Group
n
OHT HS
16
9
threshold during exercise Peak OO,, l/min
1.33*0.08* 1.75kO.11
VT-t’02, Umin 1.05t0.19* 1.41k4.0
% of Peak 00, 78% 80%
Values are means t SE. VT-VO,, VO, at which ventilatory threshold occurs. For other abbreviations see Table 4. * P I 0.01, OHT vs. HS.
80
Peak Exercise
I
I
’
2
1
3
I
5
D 7
Recovery Time (min) I I FIG. 1. Peak exercise and recovery heart rate at minutes 1, 2, 3, 5, and 7 for orthotopic heart transplantation (OHT) and heart surgery (HS) patients. OHT group significantly greater than HS group: *p < 0.05.
VT-$70, was significantly lower in the OHT patients (P < 0.01) than in the HS patients (Table 5). However, there was no significant difference between the two groups for VT%. Assessment of interreviewer agreement revealed intraclass correlation coefficients (r) of 0.69 and 0.82 for HS and OHT patients, respectively. Peak pulse pressure was significantly lower in the OHT than in the HS patients (74.6 t 5.5 vs. 97.4 t 4.4 mmHg, P < 0.05). There was no significant difference in peak 0, pulse (12.5 t 1.4 ml O,/beat for OHT vs. 11.6 t 0.6 ml O,/beat for HS) or HR-SBP product (215 t 10 X lo2 mmHg/min for OHT vs. 246 t 16 X lo2 mmHg/min for HS). DISCUSSION
Our elevated mean resting supine HR of 93 beats/min in OHT patients is in agreement with values reported by others (16,17) and is significantly higher than the HR of our HS patients. This rate most likely reflects the intrinsic rate-of the decentralized heart. Evidence of total decentralization for our OHT patients was demonstrated by the absence of an increase in HR after patients as180 2175 El70
E
;I65 '160
3 P2155 $150 ;145 g140 bl35
6 i?th DUV
7
i i Ii Recovery Time (min) FIG. 2. Systolic blood pressure at minutes 1, 2, 4, 6, and 8 of recovery for OHT and HS patients. Within-group change from minute 1 to minute 8 is significant: *‘P < 0.05. 1
i
sumed an upright position before exercise. This response agrees with previous reports (2, 6,8). The resting ejection fraction and left ventricular enddiastolic pressure values were not significantly different, and it is assumed that resting ventricular function is not different between the groups. The resting SBP and diastolic blood pressure values were both significantly different. Many OHT patients become hypertensive after surgery, and this may be a result of immunosuppressive therapy (cyclosporine and prednisone). Some of these patients may require antihypertensive agents. The significantly reduced TT for our OHT patients agrees with data previously reported by Kavanagh et al. (7). This response may be secondary to reduced skeletal muscle mass in the lower limbs of the OHT patients, secondary to their extended period of inactivity before and initially after surgery. Prednisone and/or cyclosporine may also play a role in lean mass deterioration, because the long-term effects of these therapies are not well understood. No significant difference was found in peak HR between the two groups. This agrees with Savin (13) and Degre et al. (5) but differs from Kavanagh et al. (7), who reported a significantly lower peak HR in OHT patients when compared with healthy normal subjects. Because the transplanted heart lacks all autonomic nervous input, it mainly relies on increasing levels of circulating catecholamines (epinephrine and norepinephrine) to increase its rate. Christenson and Galbo (4) have previously demonstrated that catecholamines increase at a rate that is, within limits, directly related to increases in both exercise duration and VO,. An increase in the concentration of catecholamines during exercise is a result of adrenergic and choline@ sympathetic activity. The lack of efferent sympathetic input and/or the significantly reduced TT may be explanations for the lower peak HR noted for our OHT patients, with the latter possibly limiting peak catecholamine values. Because the heart mainly relies on an increase in rate to elevate cardiac output at higher levels of exercise, the significantly lower increase in HR from rest to peak (HR reserve) in our OHT patients may be responsible for their reduced total peak vo2. Other explanations for the reduced peak Vo2 might include the following: 1) exaggerated skeletal muscle deconditioning experienced by the OHT patients due to the extended periods of bed rest both before and after surgery and 2) differences in exercise systolic and diastolic ventricular function between the two groups. The significantly greater peak RER value of the OHT patients may be related to their attenuated increase in HR during early exercise. Degre et al. (5) suggest that such an attenuated HR response requires OHT recipients to rely on accelerated anaerobic metabolism earlier
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EXERCISE
TESTING
AFTER SUELETAL
M.
