- Email: [email protected]
Long-term cardiorespiratory results of exercise training following cardiac transplantation
Long-Term Cardiorespiratory Results of Exercise Training Following Cardiac Transplantation Terence Kavanagh, MD, Donald J. Mertens, MD, MSc, Roy J. Shephard, MD, PhD, Joseph Beyene, PhD, Johanna Kennedy, RN, Robin Campbell, MS, Paul Sawyer, BPHE, and Magdi Yacoub, MD The long-term influence of exercise training after heart transplantation remains unclear. Accordingly, we performed a 12-year follow-up study of 36 patients who underwent heart transplantation. Findings for survivors were compared with those of age-matched controls over the same period. Comparisons were also made between survivors and deceased patients. The sample comprised 36 men (aged 47 ⴞ 9 years) and a group of healthy age-matched controls. The patients received 16 months of outpatient exercise training; physiologic data were collected initially and at discharge. At 12 years, further data were collected on 20 of 23 survivors and their controls; 3 of the survivors were unavailable for final assessment, and 13 patients had died in the interim. The ˙ O2peak) increased 26% survivors’ peak oxygen intake (V
after training and decreased 0.39 ml 䡠 kgⴚ1 䡠 minⴚ1 per year (27.9 ⴞ 7 to 23.7 ⴞ 6), which was a similar rate as the controls (0.37 ml 䡠 kgⴚ1 䡠 minⴚ1 per year; 33.7 ⴞ 7 to 29.2 ⴞ 7). Lean body mass (LBM) increased 3 kg by 16 months and a further 2.5 kg by 12 years, but ultimately was 3 kg below the controls. Although there was no difference in entry data between deceased patients and survivors, the latter attained greater gains in ˙ O2peak and LBM over the 16 months of training. Thus, V in heart transplantation patients who undergo training, gains in exercise capacity are lost over 12 years at a rate commensurate with normal aging. A reduced train˙ O2peak and LBM contributes to a poorer ing response in V prognosis. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:190 –194)
revious studies have established that exercise training after cardiac transplantation accelerates P recovery and maximizes the benefit of surgery.
study provides data collected on 20 of 23 survivors (3 were unavailable for final assessment) after 12 years.
1– 6
Substantial gains are made in cardiorespiratory fitness and muscle strength, and although, on average, posttraining maximum peak exercise values do not achieve those of healthy subjects, some rehabilitated patients have been able to compete regularly in the World Transplant Games,7 return to playing intercollegiate soccer,8 or finish grueling road races.9,10 What is unclear, however, is whether the training benefits and exercise habits imparted by a successful exercise program are sustained long-term. With 40% of heart transplantation recipients now surviving as long as 12 years, we believed that it was important to address this question.11 Accordingly, we report the long-term findings in 36 men who underwent successful exercise rehabilitation after orthotopic heart transplantation. All patients achieved a substantial gain in peak power ˙ O2peak) when they output and peak oxygen intake (V were tested on a cycle ergometer after training. This From the Toronto Rehabilitation Institute, Faculty of Medicine, Faculty of Physical Education and Health, and Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada; and Imperial School of Science Technology and Medicine at Heart Science Centre, Harefield, Middlesex, United Kingdom. This study was supported by a grant from Canadian Cardiac Rehabilitation Foundation, Toronto, Ontario, Canada. Manuscript received April 17, 2002; revised manuscript received and accepted August 26, 2002. Address for reprints: Terence Kavanagh, MD, Canadian Cardiac Rehabilitation Foundation, Columbus Centre, 901 Lawrence Avenue W, Toronto, Ontario M6A IC3, Canada. E-mail: terence.kavanagh @utoronto.ca.
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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
METHODS
Patient sample: This study is based on 36 men, initially aged 47 ⫾ 9 years (range 21 to 57) at time of transplantation. Presurgical diagnoses included cardiomyopathy, coronary artery disease, myocarditis, valvular disease, and bacterial endocarditis. They entered the outpatient rehabilitation program 7 ⫾ 6 months (median 4.8, range 2 to 23) after surgery. Medications remained the responsibility of the patient’s physician, in consultation with the transplantation team. Drugs given to patients included cyclosporine and azathioprine (all cases), minimal quantities of oral steroids (6 cases initially, 5 finally), nifedipine (3 initially, 4 finally), hydralazine (6 initially, 6 finally), and furosemide (9 initially, 6 finally). None were taking a -blocker drug, initially or finally. After completion of the 16-month training program, the patients were advised to continue with their final exercise prescription, and apart from a simple annual questionnaire enquiring as to their state of health, no monitoring was carried out. The final assessment was undertaken an average of 11.6 ⫾ 0.4 years after the program. At this stage, we were able to evaluate 20 of 23 surviving patients; 13 had died an average of 7.3 ⫾ 2.9 years after surgery. The causes of death were coronary artery disease (n ⫽ 6), malignancy (n ⫽ 4), and infection (n ⫽ 3). Three survivors were awaiting kidney transplantation and were unable to attend the final assessment. 0002-9149/03/$–see front matter PII S0002-9149(02)03108-9
TABLE 1 Changes in Anthropometric and Cardiorespiratory Variables in Surviving Cardiac Transplantation Patients Over 16 Months and 12 Years, and Comparison With Changes in Age-matched Normal Subjects Over the Same 12-year Interval Surviving Patients (n ⫽ 20) Variable
Pre-Training
Body mass (kg) Lean mass (kg) Heart rate at rest (beats/min) Peak heart rate (beats/min) Systolic blood pressure at rest (mm Hg) Peak systolic blood pressure (mm Hg) Diastolic blood pressure at rest (mm Hg) Peak diastolic blood pressure (mm Hg) Peak power output (W) V˙O2peak (ml 䡠 kg⫺1 䡠 min⫺1) V˙O2peak (ml 䡠 min⫺1)
70 56.7 103 133 137 173 96 100 107 22.2 1,550
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8 5 11 17 15 24 12 11 29 4 30
Post-Training 75.7 59.8 97 148 123 170 84 90 161 27.9 2,080
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 5 10 19 15 17 11 11 40 7 42
Normal Subjects (n ⫽ 20) 12 Yrs
78.7 62.3 101 153 137 185 89 95 145 23.7 1,864
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13 8 11 19 20 41 15 14 40 6 39
Initial 83.2 65.8 78 172 128 221 86 97 229 33.7 2,811
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 Yrs 11 8 16 12 16 23 8 11 47 6 65
83.6 65.7 73 164 148 229 89 99 219 29.2 2,435
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 7 16 20 25 27 13 16 53 7 66
Data are presented as means ⫾ SD.
