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Partial Normalization of the Heart Rate Response to Exercise After Cardiac Transplantation: Frequency and Relationship to Exercise Capacity
Mayo Clin Proc, December 2002, Vol 77
Heart Rate Response After Cardiac Transplantation
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Original Article
Partial Normalization of the Heart Rate Response to Exercise After Cardiac Transplantation: Frequency and Relationship to Exercise Capacity RAY W. SQUIRES, PHD; TAT-CHI LEUNG, MBCHB, MRCP; NANCY S. CYR, BS; THOMAS G. ALLISON, PHD; BRUCE D. JOHNSON, PHD; KARLA V. BALLMAN, PHD; JEAN A. WAGNER, RN CNP; LYLE J. OLSON, MD; ROBERT P. FRANTZ, MD; BROOKS S. EDWARDS, MD; SUDHIR S. KUSHWAHA, MD; JOSEPH A. DEARANI, MD; RICHARD C. DALY, MD; CHRISTOPHER G. A. MCGREGOR, MD; AND RICHARD J. RODEHEFFER, MD
• Objective: To determine the frequency of partial normalization of the heart rate response to graded exercise and its relationship to exercise capacity in cardiac transplant recipients. • Subjects and Methods: The study subjects were 95 adults (77 men, 18 women) who were available to perform a cardiopulmonary exercise test 1 year after orthotopic cardiac transplantation, which occurred between June 1988 and September 1998. All subjects received standard immunosuppressant medications. At the time of the exercise tests, the mean ± SD age of the subjects was 49±14 years. The mean ± SD resting left ventricular ejection fraction was 62%±8%. All subjects participated in a 6- to 8-week supervised exercise program, starting no later than 1 month after surgery. Subjects were given an exercise prescription for independent exercise training after finishing the supervised program. Self-reported weekly exercise training had a median value of 90 minutes (interquartile range, 0-210 minutes). Symptom-limited graded exercise was performed on a treadmill, with breath-by-breath analysis of expired air. • Results: For the entire cohort, peak exercise oxygen uptake was 19.9±4.8 mL · kg–1 · min–1 (61%±15% of age
and sex predicted). Thirty-two subjects (34%) had a partially normalized heart rate response to graded exercise. The frequency was similar for men (25/77 [33%]) and for women (7/18 [39%]) and was independent of recipient or donor age. Peak exercise heart rate (147±18 vs 134±21 beats/min; P=.008) and heart rate reserve (46±15 vs 33±15 beats/min; P<.001) were greater for subjects with a partial normalization of heart rate response. Peak exercise oxygen uptake was similar for subjects with or without partial normalization of the heart rate response (20.9±5.8 vs 19.4±4.2 mL · kg–1 · min–1; P=.22). Submaximal exercise oxygen uptake during the first few minutes of exercise was also not affected by normalization of the heart rate response. • Conclusion: At 1 year after cardiac transplantation, approximately one third of subjects had partial normalization of the heart rate response to graded exercise. However, a higher peak exercise heart rate and a larger heart rate reserve did not result in better aerobic exercise capacity. Mayo Clin Proc. 2002;77:1295-1300 V·O2 = oxygen uptake; V·O2peak = peak exercise oxygen uptake
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ardiac transplantation results in complete denervation of the myocardium.1 The loss of autonomic nervous system innervation results in an abnormal heart rate response to graded exercise testing that is related in part to dependence on the levels of circulating catecholamines for heart rate control.2 As shown in Figure 1, the resting heart rate is elevated, there is only a minimal increase in rate during the first few minutes of exercise, the maximal heart rate occurs in the recovery period after exercise rather than at peak
exercise, and there is a plateau in heart rate during recovery from exercise with a slow return to resting values. In cardiac transplant recipients, the chronotropic reserve is reduced, and exercise capacity is usually below normal compared with subjects who have undergone coronary artery bypass surgery.4 The below-normal exercise capacity may5 or may not6 be related to the reduced chronotropic responsiveness. Until recently, denervation was thought to be permanent. However, several investigators, using diverse methods such as uptake of the norepinephrine analogue C-11 hydroxyephedrine measured by positron emission tomography,5 heart rate responsiveness to intracoronary tyramine infusion,6 and uptake of iobenguane by myocardial sympathetic fibers,7 showed sympathetic nervous system reinnervation in some cardiac transplant recipients months to years after surgery. Several investigators have reported an increase in heart rate in most subjects during maximal exercise during the
From the Division of Cardiovascular Diseases and Internal Medicine (R.W.S., T.-C.L., N.S.C., T.G.A., B.D.J., J.A.W., L.J.O., R.P.F., B.S.E., S.S.K., R.J.R.), Division of Biostatistics (K.V.B.), and Division of Transplantation Surgery (J.A.D., R.C.D., C.G.A.M.), Mayo Clinic, Rochester, Minn. Dr Leung is now with the Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong. Address reprint requests and correspondence to Ray W. Squires, PhD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:1295-1300
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© 2002 Mayo Foundation for Medical Education and Research
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Heart Rate Response After Cardiac Transplantation
with a potentially important improvement in clinical status. However, the frequency and importance of this partial normalization of the heart rate response to exercise are unknown. Accordingly, the aim of this study was to determine the frequency of partial normalization of the heart rate response to exercise and the relationship to exercise capacity in a cohort of 95 cardiac transplant recipients.
180
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Before 160 140 After
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Figure 1. Heart rate response to graded exercise 1 year before and 3 months after orthotopic cardiac transplantation in 1 subject. Before transplantation, heart rate increased with each increment in exercise intensity (from 1 to 6 metabolic equivalents [METs], in which METs = multiples of resting oxygen uptake), with the highest heart rate at peak exercise (6 METs). After transplantation, the heart rate response is markedly changed and typical for myocardial denervation with an elevated resting rate, the increase in heart rate during graded exercise is blunted and delayed, and the maximal heart rate occurs in the recovery period. Reprinted with permission from Squires.3
first year after transplantation,4,8 an improvement in chronotropic reserve, and a more rapid decline in heart rate after exercise in some subjects.9 These findings are consistent Table 1. Characteristics of the 95 Transplant Recipients and Donors* Subject age (y) Subject sex, No. (%) Male Female Etiology of heart failure, No. (%) Dilated cardiomyopathy Coronary heart disease Congenital heart disease Amyloidosis Other Pretransplantation LVEF (%) PVR (Woods unit) UNOS status, No. (%) 1 2 Graft ischemic time (min) ICU after surgery (d) Donor age (y) Donor sex, No. (%) Male Female
48±14 77 (81) 18 (19) 36 (38) 32 (34) 10 (11) 8 (8) 9 (10) 20±11 2.7±1.4 65 (68) 30 (32) 152±49 8±5 30±13 70 (74) 25 (26)
*Values are expressed as mean ± SD unless indicated otherwise. ICU = intensive care unit; LVEF = left ventricular ejection fraction; PVR = pulmonary vascular resistance; UNOS = United Network for Organ Sharing.