K.Y 1) + -Add to (rtlmulrto) 1) --subtm8tfmm(lnhlblti 3) a tvatt - Y8gnRud8of Inon 01~
dwfwu (4
b.--Noahmgo
lntua maPow for doaenmllzod prtknt
PM
3. Cardiovascular adjustments normal and decentralized subjects. FIG.
to acute dynamic exercise in
during exerci se than their innervated counterparts. Savin et a.l. (15) suggest that the earlier accelerated ana .erobit metabolism in OHT patients is secondary to decreased 0, uptake but does not distinguish whether this is secondary to shortcomings in central delivery or peripheral utilization. A review of the possible mechanisms that take place during acute dynamic exercise in innervated and decentralized subjects is shown in Fig. 3. From minute 2 to minute 8 of recovery, the HRs are significantly higher in the OHT patients. This suggests the absence of parasympathetic innervation to the myocardium in the OHT patients, although myocardial stretch and catecholamine clearance rate may also play a role. The effects of circulating catecholamines last from several seconds to several mi .nutes before they are removed from the blood (18). As our data indicate, the lack of parasympathetic innervation (and possibly a delayed catecholamine clearance rate) in the OHT patients results in an early recovery HR that is slightly higher than the peak exercise value. Despite a significantly lower absolute VT between the two groups (1.05 vs. 1.41 l/min for OHT and HS, respectively), the lack of a difference for VT% (79 vs. 80% for OHT and HS patients, respectively) demonstrates that both groups reach anaerobic threshold (AT) at similar percentages of their peak VO,. Our VT% value for OHT patients is very similar to the 78% value reported by Kavanagh et al. (7) both before and after exercise training. According to Wasserman et al. (20), the lower end of normal VT% is 40%, while many aerobically trained individuals approach 70-80%. Our reported VT% values for OHT vs. HS patients are in conflict with the data of Wasserman et al. (20). Possible explanations may be deconditioned peripheral skeletal muscles or the detection of VT after AT occurred. Wasserman et al. (19) have reported that there is no observable difference in the VT.vo2 value calculated from the VT method we used and AT calculated from lactate values. Gas exchange m ethods for determining AT remain controversial and warrant future studies involving the measurement of blood lactate concentrations in OHT patients. These results suggest that OHT patients accelerate anaerobic metabolism at a significantlv lower absolute
HEART
TRANSPLANTATION
263
TO, than HS patients,
and this response may limit both submaximal and peak exercise. The prescription of exercise or activity using VT% may be misleading, if the absolute 00, values are not taken into consideration. Exercise prescription recommendations. Several investigators have previously demonstrated the ability of OHT patients to benefit from an aerobic exercise conditioning program (7,9,16). Presently, the Borg Rating of Perceived Exertion scale is the preferred method for guiding exercise intensity in OHT patients (8,9). Use of the percentage of measured peak HR method for computing training HR is presently not recommended in OHT patients, because it may result in an underestimation of the upper end of training HR range (9). A similar result may also occur with the use of the HR-reserve method, if periodic follow-up testing is not employed (9). Increasing the duration of a graded exercise test (GXT) by extending each stage of the protocol from 3 to 5 or 6 min may result in a greater peak HR, secondary to increased levels of circulating catecholamines. This practice may prove useful when exercise is prescribed with the use of HR-based methods. VT may represent another method for guiding exercise training intensity in OHT patients. This method involves matching training work load or HR to the GXT work load or HR measured at VT-VO,. If the VT is matched to HR, periodic GXT may be necessary because exercise training HR has been shown to increase during an 8- to 12-wk exercise program (9). This response may affect the VT-to-HR relationship. When compared with that of patients with an innervated heart, HR in OHT patients is significantly increased during exercise recovery, whereas recovery SBP is not significantly different. Therefore, it appears that it is not necessary for OHT recipients to achieve near resting HR values within 8 min after exercise is stopped. Monitoring systolic BP appears to be a more useful tool to assess adequate recovery of the heart and cardiovascular system. Future research is needed to address the determinates of peak Oo, and limits of peak HR and to assess circulating catecholamine and lactate threshold response. As more OHT patients participate in exercise programs to facilitate return to an active lifestyle, a better understanding of the methods used in guiding exercise intensity is also required. Address for reprint requests: S. Keteyian, 2921 West Grand Blvd., NCP 1107, Detroit, MI 48202. Received 9 January 1991; accepted in final form 16 January 1992. REFERENCES 1. BEAVER, W. L., K. WASSERMAN, AND B. J. WHIPP. A new method for detecting anaerobic threshold by gas exchange. J. A&. Physiol. 60:2020-2027,1986. 2. BECK, W., C. N. BARNARD, AND V. SCHRIRE. Heart rate after cardiac transplantation. Am. J. Physiol. 218: 475-484, 1970. 3. BORG, G. Perceived exertion as an indicator of somatic stress. Band. J. Rehabil. Med. 2: 92-98, 1970. 4. CHRISTENSEN, N. J., AND H. GALBO. Sympathetic nervous activity during exercise. Annu. Rev. PhysioZ. 45: 139-153, 1983. 5. DEGRE, S. G., G. L. NISET, J. M. DE SMET, T. IBRAHAM, AND E. STOUPEL. Cardiorespiratory response to early exercise testing after heart transplantation. Am. J. Cardiol. 60: 926-928. 1987.