SUBJECTS AND METHODS The study was approved by the Mayo Foundation Institutional Review Board. The study subjects were 95 adults who underwent orthotopic cardiac transplantation between June 1988 and September 1998 and who were available and able to perform a cardiopulmonary exercise test at 1 year after surgery. This represents 72% of the 132 adults who underwent transplantation during this period who survived at least 1 year. Subjects were excluded if they had rate-responsive pacemakers or musculoskeletal limitations that precluded performance of an exercise test. Thirty-seven subjects also performed an “early” exercise test within the first 3 months after transplantation for clinical reasons. Characteristics of the subjects and donors at the time of transplantation are presented in Table 1. Most subjects were men, and the mean age was younger than 50 years. Sixty-eight subjects (72%) underwent transplantation for treatment of dilated cardiomyopathy or coronary heart disease. The mean waiting time for surgery was approximately 10 months (median, 5.6 months). At the time of cardiopulmonary exercise testing 1 year after surgery, the mean ± SD number of treated acute rejection episodes was 1.1±1.3 (range, 0 to 5). The average body weight was 84.5±17.2 kg, body mass index was 28.0±5.2 kg/m2, and resting left ventricular ejection fraction was 62%±8%. Seventy-five of the subjects (79%) required antihypertensive medications. Three subjects (3%) took β-blockers, 43 (45%) took calcium channel blockers, and 33 (35%) took angiotensin-converting enzyme inhibitors. The average maintenance dosage of prednisone was 10.5±4.9 mg/d. All subjects received cyclosporine (goal blood level of 100-150 ng/dL) and azathioprine for additional immunosuppression. After transplantation, all subjects participated in a supervised exercise program for 6 to 8 weeks, beginning no later than 1 month after surgery. They were provided with an exercise prescription at the completion of the supervised exercise program and were encouraged to perform regular independent exercise. One year after transplantation, the median self-reported weekly exercise duration was 90 minutes (interquartile range, 0-210 minutes per week; minimum and maximum values, 0 and 630 minutes, respectively).
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Mayo Clin Proc, December 2002, Vol 77
Cardiopulmonary Exercise Testing Symptom-limited graded exercise testing was performed on a motor-driven treadmill (Marquette Electronics, Milwaukee, Wis, or Quinton Instruments, Seattle, Wash). The protocol has been described previously.4 The test began at a slow walking speed with increases in either treadmill grade or speed every 2 minutes and included an active recovery period after peak exercise of slow walking for a duration of 3 minutes, followed by resting while seated. The 12-lead electrocardiogram (Marquette Electronics) was monitored continuously, with heart rate recorded for each minute of exercise and for at least 6 minutes during the recovery period. Breath-by-breath analysis of expired air was performed with use of a calibrated, computerized metabolic cart (Medical Graphics Corp, St · Paul, Minn). Oxygen uptake (VO2), carbon dioxide production, and minute ventilation were averaged during 30-second intervals. The respiratory exchange ratio was calcu· lated. Peak exercise oxygen uptake (VO2peak) was defined as the highest 30-second average during exercise. Percent · predicted VO2peak for age and sex was calculated.10 Blood pressure levels were measured by the standard cuff method for each work stage of the test per our laboratory standards, although these results are not reported. Operational Definitions of Heart Rate Responses The heart rate response for each minute of exercise and recovery was assessed for each test. The heart rate response for each subject was arbitrarily defined as “denervated” or “partially normalized.” The classic denervated heart rate response is shown in Figure 1. A definition of the heart rate response as partially normalized required all the following: (1) increase in heart rate for each minute of progressive exercise, (2) highest heart rate at the peak exercise intensity, and (3) decrease in heart rate for each minute of the recovery period. Statistical Analyses Differences between study subjects with and without partial normalization of the heart rate response were assessed by using a 2-tailed t test. The relationship between selected pairs of variables was assessed by using Pearson correlation coefficients. Descriptive statistics for both groups were calculated as mean ± SDs. In all instances, statistical significance was P<.05. RESULTS Responses of the Entire Cohort to Exercise Cardiopulmonary exercise test results at 1 year after transplantation and general characteristics for the entire cohort of 95 subjects are presented in Table 2. Marked heterogeneity in heart rate responses to exercise as well as in
Heart Rate Response After Cardiac Transplantation
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Table 2. Characteristics and Cardiopulmonary Exercise Test Variables 1 Year After Cardiac Transplantation for the 95 Study Subjects* Age (y) Allograft coronary artery disease,† No. (%) Exercise test duration (min) Range Heart rate (beats/min) At rest Range At peak exercise Range Reserve (peak – rest) Range . VO2peak (L/min) . Range VO2peak (mL · kg–1 · min–1) Range . % Predicted VO2peak Range RERpeak Range
49±14 23 (24) 7.6±2.3 4.0 to 14.0 102±13 73 to 136 138±22 93 to 192 37±16 6 to 100 1.6±0.4 0.9 to 3.4 19.9±4.8 11.3 to 37.7 61±15 39 to 110 1.2±0.1 0.8 to 1.4
*Values are. expressed as mean ± SD unless indicated otherwise. % Predicted VO2peak = percentage of age- and sex-predicted peak exercise oxygen uptake; RERpeak = respiratory exchange ratio at peak exercise. †Angiographically defined as >20% focal stenosis or diffuse obliterative changes.
· VO2peak were present. The mean respiratory exchange ratio at peak exercise averaged 1.2 and was consistent with nearmaximal subject effort during the progressive exercise tests. Frequency of Partial Normalization of Heart Rate Response to Exercise Thirty-two subjects (34%) had a partially normalized heart rate response to graded exercise (as defined for this study) at 1 year after orthotopic cardiac transplantation. The frequency was similar for men (25/77 subjects [33%]) and for women (7/18 subjects [39%]). At transplantation, the age of the subjects with heart rate normalization was similar to that of subjects without heart rate normalization (47±14 vs 49±14 years; P=.41). Likewise, donor age was similar for both groups (29±13 vs 30±13 years; P=.63). Primary causes of heart failure in subjects with heart rate normalization were dilated cardiomyopathy (14 subjects) and coronary heart disease (12 subjects). Body mass index was similar for subjects with and without heart rate normalization (27.2±4.2 vs 28.4±5.7 kg/m2; P=.42). Self-reported minutes of physical activity per week were also similar for the 2 groups (median, 95 min/wk; interquartile range, 0214 min/wk vs median, 85 min/wk; interquartile range, 0210 min/wk; P=.67). The heart rate response to exercise at 1 year after transplantation for the 37 subjects who performed an early exercise test within the first 3 months after surgery was classified as denervated in 27 subjects and partially normalized in 10 subjects. At the early test, all 37 subjects had
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Heart rate (beats/min)
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Figure 2. Heart rate response to 7 minutes of treadmill graded exercise and 3 minutes of recovery (R1-R3) for 1 subject 3 months and 12 months after cardiac transplantation. The response at 3 months is denervated whereas at 12 months is partially normalized.
a denervated heart rate response. The mean peak exercise heart rate for the early exercise test for subjects later classified as having either denervated or partially normalized responses were similar (128±20 vs 133±19 beats/min; P=.53). The heart rate response of a single subject to graded exercise at the early and 12-month test is shown in Figure 2. The marked improvement in heart rate responsiveness seen at 12 months is consistent with partial normalization. Relationship of Heart Rate Normalization to Exercise Capacity A comparison of cardiopulmonary exercise test variables for subjects with and without partial normalization of
Table 3. Comparison of Cardiopulmonary Test Variables for Subjects With a Partially Normalized or Denervated Heart Rate Response*
Variable Heart rate (beats/min) At rest At peak exercise Reserve (peak – rest) Exercise test duration (min) . VO2peak L/min mL · kg–1 .· min–1 % Predicted VO2peak RERpeak . VEpeak (L/min)
Partially normalized (n=32)
Denervated (n=63)
P value
100±12 147±18 46±15 8.3±2.1
103±14 134±21 33±15 7.3±2.3
.33 .008 <.001 .02
1.6±0.4 1.6±0.5 .71 20.9±5.8 19.4±4.2 .22 63±14 60±15 .33 1.2±0.1 1.2±0.1 .98 72.8±24.3 73.1±22.9 .90 . *All values are expressed as mean ± SD. VEpeak = minute ventilation at peak exercise. For expansion of other abbreviations, see footnote to Table 2.
the heart rate response is presented in Table 3. Resting heart rates were similar, whereas peak exercise heart rate and heart rate reserve (chronotropic reserve) were greater for those with partial heart rate normalization. Exercise test duration averaged 1 minute longer for subjects with nor· malization. Nonetheless, VO2peak, peak respiratory exchange ratio, and peak exercise minute ventilation did not differ for the 2 groups of subjects. To assess the effects of partial normalization of the heart rate response on submaximal exercise performance, we · compared the VO2 for each of the first 3 minutes of the exercise test (Table 4). Despite a more rapid increase in heart rate at the onset of exercise in the subjects with normalization, there were no differences in submaximal · exercise VO2. For subjects with partial heart rate normalization, the · correlation of VO2peak and exercise test duration was relatively strong (r=0.51; P=.005), as would be expected. However, the correlations of peak exercise heart rate and heart · rate reserve with VO2peak were weak (r=0.16 and P=.39 and r=0.03 and P=.88, respectively). DISCUSSION The main finding of this study was that partial normalization of the heart rate response to graded exercise occurred in approximately one third of subjects at 1 year after transplantation. In these subjects, heart rate increased consistently during exercise, peak exercise heart rate was substantially higher than for subjects without partial normalization, and recovery heart rate decreased in a consistent manner. This outcome is in contrast to the denervated response typically observed during the first few months after transplantation, characterized by a blunted increase in heart rate at the onset of exercise, the maximum rate in the early recovery period after peak exercise, and a plateau in heart rate for several minutes after peak exercise. In the small subgroup of subjects who performed an early exercise test within 3 months of transplantation, the heart rate responses were similar for subjects who were classified as having either denervated or partially normalized responses at 1 year. Therefore, it is unlikely that these subjects differed in their heart rate response to exercise in the first few months after surgery. The time course for subjects to develop a partially normalized heart rate response to exercise cannot be determined from the current study. Clearly, the chronotropic response improves during graded exercise testing in some subjects throughout the first year after transplantation.4,8,9 Resting heart rates did not differ for subjects with or without partial normalization, and this finding is consistent with a lack of parasympathetic reinnervation, which has
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Mayo Clin Proc, December 2002, Vol 77