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EXERCISE
264
TESTING
AFTER
6. HASKELL, W. N. B. INGLES,
L., W. M. SAVIN, J. S. SCHROEDER, E. A. ALDERMAN, G. T. DAUGHTERS, AND E. B. STINSON. Cardiovascular responses to handgrip isometric exercise in patients following cardiac transplantation. Circ. Res. 48: X6-161, 1981. 7. KAVANAGH, T., M. YACOUB, R. MERTENS, J. KENNEDY, R. B. CAMPBELL, AND P. SAWYER. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulution
77: 162-171,1988. 8. KETEYIAN, S.,
J. EHRMAN, F. FEDEL, AND K. RHOADS. Exercise following cardiac transplantation: recommendations for rehabilitation. Sports Med. 8: 251-259, 1989. 9. KETEYIAN, S., J. EHRMAN, F. FEDEL, AND K. RHOADS. Heart rateperceived exertion relationship during exercise in orthotopic heart transplant recipients. J. Cardiopulm. Rehabil. 10: 287-293, 1990. 10. KRIETT, J. M., AND M. P. KAYE. The registry of the International Society for Heart Transplantation: Seventh Annual Official Report-1990. J. Heart Transplant. 9: 323-330, 1990. 11. NISET, G., J. R. POORTMANS, R. LECLERCQ, M. BRASSEUR, J. M. DESMET, S. G. DEGRE, AND G. PRIMO. Metabolic implications during a 20-km run after heart transplantation. Int. J. Sports Med. 6: 340-343,1985. 12. POPE, S. E.,
E. B. STINSON, AND G. T. DAUGHTERS. Exercise response of the denervated heart in long-term cardiac transplant recipients. Am. J. Cardiol. 46: 213, 1980.
HEART
TRANSPLANTATION
13. SAVIN, W. M. Role of the Adrenergic Nervous System in the Production of Cardiovascular Training Effects in Man (Dissertation). Palo
Alto, CA: Stanford University, 1984, p. 68-96. S. SCHROEDER, AND E. B. STINof cardiac transplant patients to graded, symptom-limited exercise. Circukztion 62: 55-60, 1980. 15. SAVIN, W. M., J. S. SCHROEDER, AND W. L. HASKELL. Response of cardiac transplant recipients to static and dynamic exercise: a review. J. Heart Transplant. 1: 72-79, 1982. 16. SQUIRES, R. W., P. R. ARTHURM, G. T. GAU, A. MURI, AND W. B. LAMBERT. Exercise after cardiac transplantation: a report of two cases. J. Cardiopulm. Rehabil. 3: 570-574, 1983. 17. STINSON, E. B., R. B. GRIEPP, J. S. SCHROEDER, E. DONG, AND N. E. SHUMWAY. Hemodynamic observations one and two years after cardiac transplantation in man. Circulation 45: 1183-1194,
14. SAVIN, W. M., W. L. HASKELL, J. SON. Cardiorespiratory responses
1972. 18. VANDER, A. J., J. H. SHERMAN, AND D. S. LUCIANO. Human Physiology: The Mechanism of Body Function (3rd ed.). Philadelphia, PA: McGraw-Hill, 1980. 19. WASSERMAN, K., W. L. BEAVER, AND B. J. WHIPP. Reply to the editor. J. Appl. Physiol. 67: 2641, 1989. 20. WASSERMAN, K., B. J. WHIPP, S. N. KOYAL, AND W. L. BEAVER.
Anaerobic threshold and respiratory gas exchange during exercise. J. Appl.
Physiol.
35: 236-243,
1973.