been reported previously.11 The magnitude of the increase in heart rate during exercise (heart rate reserve) was greater; however, peak exercise heart rates averaged 30 beats/min lower than expected for healthy individuals of the same age.12 The finding of partial heart rate normalization to exercise was similar in men and women and was independent of recipient or donor age, amount of habitual physical activity, or body mass index. Partial heart rate normalization occurred in equal numbers of subjects with coronary heart disease and dilated cardiomyopathy as indications for transplantation. The improved responsiveness of heart · rate was not associated with a higher VO2peak or a more · rapid increase in VO2 during the first few minutes of exercise. Therefore, the clinical importance of this finding is inapparent. Subjects with and without partial heart rate normalization had the same mean peak exercise oxygen uptake. Because the denervated group had a substantially lower peak exercise heart rate, stroke volume was probably higher as a result of a greater end-diastolic volume in order to derive the same cardiac output and oxygen uptake. This compensation in heart rate and stroke volume during exercise may be similar to the effects of aging in healthy subjects.13 Sympathetic reinnervation of the sinoatrial node is the most likely mechanism resulting in the somewhat normalized heart rate response to exercise observed in the current study. However, we made no attempt to measure autonomic nervous system activity directly. An alternative explanation is increased sensitivity to circulating catecholamines in subjects with a more normal heart rate increase during exercise.14 However, this does not explain the initial increase in heart rate observed at the onset of exercise because a time lag exists between the beginning of exercise and the increase in circulating catecholamines.15 Previous investigations have shown that biochemically determined cardiac reinnervation is associated with improved heart rate responsiveness to exercise with higher peak exercise heart rates and larger heart rate reserves.5,6,16,17 In these investigations, 55% to 60% of subjects had biochemical evidence of sympathetic reinnervation at 2 to 4 years after transplantation. Average peak exercise heart rates and heart rate reserves ranged from 137 to 143 beats/ min and 40 to 53 beats/min, respectively, and are similar to values in the current study for subjects with partial normalization of the heart rate response. The relationship of adequacy of the chronotropic response to exercise and aerobic capacity after cardiac transplantation is controversial. For example, Schwaiblmair · et al5 reported a higher VO2peak (21.0 vs 16.1 mL · kg–1 · –1 min ) at 2 to 5 years after surgery for 20 subjects with a
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Table 4. Comparison of the Transition in Submaximal V· O2 (mL · kg–1 · min–1) During the First 3 Minutes of Progressive Exercise for Subjects With a Partially Normalized or Denervated Heart Rate Response* Heart rate response
Minutes
Partially normalized (n=32)
Denervated (n=63)
P value
1 2 3
8.2±1.6 11.0±1.7 12.3±1.7
7.9±1.5 10.5±1.8 12.1±1.5
.34 .29 .56
*All values are expressed as mean ± SD.
greater heart rate reserve (40 vs 26 beats/min) and peak exercise heart rate (137 vs 120 beats/min) compared with 15 subjects with a poorer chronotropic response. Conversely, Wilson et al6 found no significant difference in · VO2peak (19.9 vs 18.6 mL · kg–1 · min–1) in 28 subjects with or without a better chronotropic response (heart rate reserve, 52 vs 41 beats/min; peak heart rate, 142 vs 126 beats/ min) when assessed an average of 2.5 years after transplantation. Kemp et al14 studied 68 subjects at 1 year af· ter surgery and found a higher VO2peak (23.5 vs 18.7 mL · –1 –1 kg · min ) for patients with a higher peak heart rate (149 vs 136 beats/min) and heart rate reserve (52 vs 31 beats/ min). However, Mandak et al8 reported an extremely weak correlation (r=0.1) between the heart rate reserve and · VO2peak in 60 subjects studied between 6 and 60 months after transplantation, consistent with our results. Because of the large number of subjects and the consistent assessment of exercise responses at 1 year after transplantation, the current study provides strong evidence for the lack of relationship between the chronotropic response and aerobic exercise capacity in these subjects. Several potential factors may help explain why cardiac transplant recipients with a partially normalized heart rate response to exercise did not have a better aerobic capacity than subjects with a more blunted heart rate response. The contractile function of the heart may be impaired secondary to cold ischemia of the graft during harvesting, early rejection episodes, or cyclosporine treatment resulting in myocardial fibrosis and hypertension.17 Chronic heart failure before transplantation may result in skeletal muscle abnormalities that persist after surgery, such as decreased aerobic metabolic enzyme activity, reduced capillary numbers per muscle fiber, and impaired vasodilatory capacity, all of which may result in a lower arterial–mixed venous oxygen difference and oxygen uptake.18,19 Additional factors such as corticosteroid-induced myopathy, progressive osteopenia, peripheral arterial disease, and diastolic dysfunction may limit exercise capacity independent of the chronotropic response.6
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The definition of partial normalization of the heart rate response to exercise used in the current study was necessarily arbitrary. We required no specific amount of increase in heart rate or a percentage of predicted peak exercise heart rate as part of the criteria for normalization. We chose to focus on heart rate responsiveness early in exercise and during the recovery period after peak exercise. We believe our definition is logical and appropriate given the typical denervated heart rate response to exercise. In conclusion, partial normalization of the heart rate response to graded exercise, as defined in this study, occurs in approximately one third of subjects at 1 year after cardiac transplantation. Despite a higher peak exercise heart rate and a larger heart rate reserve, it does not result in better aerobic exercise capacity.
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Bristow MR. The surgically denervated, transplanted human heart. Circulation. 1990;82:658-660. Savin WM, Haskell WL, Schroeder JS, Stinson EB. Cardiorespiratory responses of cardiac transplant patients to graded, symptomlimited exercise. Circulation. 1980;62:55-60. Squires RW. Cardiac rehabilitation issues for heart transplantation patients. J Cardiopulm Rehabil. 1990;10:159-168. Daida H, Squires RW, Allison TG, Johnson BD, Gau GT. Sequential assessment of exercise tolerance in heart transplantation compared with coronary artery bypass surgery after phase II cardiac rehabilitation. Am J Cardiol. 1996;77:696-700. Schwaiblmair M, von Scheidt W, Uberfuhr P, et al. Functional significance of cardiac reinnervation in heart transplant recipients. J Heart Lung Transplant. 1999;18:838-845. Wilson RF, Johnson TH, Haidet GC, Kubo SH, Mianuelli M. Sympathetic reinnervation of the sinus node and exercise hemodynamics after cardiac transplantation. Circulation. 2000;101:27272733. De Marco T, Dae M, Yuen-Green MS, et al. Iodine-123 metaiodobenzylguanadine scintigraphic assessment of the transplanted hu-
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man heart: evidence for late reinnervation. J Am Coll Cardiol. 1995;25:927-931. Mandak JS, Aaronson KD, Mancini DM. Serial assessment of exercise capacity after heart transplantation. J Heart Lung Transplant. 1995;14:468-478. Scott CD, Dark JH, McComb JM. Evolution of the chronotropic response to exercise after cardiac transplantation. Am J Cardiol. 1995;76:1292-1296. Wasserman K, Hansen JE, Sue DY, Whipp BJ. Principles of Exercise Testing and Interpretation. Philadelphia, Pa: Lea & Febiger; 1987:73. Arrowood JA, Minisi AJ, Goudreau E, Davis AB, King AL. Absence of parasympathetic control of heart rate after human orthotopic cardiac transplantation. Circulation. 1997;96:3492-3498. Sheffield LT, Holt JH, Reeves TJ. Exercise graded by heart rate in electrocardiographic testing for angina pectoris. Circulation. 1965; 32:622-629. Rodeheffer RJ, Gerstenblith G, Becker LC, Fleg JL, Weisfeldt ML, Lakatta EG. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate. Circulation. 1984;69:203-213. Kemp DL, Jennison SH, Stelken AM, Younis LT, Miller LW. Association of resting heart rate and chronotropic response. Am J Cardiol. 1995;75:751-752. Terjung R. Endocrine response to exercise. Exerc Sport Sci Rev. 1979;7:153-180. Uberfuhr P, Ziegler S, Schwaiblmair M, Reichart B, Schwaiger M. Incomplete sympathetic reinnervation of the orthotopically transplanted human heart: observation up to 13 years after heart transplantation. Eur J Cardiothorac Surg. 2000;17:161-168. Bengel FM, Uberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med. 2001;345:731738. Schaufelberger M, Eriksson BO, Lonn L, Rundqvist B, Sunnerhagen KS, Swedberg K. Skeletal muscle characteristics, muscle strength and thigh muscle area in patients before and after cardiac transplantation. Eur J Heart Fail. 2001;3:59-67. Mettauer B, Lampert E, Petitjean P, et al. Persistent exercise intolerance following cardiac transplantation despite normal oxygen transport. Int J Sports Med. 1996;17:277-286.
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Heart Rate Response After Cardiac Transplantation
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Original Article
Partial Normalization of the Heart Rate Response to Exercise After Cardiac Transplantation: Frequency and Relationship to Exercise Capacity RAY W. SQUIRES, PHD; TAT-CHI LEUNG, MBCHB, MRCP; NANCY S. CYR, BS; THOMAS G. ALLISON, PHD; BRUCE D. JOHNSON, PHD; KARLA V. BALLMAN, PHD; JEAN A. WAGNER, RN CNP; LYLE J. OLSON, MD; ROBERT P. FRANTZ, MD; BROOKS S. EDWARDS, MD; SUDHIR S. KUSHWAHA, MD; JOSEPH A. DEARANI, MD; RICHARD C. DALY, MD; CHRISTOPHER G. A. MCGREGOR, MD; AND RICHARD J. RODEHEFFER, MD
• Objective: To determine the frequency of partial normalization of the heart rate response to graded exercise and its relationship to exercise capacity in cardiac transplant recipients. • Subjects and Methods: The study subjects were 95 adults (77 men, 18 women) who were available to perform a cardiopulmonary exercise test 1 year after orthotopic cardiac transplantation, which occurred between June 1988 and September 1998. All subjects received standard immunosuppressant medications. At the time of the exercise tests, the mean ± SD age of the subjects was 49±14 years. The mean ± SD resting left ventricular ejection fraction was 62%±8%. All subjects participated in a 6- to 8-week supervised exercise program, starting no later than 1 month after surgery. Subjects were given an exercise prescription for independent exercise training after finishing the supervised program. Self-reported weekly exercise training had a median value of 90 minutes (interquartile range, 0-210 minutes). Symptom-limited graded exercise was performed on a treadmill, with breath-by-breath analysis of expired air. • Results: For the entire cohort, peak exercise oxygen uptake was 19.9±4.8 mL · kg–1 · min–1 (61%±15% of age
and sex predicted). Thirty-two subjects (34%) had a partially normalized heart rate response to graded exercise. The frequency was similar for men (25/77 [33%]) and for women (7/18 [39%]) and was independent of recipient or donor age. Peak exercise heart rate (147±18 vs 134±21 beats/min; P=.008) and heart rate reserve (46±15 vs 33±15 beats/min; P<.001) were greater for subjects with a partial normalization of heart rate response. Peak exercise oxygen uptake was similar for subjects with or without partial normalization of the heart rate response (20.9±5.8 vs 19.4±4.2 mL · kg–1 · min–1; P=.22). Submaximal exercise oxygen uptake during the first few minutes of exercise was also not affected by normalization of the heart rate response. • Conclusion: At 1 year after cardiac transplantation, approximately one third of subjects had partial normalization of the heart rate response to graded exercise. However, a higher peak exercise heart rate and a larger heart rate reserve did not result in better aerobic exercise capacity. Mayo Clin Proc. 2002;77:1295-1300 V·O2 = oxygen uptake; V·O2peak = peak exercise oxygen uptake
C
ardiac transplantation results in complete denervation of the myocardium.1 The loss of autonomic nervous system innervation results in an abnormal heart rate response to graded exercise testing that is related in part to dependence on the levels of circulating catecholamines for heart rate control.2 As shown in Figure 1, the resting heart rate is elevated, there is only a minimal increase in rate during the first few minutes of exercise, the maximal heart rate occurs in the recovery period after exercise rather than at peak
exercise, and there is a plateau in heart rate during recovery from exercise with a slow return to resting values. In cardiac transplant recipients, the chronotropic reserve is reduced, and exercise capacity is usually below normal compared with subjects who have undergone coronary artery bypass surgery.4 The below-normal exercise capacity may5 or may not6 be related to the reduced chronotropic responsiveness. Until recently, denervation was thought to be permanent. However, several investigators, using diverse methods such as uptake of the norepinephrine analogue C-11 hydroxyephedrine measured by positron emission tomography,5 heart rate responsiveness to intracoronary tyramine infusion,6 and uptake of iobenguane by myocardial sympathetic fibers,7 showed sympathetic nervous system reinnervation in some cardiac transplant recipients months to years after surgery. Several investigators have reported an increase in heart rate in most subjects during maximal exercise during the
From the Division of Cardiovascular Diseases and Internal Medicine (R.W.S., T.-C.L., N.S.C., T.G.A., B.D.J., J.A.W., L.J.O., R.P.F., B.S.E., S.S.K., R.J.R.), Division of Biostatistics (K.V.B.), and Division of Transplantation Surgery (J.A.D., R.C.D., C.G.A.M.), Mayo Clinic, Rochester, Minn. Dr Leung is now with the Pamela Youde Nethersole Eastern Hospital, Chai Wan, Hong Kong. Address reprint requests and correspondence to Ray W. Squires, PhD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2002;77:1295-1300
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© 2002 Mayo Foundation for Medical Education and Research
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with a potentially important improvement in clinical status. However, the frequency and importance of this partial normalization of the heart rate response to exercise are unknown. Accordingly, the aim of this study was to determine the frequency of partial normalization of the heart rate response to exercise and the relationship to exercise capacity in a cohort of 95 cardiac transplant recipients.