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EHRMAN, STEVEN KETEYIAN, LEVINE, AND ROBERT SHEPARD
FRANK
FEDEL,
KENNETH
RHOADS,
Henry Ford Heart and Vascular Institute and Division of Cardiovascular Medicine, Department of Internal Medicine, Henry Ford Hospital, Detroit 48202; and Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan 48201 (VO,) when comparing EHRMAN, JONATHAN, STEVEN KETEYIAN, FRANK FEDEL, consumption KENNETHRHOADS,T. BARRYLEVINE,ANDROBERTSHEPARD. normal healthy subjects. Cardiovascular responses of heart transplant exercise testing. J. Appl. Physiol. 73(l):
recipients
to graded
260-264, 1992.-A group of orthotopic heart transplant (OHT, n = 28) and heart
surgery (n = 19) patients, with similar ejection fractions and left ventricular end-diastolic pressures, were exercised to symptom-limited maximum to describe differences in cardiovascular and gasexchange responses.Testing was performed at a mean of 3 and 6 mo after surgery, respectively (P < 0.05). OHT patients have a greater resting systolic and diastolic blood pressure(P < 0.01) and a significantly greater (P < 0.01) heart rate (HR) at rest in the supineand standingpositions and during minutes 2 through 7 of supine recovery. Peak treadmill time was significantly less(P < 0.01) in OHT patients. No significant differences were found for systolic blood pressure (SBP) during recovery, peak HR, ventilation, relative 0, uptake (VO,), body weight, ventilatory equivalents for 0, and CO,, 0, pulse, and HR-SBP product (peak HR X peak SBP). Peak pulsepressure,heart rate reserve, total vo2, and absolute VO, at ventilatory threshold were significantly lower (P c 0.01) in the OHT patients. We concluded that I) complete cardiac decentralization is evident, 2) the significantly reduced TO, at ventilatory threshold should be consideredwhen activities of daily living are prescribed,and 3) SBP responseis more appropriate than HR for assessingrecovery of the decentralized heart after maximal exercise. decentralization; ventilatory threshold
ORTHOTOPIC HEART TRANSPLANTATION (OHT) surgery
is established as an effective alternative for individuals with end-stage heart disease. Over 2,400 procedures were performed in 1989 with up to an 85% 1-yr and 81% 5-yr survival rate, depending on the immunosuppressive drug treatment utilized (10). The transplanted heart is severed from the central nervous system (decentralized) but performs adequately when stressed. Pope et al. (12) demonstrated that patients with a decentralized heart respond to exercise in a sequential and attenuated manner, with stroke volume increasing initially, followed by a subsequent increase in heart rate (HR). These responses increase at a slower rate during exercise than does an innervated heart. Peak HR is reported to be similar in both OHT and coronary artery bypass graft patients (5). In 1988, Kavanagh et al. (7) reported a significantly lower peak HR and oxygen 260
OHT patients with
The purpose of this investigation was to compare the cardiovascular and gas exchange responses of OHT and heart surgery (HS) patients at initial postoperative testing. Because little comparative data presently exist, the results of this study should facilitate the development of effective exercise prescriptions for heart transplant recipients. METHODS Subjects. The two study groups consisted of 28 OHT recipients and 19 consecutive HS patients (14 coronary artery bypass grafts, 4 mitral valve replacements, and 1 aortic valve replacement). Before surgery OHT patients demonstrated New York Heart Association functional class 3 or 4, with etiologies including ischemic cardiomyopathy, myocarditis, valvular heart disease, and idiopathic cardiomyopathy. All OHT patients were determined to be free of acute rejection and systemic infection. This study was approved by the hospital’s Human Subjects Committee, and informed consent was obtained from each patient. Patient characteristics are presented in Table 1. The HS patients were chosen as a comparison group because of their 1) innervated myocardium; 2) recent surgery requiring a sternotomy and extracorporeal circulation; and 3) similar exercise habits before and after surgery. All OHT patients were receiving standard triple-dose immunosuppressive therapy (cyclosporine, Imuran, and Prednisone), and beta-blocker medications were taken by two OHT and four HS patients. Calcium-channel blocker therapy was received by four OHT patients and one HS patient. Cardiac catherization results revealed a mean ejection fraction and left ventricular end-diastolic pressure of 69 t 2.0 and 14 t 1 (*SE) mmHg, respectively, for the OHT patients at 1 yr postoperative and 66 t 4 and 18 t 4, respectively, for the HS patients before surgery (n = 28 and 12, respectively). Neither of the variables were significantly different between the two groups. Testing procedures. A medical history and physical examination were performed by a cardiologist on each patient before testing. Before a graded exercise treadmill test, supine and standing 12-lead electrocardiograms (ECG) were obtained on each patient, from which HR
0161-7567/92 $2.00 Copyright 0 1992 the American Physiological Society
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EXERCISE TABLE
TESTING
AFTER
1. Subject characteristics
Group
n
Age, yr
OHT HS
28 19
45t1.9" 59k3.1
Height,
cm
HEART TABLE
Weight,
kg
261
TRANSPLANTATION
3. Heart rate and blood pressure values
Months Postoperative
Heart
Rate, min”
Resting
44.4t0.4 43.8t0.6
79.5t4.2 80.4t3.3
3.0t0.4* 6.0t1.7
Values are means + SE. OHT, orthotopic heart transplantation; heart surgery. * P zsi0.05, OHT vs. HS. TABLE Stage 1
2 3 4 5 6 7
HS,
3 6 9 12 15 18 21
Speed, mph
2.0 2.0 3.0 3.0 3.0 3.5 4.0
mmHg
Group
n
Supine
Standing
Peak
Systolic
Diastolic
OHT HS
28 19
93+2* 74t3
94t2* 83k4
132t4 14o_t5
164t4.9" 129k4.5
96.0t2.3* 78.2k2.1
Values are means t SE. For abbreviations, see Table 1. * P < 0.001, OHT vs. HS.
2. Graded exercise protocol used for testing Cumulative Duration, min
Resting Blood Pressure,
Grade,
0 7.0 7.5 12.5 17.5 16.0 18.0
%
TABLE
4. Respiratory responsesduring peak exercise VE,
h,
Group
n
l/min
ml kg-’
OHT HS
16 9
75.Ok5.0 78.9t8.7
l
&ifE, l
min-’
17.5kO.9 20.4tl.l
l/min
RER
51.3k4.0 45.6t3.1
1.25*0.01* 1.13kO.03
Values are means + SE. VE, ventilation; OO,, 0, consumption; ventilatory equivalent for 0,; RER, respiratory exchange ratio. For other abbreviations, see Table 1. * P I 0.05, OHT vs. HS. O$E,
was determined. An appropriately sized blood pressure ordinate, respectively. The vo2 (l/min) at which each re(BP) cuff was attached to a mercury sphygmomanometer viewer determined a patient’s VT to have occurred (VTand applied to the right arm of each patient. A 12-lead VO,) was calculated, and a mean VT-VO, was computed continuous monitoring ECG stress system was used for each patient. Mean VT-VO, was also expressed for (model 3000, Quinton Instruments, Seattle, WA), and a each patient as a percentage of peak VO, [VT% = demonstration of walking on the treadmill was presented (VT - \jo,lpeak 00,) X 1001. Mean values were then to each patient. Depending on availability of the neces- calculated for both study groups. sary equipment, patients from each group also underStatistical analysis. All variables were analyzed with went gas exchange analysis (n = 16 for OHT and n = 9 the use of the Student’s two-sample t test, and Bonfor HS). Mean postoperative time was significantly dif- ferroni’s multiple comparison adjustment was applied to ferent for the entire group of patients; however, there recovery HR. Systolic BP during recovery was analyzed was no significant difference between the OHT (n = 9) with univariate repeated-measures y analysis of variance and HS (n = 15) patients who underwent gas exchange group effect. Interreviewer agreement was determined analysis (3.2 t 1.8 vs. 2.7 t 3.2, P = 0.71). A Horizon II with the intraclass correlation coefficient. metabolic system (Sensormedics, Anaheim, CA) was utilized and calibrated according to manufacturer’s recomRESULTS mendations before each test. This system provided continuous measurement of expired gases and reported an Resting supine and standing HR were significantly greater (P < 0.01) for the OHT patients. Resting systolic average value every 15 s. and diastolic BP were also significantly higher for the The treadmill protocol and metabolic cart were simultaneously started after it was felt that the patient was OHT patients (P < 0.01). Peak HR was not significantly different between the two groups, and the mean increase walking comfortably without using handrail support. in HR from rest to peak exercise (HR reserve) for HS The exercise protocol was modified from Savin et al. (I4 and is shown in Table 2. The test was performed to and OHT patients was 68 and 40 min-‘, respectively (P zz symptom-limited maximum exertion. BP, HR, and an 0.01). HR results are given in Table 3. Total exercise treadmill time (TT) was significantly ECG were recorded at the end of each 3-min stage. At the greater (P < 0.01) for the HS than for the OHT patients end of the test the treadmill was stopped, and the patient greater was placed in the supine position. BP, HR, and ECG were (7.9 vs. 10.0 min). Peak RER was significantly (P < 0.01) for OHT patients, with all but one patient monitored throughout an 8-min recovery period. VO, (l/min and ml. kg-l. min-l), ventilatory equivaachieving a peak value of ~1.00. For the remaining gas lent for oxygen (O&5, l/l), ventilatory equivalent for exchange measurements, no significant differences were noted between groups except absolute VO, (Urnin), which c!rbon dioxide (COJE, l/l), expired carbon dioxide (VCO,, Urnin), respiratory exchange ratio (RER), and was 14.2% greater in the HS patients (P < 0.01). Comventilation (VE, l/min) were recorded throughout the plete results can be found in Tables 4 and 5. test and used to determine ventilatory threshold (VT). The HS patients demonstrated a more rapid decline in HR during recovery than did the OHT patients (Fig. 1). Methods described by Beaver et al. (1) and Wasserman RHR at minutes 2, 3, 5, and 7 were significantly greater et al. (20) were used as guidelines by four independent and experienced reviewers, when evaluating the followin the OHT patients (P < 0.01). Both groups demoning four graphs: 1) TO, (x) and VCO, (y); 2) time (x) strated a significant decrease in systolic BP from minute and O$E and COJE (y); 3) time (x) and VE (y); and 4) 1 to minute 6 of recovery, and at each time point there time (x) and RER (y), where x and y are the abscissa and was no significant difference between groups (Fig. 2). Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on November 2, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
262 150T 140
EXERCISE
a
TESTING
AFTER
HEART TABLE
0 OHT 0 HS
TRANSPLANTATION
5. Ventilatory
Group
n
OHT HS
16
9
threshold during exercise Peak OO,, l/min
1.33*0.08* 1.75kO.11
VT-t’02, Umin 1.05t0.19* 1.41k4.0
% of Peak 00, 78% 80%
Values are means t SE. VT-VO,, VO, at which ventilatory threshold occurs. For other abbreviations see Table 4. * P I 0.01, OHT vs. HS.