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Before 160 140 After
120
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Figure 1. Heart rate response to graded exercise 1 year before and 3 months after orthotopic cardiac transplantation in 1 subject. Before transplantation, heart rate increased with each increment in exercise intensity (from 1 to 6 metabolic equivalents [METs], in which METs = multiples of resting oxygen uptake), with the highest heart rate at peak exercise (6 METs). After transplantation, the heart rate response is markedly changed and typical for myocardial denervation with an elevated resting rate, the increase in heart rate during graded exercise is blunted and delayed, and the maximal heart rate occurs in the recovery period. Reprinted with permission from Squires.3
first year after transplantation,4,8 an improvement in chronotropic reserve, and a more rapid decline in heart rate after exercise in some subjects.9 These findings are consistent Table 1. Characteristics of the 95 Transplant Recipients and Donors* Subject age (y) Subject sex, No. (%) Male Female Etiology of heart failure, No. (%) Dilated cardiomyopathy Coronary heart disease Congenital heart disease Amyloidosis Other Pretransplantation LVEF (%) PVR (Woods unit) UNOS status, No. (%) 1 2 Graft ischemic time (min) ICU after surgery (d) Donor age (y) Donor sex, No. (%) Male Female
48±14 77 (81) 18 (19) 36 (38) 32 (34) 10 (11) 8 (8) 9 (10) 20±11 2.7±1.4 65 (68) 30 (32) 152±49 8±5 30±13 70 (74) 25 (26)
*Values are expressed as mean ± SD unless indicated otherwise. ICU = intensive care unit; LVEF = left ventricular ejection fraction; PVR = pulmonary vascular resistance; UNOS = United Network for Organ Sharing.
SUBJECTS AND METHODS The study was approved by the Mayo Foundation Institutional Review Board. The study subjects were 95 adults who underwent orthotopic cardiac transplantation between June 1988 and September 1998 and who were available and able to perform a cardiopulmonary exercise test at 1 year after surgery. This represents 72% of the 132 adults who underwent transplantation during this period who survived at least 1 year. Subjects were excluded if they had rate-responsive pacemakers or musculoskeletal limitations that precluded performance of an exercise test. Thirty-seven subjects also performed an “early” exercise test within the first 3 months after transplantation for clinical reasons. Characteristics of the subjects and donors at the time of transplantation are presented in Table 1. Most subjects were men, and the mean age was younger than 50 years. Sixty-eight subjects (72%) underwent transplantation for treatment of dilated cardiomyopathy or coronary heart disease. The mean waiting time for surgery was approximately 10 months (median, 5.6 months). At the time of cardiopulmonary exercise testing 1 year after surgery, the mean ± SD number of treated acute rejection episodes was 1.1±1.3 (range, 0 to 5). The average body weight was 84.5±17.2 kg, body mass index was 28.0±5.2 kg/m2, and resting left ventricular ejection fraction was 62%±8%. Seventy-five of the subjects (79%) required antihypertensive medications. Three subjects (3%) took β-blockers, 43 (45%) took calcium channel blockers, and 33 (35%) took angiotensin-converting enzyme inhibitors. The average maintenance dosage of prednisone was 10.5±4.9 mg/d. All subjects received cyclosporine (goal blood level of 100-150 ng/dL) and azathioprine for additional immunosuppression. After transplantation, all subjects participated in a supervised exercise program for 6 to 8 weeks, beginning no later than 1 month after surgery. They were provided with an exercise prescription at the completion of the supervised exercise program and were encouraged to perform regular independent exercise. One year after transplantation, the median self-reported weekly exercise duration was 90 minutes (interquartile range, 0-210 minutes per week; minimum and maximum values, 0 and 630 minutes, respectively).
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Mayo Clin Proc, December 2002, Vol 77
Cardiopulmonary Exercise Testing Symptom-limited graded exercise testing was performed on a motor-driven treadmill (Marquette Electronics, Milwaukee, Wis, or Quinton Instruments, Seattle, Wash). The protocol has been described previously.4 The test began at a slow walking speed with increases in either treadmill grade or speed every 2 minutes and included an active recovery period after peak exercise of slow walking for a duration of 3 minutes, followed by resting while seated. The 12-lead electrocardiogram (Marquette Electronics) was monitored continuously, with heart rate recorded for each minute of exercise and for at least 6 minutes during the recovery period. Breath-by-breath analysis of expired air was performed with use of a calibrated, computerized metabolic cart (Medical Graphics Corp, St · Paul, Minn). Oxygen uptake (VO2), carbon dioxide production, and minute ventilation were averaged during 30-second intervals. The respiratory exchange ratio was calcu· lated. Peak exercise oxygen uptake (VO2peak) was defined as the highest 30-second average during exercise. Percent · predicted VO2peak for age and sex was calculated.10 Blood pressure levels were measured by the standard cuff method for each work stage of the test per our laboratory standards, although these results are not reported. Operational Definitions of Heart Rate Responses The heart rate response for each minute of exercise and recovery was assessed for each test. The heart rate response for each subject was arbitrarily defined as “denervated” or “partially normalized.” The classic denervated heart rate response is shown in Figure 1. A definition of the heart rate response as partially normalized required all the following: (1) increase in heart rate for each minute of progressive exercise, (2) highest heart rate at the peak exercise intensity, and (3) decrease in heart rate for each minute of the recovery period. Statistical Analyses Differences between study subjects with and without partial normalization of the heart rate response were assessed by using a 2-tailed t test. The relationship between selected pairs of variables was assessed by using Pearson correlation coefficients. Descriptive statistics for both groups were calculated as mean ± SDs. In all instances, statistical significance was P<.05. RESULTS Responses of the Entire Cohort to Exercise Cardiopulmonary exercise test results at 1 year after transplantation and general characteristics for the entire cohort of 95 subjects are presented in Table 2. Marked heterogeneity in heart rate responses to exercise as well as in
Heart Rate Response After Cardiac Transplantation
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Table 2. Characteristics and Cardiopulmonary Exercise Test Variables 1 Year After Cardiac Transplantation for the 95 Study Subjects* Age (y) Allograft coronary artery disease,† No. (%) Exercise test duration (min) Range Heart rate (beats/min) At rest Range At peak exercise Range Reserve (peak – rest) Range . VO2peak (L/min) . Range VO2peak (mL · kg–1 · min–1) Range . % Predicted VO2peak Range RERpeak Range
49±14 23 (24) 7.6±2.3 4.0 to 14.0 102±13 73 to 136 138±22 93 to 192 37±16 6 to 100 1.6±0.4 0.9 to 3.4 19.9±4.8 11.3 to 37.7 61±15 39 to 110 1.2±0.1 0.8 to 1.4
*Values are. expressed as mean ± SD unless indicated otherwise. % Predicted VO2peak = percentage of age- and sex-predicted peak exercise oxygen uptake; RERpeak = respiratory exchange ratio at peak exercise. †Angiographically defined as >20% focal stenosis or diffuse obliterative changes.