80
Peak Exercise
I
I
’
2
1
3
I
5
D 7
Recovery Time (min) I I FIG. 1. Peak exercise and recovery heart rate at minutes 1, 2, 3, 5, and 7 for orthotopic heart transplantation (OHT) and heart surgery (HS) patients. OHT group significantly greater than HS group: *p < 0.05.
VT-$70, was significantly lower in the OHT patients (P < 0.01) than in the HS patients (Table 5). However, there was no significant difference between the two groups for VT%. Assessment of interreviewer agreement revealed intraclass correlation coefficients (r) of 0.69 and 0.82 for HS and OHT patients, respectively. Peak pulse pressure was significantly lower in the OHT than in the HS patients (74.6 t 5.5 vs. 97.4 t 4.4 mmHg, P < 0.05). There was no significant difference in peak 0, pulse (12.5 t 1.4 ml O,/beat for OHT vs. 11.6 t 0.6 ml O,/beat for HS) or HR-SBP product (215 t 10 X lo2 mmHg/min for OHT vs. 246 t 16 X lo2 mmHg/min for HS). DISCUSSION
Our elevated mean resting supine HR of 93 beats/min in OHT patients is in agreement with values reported by others (16,17) and is significantly higher than the HR of our HS patients. This rate most likely reflects the intrinsic rate-of the decentralized heart. Evidence of total decentralization for our OHT patients was demonstrated by the absence of an increase in HR after patients as180 2175 El70
E
;I65 '160
3 P2155 $150 ;145 g140 bl35
6 i?th DUV
7
i i Ii Recovery Time (min) FIG. 2. Systolic blood pressure at minutes 1, 2, 4, 6, and 8 of recovery for OHT and HS patients. Within-group change from minute 1 to minute 8 is significant: *‘P < 0.05. 1
i
sumed an upright position before exercise. This response agrees with previous reports (2, 6,8). The resting ejection fraction and left ventricular enddiastolic pressure values were not significantly different, and it is assumed that resting ventricular function is not different between the groups. The resting SBP and diastolic blood pressure values were both significantly different. Many OHT patients become hypertensive after surgery, and this may be a result of immunosuppressive therapy (cyclosporine and prednisone). Some of these patients may require antihypertensive agents. The significantly reduced TT for our OHT patients agrees with data previously reported by Kavanagh et al. (7). This response may be secondary to reduced skeletal muscle mass in the lower limbs of the OHT patients, secondary to their extended period of inactivity before and initially after surgery. Prednisone and/or cyclosporine may also play a role in lean mass deterioration, because the long-term effects of these therapies are not well understood. No significant difference was found in peak HR between the two groups. This agrees with Savin (13) and Degre et al. (5) but differs from Kavanagh et al. (7), who reported a significantly lower peak HR in OHT patients when compared with healthy normal subjects. Because the transplanted heart lacks all autonomic nervous input, it mainly relies on increasing levels of circulating catecholamines (epinephrine and norepinephrine) to increase its rate. Christenson and Galbo (4) have previously demonstrated that catecholamines increase at a rate that is, within limits, directly related to increases in both exercise duration and VO,. An increase in the concentration of catecholamines during exercise is a result of adrenergic and choline@ sympathetic activity. The lack of efferent sympathetic input and/or the significantly reduced TT may be explanations for the lower peak HR noted for our OHT patients, with the latter possibly limiting peak catecholamine values. Because the heart mainly relies on an increase in rate to elevate cardiac output at higher levels of exercise, the significantly lower increase in HR from rest to peak (HR reserve) in our OHT patients may be responsible for their reduced total peak vo2. Other explanations for the reduced peak Vo2 might include the following: 1) exaggerated skeletal muscle deconditioning experienced by the OHT patients due to the extended periods of bed rest both before and after surgery and 2) differences in exercise systolic and diastolic ventricular function between the two groups. The significantly greater peak RER value of the OHT patients may be related to their attenuated increase in HR during early exercise. Degre et al. (5) suggest that such an attenuated HR response requires OHT recipients to rely on accelerated anaerobic metabolism earlier
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EXERCISE
TESTING
AFTER SUELETAL
M.
K.Y 1) + -Add to (rtlmulrto) 1) --subtm8tfmm(lnhlblti 3) a tvatt - Y8gnRud8of Inon 01~
dwfwu (4
b.--Noahmgo
lntua maPow for doaenmllzod prtknt
PM
3. Cardiovascular adjustments normal and decentralized subjects. FIG.
to acute dynamic exercise in
during exerci se than their innervated counterparts. Savin et a.l. (15) suggest that the earlier accelerated ana .erobit metabolism in OHT patients is secondary to decreased 0, uptake but does not distinguish whether this is secondary to shortcomings in central delivery or peripheral utilization. A review of the possible mechanisms that take place during acute dynamic exercise in innervated and decentralized subjects is shown in Fig. 3. From minute 2 to minute 8 of recovery, the HRs are significantly higher in the OHT patients. This suggests the absence of parasympathetic innervation to the myocardium in the OHT patients, although myocardial stretch and catecholamine clearance rate may also play a role. The effects of circulating catecholamines last from several seconds to several mi .nutes before they are removed from the blood (18). As our data indicate, the lack of parasympathetic innervation (and possibly a delayed catecholamine clearance rate) in the OHT patients results in an early recovery HR that is slightly higher than the peak exercise value. Despite a significantly lower absolute VT between the two groups (1.05 vs. 1.41 l/min for OHT and HS, respectively), the lack of a difference for VT% (79 vs. 80% for OHT and HS patients, respectively) demonstrates that both groups reach anaerobic threshold (AT) at similar percentages of their peak VO,. Our VT% value for OHT patients is very similar to the 78% value reported by Kavanagh et al. (7) both before and after exercise training. According to Wasserman et al. (20), the lower end of normal VT% is 40%, while many aerobically trained individuals approach 70-80%. Our reported VT% values for OHT vs. HS patients are in conflict with the data of Wasserman et al. (20). Possible explanations may be deconditioned peripheral skeletal muscles or the detection of VT after AT occurred. Wasserman et al. (19) have reported that there is no observable difference in the VT.vo2 value calculated from the VT method we used and AT calculated from lactate values. Gas exchange m ethods for determining AT remain controversial and warrant future studies involving the measurement of blood lactate concentrations in OHT patients. These results suggest that OHT patients accelerate anaerobic metabolism at a significantlv lower absolute
HEART
TRANSPLANTATION
263
TO, than HS patients,
and this response may limit both submaximal and peak exercise. The prescription of exercise or activity using VT% may be misleading, if the absolute 00, values are not taken into consideration. Exercise prescription recommendations. Several investigators have previously demonstrated the ability of OHT patients to benefit from an aerobic exercise conditioning program (7,9,16). Presently, the Borg Rating of Perceived Exertion scale is the preferred method for guiding exercise intensity in OHT patients (8,9). Use of the percentage of measured peak HR method for computing training HR is presently not recommended in OHT patients, because it may result in an underestimation of the upper end of training HR range (9). A similar result may also occur with the use of the HR-reserve method, if periodic follow-up testing is not employed (9). Increasing the duration of a graded exercise test (GXT) by extending each stage of the protocol from 3 to 5 or 6 min may result in a greater peak HR, secondary to increased levels of circulating catecholamines. This practice may prove useful when exercise is prescribed with the use of HR-based methods. VT may represent another method for guiding exercise training intensity in OHT patients. This method involves matching training work load or HR to the GXT work load or HR measured at VT-VO,. If the VT is matched to HR, periodic GXT may be necessary because exercise training HR has been shown to increase during an 8- to 12-wk exercise program (9). This response may affect the VT-to-HR relationship. When compared with that of patients with an innervated heart, HR in OHT patients is significantly increased during exercise recovery, whereas recovery SBP is not significantly different. Therefore, it