· VO2peak were present. The mean respiratory exchange ratio at peak exercise averaged 1.2 and was consistent with nearmaximal subject effort during the progressive exercise tests. Frequency of Partial Normalization of Heart Rate Response to Exercise Thirty-two subjects (34%) had a partially normalized heart rate response to graded exercise (as defined for this study) at 1 year after orthotopic cardiac transplantation. The frequency was similar for men (25/77 subjects [33%]) and for women (7/18 subjects [39%]). At transplantation, the age of the subjects with heart rate normalization was similar to that of subjects without heart rate normalization (47±14 vs 49±14 years; P=.41). Likewise, donor age was similar for both groups (29±13 vs 30±13 years; P=.63). Primary causes of heart failure in subjects with heart rate normalization were dilated cardiomyopathy (14 subjects) and coronary heart disease (12 subjects). Body mass index was similar for subjects with and without heart rate normalization (27.2±4.2 vs 28.4±5.7 kg/m2; P=.42). Self-reported minutes of physical activity per week were also similar for the 2 groups (median, 95 min/wk; interquartile range, 0214 min/wk vs median, 85 min/wk; interquartile range, 0210 min/wk; P=.67). The heart rate response to exercise at 1 year after transplantation for the 37 subjects who performed an early exercise test within the first 3 months after surgery was classified as denervated in 27 subjects and partially normalized in 10 subjects. At the early test, all 37 subjects had
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3 mo 12 mo
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Figure 2. Heart rate response to 7 minutes of treadmill graded exercise and 3 minutes of recovery (R1-R3) for 1 subject 3 months and 12 months after cardiac transplantation. The response at 3 months is denervated whereas at 12 months is partially normalized.
a denervated heart rate response. The mean peak exercise heart rate for the early exercise test for subjects later classified as having either denervated or partially normalized responses were similar (128±20 vs 133±19 beats/min; P=.53). The heart rate response of a single subject to graded exercise at the early and 12-month test is shown in Figure 2. The marked improvement in heart rate responsiveness seen at 12 months is consistent with partial normalization. Relationship of Heart Rate Normalization to Exercise Capacity A comparison of cardiopulmonary exercise test variables for subjects with and without partial normalization of
Table 3. Comparison of Cardiopulmonary Test Variables for Subjects With a Partially Normalized or Denervated Heart Rate Response*
Variable Heart rate (beats/min) At rest At peak exercise Reserve (peak – rest) Exercise test duration (min) . VO2peak L/min mL · kg–1 .· min–1 % Predicted VO2peak RERpeak . VEpeak (L/min)
Partially normalized (n=32)
Denervated (n=63)
P value
100±12 147±18 46±15 8.3±2.1
103±14 134±21 33±15 7.3±2.3
.33 .008 <.001 .02
1.6±0.4 1.6±0.5 .71 20.9±5.8 19.4±4.2 .22 63±14 60±15 .33 1.2±0.1 1.2±0.1 .98 72.8±24.3 73.1±22.9 .90 . *All values are expressed as mean ± SD. VEpeak = minute ventilation at peak exercise. For expansion of other abbreviations, see footnote to Table 2.