appears that it is not necessary for OHT recipients to achieve near resting HR values within 8 min after exercise is stopped. Monitoring systolic BP appears to be a more useful tool to assess adequate recovery of the heart and cardiovascular system. Future research is needed to address the determinates of peak Oo, and limits of peak HR and to assess circulating catecholamine and lactate threshold response. As more OHT patients participate in exercise programs to facilitate return to an active lifestyle, a better understanding of the methods used in guiding exercise intensity is also required. Address for reprint requests: S. Keteyian, 2921 West Grand Blvd., NCP 1107, Detroit, MI 48202. Received 9 January 1991; accepted in final form 16 January 1992. REFERENCES 1. BEAVER, W. L., K. WASSERMAN, AND B. J. WHIPP. A new method for detecting anaerobic threshold by gas exchange. J. A&. Physiol. 60:2020-2027,1986. 2. BECK, W., C. N. BARNARD, AND V. SCHRIRE. Heart rate after cardiac transplantation. Am. J. Physiol. 218: 475-484, 1970. 3. BORG, G. Perceived exertion as an indicator of somatic stress. Band. J. Rehabil. Med. 2: 92-98, 1970. 4. CHRISTENSEN, N. J., AND H. GALBO. Sympathetic nervous activity during exercise. Annu. Rev. PhysioZ. 45: 139-153, 1983. 5. DEGRE, S. G., G. L. NISET, J. M. DE SMET, T. IBRAHAM, AND E. STOUPEL. Cardiorespiratory response to early exercise testing after heart transplantation. Am. J. Cardiol. 60: 926-928. 1987.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on November 2, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
EXERCISE
264
TESTING
AFTER
6. HASKELL, W. N. B. INGLES,
L., W. M. SAVIN, J. S. SCHROEDER, E. A. ALDERMAN, G. T. DAUGHTERS, AND E. B. STINSON. Cardiovascular responses to handgrip isometric exercise in patients following cardiac transplantation. Circ. Res. 48: X6-161, 1981. 7. KAVANAGH, T., M. YACOUB, R. MERTENS, J. KENNEDY, R. B. CAMPBELL, AND P. SAWYER. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulution
77: 162-171,1988. 8. KETEYIAN, S.,
J. EHRMAN, F. FEDEL, AND K. RHOADS. Exercise following cardiac transplantation: recommendations for rehabilitation. Sports Med. 8: 251-259, 1989. 9. KETEYIAN, S., J. EHRMAN, F. FEDEL, AND K. RHOADS. Heart rateperceived exertion relationship during exercise in orthotopic heart transplant recipients. J. Cardiopulm. Rehabil. 10: 287-293, 1990. 10. KRIETT, J. M., AND M. P. KAYE. The registry of the International Society for Heart Transplantation: Seventh Annual Official Report-1990. J. Heart Transplant. 9: 323-330, 1990. 11. NISET, G., J. R. POORTMANS, R. LECLERCQ, M. BRASSEUR, J. M. DESMET, S. G. DEGRE, AND G. PRIMO. Metabolic implications during a 20-km run after heart transplantation. Int. J. Sports Med. 6: 340-343,1985. 12. POPE, S. E.,
E. B. STINSON, AND G. T. DAUGHTERS. Exercise response of the denervated heart in long-term cardiac transplant recipients. Am. J. Cardiol. 46: 213, 1980.
HEART
TRANSPLANTATION
13. SAVIN, W. M. Role of the Adrenergic Nervous System in the Production of Cardiovascular Training Effects in Man (Dissertation). Palo
Alto, CA: Stanford University, 1984, p. 68-96. S. SCHROEDER, AND E. B. STINof cardiac transplant patients to graded, symptom-limited exercise. Circukztion 62: 55-60, 1980. 15. SAVIN, W. M., J. S. SCHROEDER, AND W. L. HASKELL. Response of cardiac transplant recipients to static and dynamic exercise: a review. J. Heart Transplant. 1: 72-79, 1982. 16. SQUIRES, R. W., P. R. ARTHURM, G. T. GAU, A. MURI, AND W. B. LAMBERT. Exercise after cardiac transplantation: a report of two cases. J. Cardiopulm. Rehabil. 3: 570-574, 1983. 17. STINSON, E. B., R. B. GRIEPP, J. S. SCHROEDER, E. DONG, AND N. E. SHUMWAY. Hemodynamic observations one and two years after cardiac transplantation in man. Circulation 45: 1183-1194,
14. SAVIN, W. M., W. L. HASKELL, J. SON. Cardiorespiratory responses
1972. 18. VANDER, A. J., J. H. SHERMAN, AND D. S. LUCIANO. Human Physiology: The Mechanism of Body Function (3rd ed.). Philadelphia, PA: McGraw-Hill, 1980. 19. WASSERMAN, K., W. L. BEAVER, AND B. J. WHIPP. Reply to the editor. J. Appl. Physiol. 67: 2641, 1989. 20. WASSERMAN, K., B. J. WHIPP, S. N. KOYAL, AND W. L. BEAVER.
Anaerobic threshold and respiratory gas exchange during exercise. J. Appl.
Physiol.
35: 236-243,
1973.
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