the heart rate response is presented in Table 3. Resting heart rates were similar, whereas peak exercise heart rate and heart rate reserve (chronotropic reserve) were greater for those with partial heart rate normalization. Exercise test duration averaged 1 minute longer for subjects with nor· malization. Nonetheless, VO2peak, peak respiratory exchange ratio, and peak exercise minute ventilation did not differ for the 2 groups of subjects. To assess the effects of partial normalization of the heart rate response on submaximal exercise performance, we · compared the VO2 for each of the first 3 minutes of the exercise test (Table 4). Despite a more rapid increase in heart rate at the onset of exercise in the subjects with normalization, there were no differences in submaximal · exercise VO2. For subjects with partial heart rate normalization, the · correlation of VO2peak and exercise test duration was relatively strong (r=0.51; P=.005), as would be expected. However, the correlations of peak exercise heart rate and heart · rate reserve with VO2peak were weak (r=0.16 and P=.39 and r=0.03 and P=.88, respectively). DISCUSSION The main finding of this study was that partial normalization of the heart rate response to graded exercise occurred in approximately one third of subjects at 1 year after transplantation. In these subjects, heart rate increased consistently during exercise, peak exercise heart rate was substantially higher than for subjects without partial normalization, and recovery heart rate decreased in a consistent manner. This outcome is in contrast to the denervated response typically observed during the first few months after transplantation, characterized by a blunted increase in heart rate at the onset of exercise, the maximum rate in the early recovery period after peak exercise, and a plateau in heart rate for several minutes after peak exercise. In the small subgroup of subjects who performed an early exercise test within 3 months of transplantation, the heart rate responses were similar for subjects who were classified as having either denervated or partially normalized responses at 1 year. Therefore, it is unlikely that these subjects differed in their heart rate response to exercise in the first few months after surgery. The time course for subjects to develop a partially normalized heart rate response to exercise cannot be determined from the current study. Clearly, the chronotropic response improves during graded exercise testing in some subjects throughout the first year after transplantation.4,8,9 Resting heart rates did not differ for subjects with or without partial normalization, and this finding is consistent with a lack of parasympathetic reinnervation, which has
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Mayo Clin Proc, December 2002, Vol 77
been reported previously.11 The magnitude of the increase in heart rate during exercise (heart rate reserve) was greater; however, peak exercise heart rates averaged 30 beats/min lower than expected for healthy individuals of the same age.12 The finding of partial heart rate normalization to exercise was similar in men and women and was independent of recipient or donor age, amount of habitual physical activity, or body mass index. Partial heart rate normalization occurred in equal numbers of subjects with coronary heart disease and dilated cardiomyopathy as indications for transplantation. The improved responsiveness of heart · rate was not associated with a higher VO2peak or a more · rapid increase in VO2 during the first few minutes of exercise. Therefore, the clinical importance of this finding is inapparent. Subjects with and without partial heart rate normalization had the same mean peak exercise oxygen uptake. Because the denervated group had a substantially lower peak exercise heart rate, stroke volume was probably higher as a result of a greater end-diastolic volume in order to derive the same cardiac output and oxygen uptake. This compensation in heart rate and stroke volume during exercise may be similar to the effects of aging in healthy subjects.13 Sympathetic reinnervation of the sinoatrial node is the most likely mechanism resulting in the somewhat normalized heart rate response to exercise observed in the current study. However, we made no attempt to measure autonomic nervous system activity directly. An alternative explanation is increased sensitivity to circulating catecholamines in subjects with a more normal heart rate increase during exercise.14 However, this does not explain the initial increase in heart rate observed at the onset of exercise because a time lag exists between the beginning of exercise and the increase in circulating catecholamines.15 Previous investigations have shown that biochemically determined cardiac reinnervation is associated with improved heart rate responsiveness to exercise with higher peak exercise heart rates and larger heart rate reserves.5,6,16,17 In these investigations, 55% to 60% of subjects had biochemical evidence of sympathetic reinnervation at 2 to 4 years after transplantation. Average peak exercise heart rates and heart rate reserves ranged from 137 to 143 beats/ min and 40 to 53 beats/min, respectively, and are similar to values in the current study for subjects with partial normalization of the heart rate response. The relationship of adequacy of the chronotropic response to exercise and aerobic capacity after cardiac transplantation is controversial. For example, Schwaiblmair · et al5 reported a higher VO2peak (21.0 vs 16.1 mL · kg–1 · –1 min ) at 2 to 5 years after surgery for 20 subjects with a
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Table 4. Comparison of the Transition in Submaximal V· O2 (mL · kg–1 · min–1) During the First 3 Minutes of Progressive Exercise for Subjects With a Partially Normalized or Denervated Heart Rate Response* Heart rate response
Minutes
Partially normalized (n=32)
Denervated (n=63)
P value
1 2 3
8.2±1.6 11.0±1.7 12.3±1.7
7.9±1.5 10.5±1.8 12.1±1.5
.34 .29 .56
*All values are expressed as mean ± SD.
greater heart rate reserve (40 vs 26 beats/min) and peak exercise heart rate (137 vs 120 beats/min) compared with 15 subjects with a poorer chronotropic response. Conversely, Wilson et al6 found no significant difference in · VO2peak (19.9 vs 18.6 mL · kg–1 · min–1) in 28 subjects with or without a better chronotropic response (heart rate reserve, 52 vs 41 beats/min; peak heart rate, 142 vs 126 beats/ min) when assessed an average of 2.5 years after transplantation. Kemp et al14 studied 68 subjects at 1 year af· ter surgery and found a higher VO2peak (23.5 vs 18.7 mL · –1 –1 kg · min ) for patients with a higher peak heart rate (149 vs 136 beats/min) and heart rate reserve (52 vs 31 beats/ min). However, Mandak et al8 reported an extremely weak correlation (r=0.1) between the heart rate reserve and · VO2peak in 60 subjects studied between 6 and 60 months after transplantation, consistent with our results. Because of the large number of subjects and the consistent assessment of exercise responses at 1 year after transplantation, the current study provides strong evidence for the lack of relationship between the chronotropic response and aerobic exercise capacity in these subjects. Several potential factors may help explain why cardiac transplant recipients with a partially normalized heart rate response to exercise did not have a better aerobic capacity than subjects with a more blunted heart rate response. The contractile function of the heart may be impaired secondary to cold ischemia of the graft during harvesting, early rejection episodes, or cyclosporine treatment resulting in myocardial fibrosis and hypertension.17 Chronic heart failure before transplantation may result in skeletal muscle abnormalities that persist after surgery, such as decreased aerobic metabolic enzyme activity, reduced capillary numbers per muscle fiber, and impaired vasodilatory capacity, all of which may result in a lower arterial–mixed venous oxygen difference and oxygen uptake.18,19 Additional factors such as corticosteroid-induced myopathy, progressive osteopenia, peripheral arterial disease, and diastolic dysfunction may limit exercise capacity independent of the chronotropic response.6
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The definition of partial normalization of the heart rate response to exercise used in the current study was necessarily arbitrary. We required no specific amount of increase in heart rate or a percentage of predicted peak exercise heart rate as part of the criteria for normalization. We chose to focus on heart rate responsiveness early in exercise and during the recovery period after peak exercise. We believe our definition is logical and appropriate given the typical denervated heart rate response to exercise. In conclusion, partial normalization of the heart rate response to graded exercise, as defined in this study, occurs in approximately one third of subjects at 1 year after cardiac transplantation. Despite a higher peak exercise heart rate and a larger heart rate reserve, it does not result in better aerobic exercise capacity.
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