Exercise program: The primary element was walking, progressing to jogging, initially covering a distance of 1.6 km 5 times weekly, at a pace that required ˙ O2peak, cou60% to 70% of the patient’s measured V pled with a perception of effort equivalent to 13 to 14 on the original Borg scale.12 The objective was to progress to jogging 4.8 km in 36 minutes (8.0 km/ hour) by 6 to 8 months. The average length of time on the program was 16 ⫾ 7 months; few workouts were missed because of injuries or other medical setbacks. All patients progressed to walking and/or jogging an average distance of 24 km/week at an average pace of 8.5 min/km (7.1 km/hour). The 8 most highly motivated patients achieved ⱖ32 km/week at an average pace of 6.5 min/km (9.2 km/hour). Anthropometric measurements: In addition to height and body mass, body fat was calculated from skinfolds13 and LBM was estimated from total body mass and percent body fat. Cardiopulmonary exercise testing: The peak power ˙ O2peak were determined by a progressive output and V cycle ergometry test, using a MedGraphics Metabolic Cart (St. Paul, Minnesota). The power output was increased stepwise by 16.7 W every minute until: (1) voluntary fatigue or indications to halt the test, or (2) an oxygen plateau was attained.3,14 The electrocardiogram (leads V1, CM5, III) was monitored continuously, blood pressure was recorded every 2 minutes, and the rating of perceived exertion was measured at 1-minute intervals. Anthropometric measurements, peak power output, ˙ O2peak were completed on entry, after 16 ⫾ 7 and V months of conditioning, and 11.6 ⫾ 0.4 years after surgery. The initial and final status of the surviving patients was compared with the same age-matched healthy men. Finally, patients were questioned at the 12-year assessment as to their current level of physical activity. Statistical analyses: Primary analysis was based on prospective data, using paired t tests to examine and compare 16-month and 12-year changes in anthropometric and physiologic characteristics between the patients and a group of healthy men matched for age
and occupation (blue-collar, white-collar, professional and/or managerial), none of whom were regular exercisers and none gave a history of athleticism. Independent sample t tests were used to compare 16-month changes for the 20 survivors with findings for the 13 subjects who died. Moreover, the changes within each group were analyzed using paired t tests, and a Bonferroni correction was applied to allow for multiple comparisons. Finally, univariate and multivariate logistic regression analyses were developed to predict the risk of death.
RESULTS
Current exercise habits: Eight of the 20 survivors admitted to abandoning their prescribed exercise an average of 3 years (1 to 7) after discharge from the program and for a variety of reasons, such as “too tired,” back or knee problems, or “other interests.” The remaining 12 patients reported that they were continuing with some form of regular physical activity an average of 3.5 times weekly. Ten of the 12 were continuing with their exercise prescription and believed they were doing enough to keep healthy, whereas 2 believed they should be doing more.
Long-term responses of survivors and healthy controls (Table 1): The body composition of the control
subjects remained relatively stable over the 12 years of observation. In contrast, the cardiac transplantation recipients entered the study with a low body mass; this showed a substantial increase at 16 months, with a further increase at 12 years. The gain was due largely to an increase in lean tissue. As is typical of the denervated state, heart rates at rest were initially higher and peak heart rates lower in the transplant patients than in the controls. Similarly, systolic pressures at rest were higher and peak systolic pressures were initially lower in the transplant group than in the controls. After 12 years, pressures at rest were lower in the transplant patients than in the controls; the discrepancy in peak values was unchanged. Diastolic pressure at rest decreased significantly in the transplant patients at 16 months and increased only slightly at 12 years, by which time it was similar to the values of the controls. The average peak diastolic
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ever, based on our previous experience,15 we decided to force the rela˙ O2peak into a multivariate equative V tion, along with diastolic blood pressure at rest, and LBM. As a result, no significant effect was seen for diastolic blood pressure at rest, but effects were detected for LBM (p ⫽ ˙ O2peak (p ⫽ 0.009) and relative V 0.03), with hazard ratios of 0.57 (95% confidence interval 0.38 to 0.87) and 0.79 (95% confidence interval 0.64 to 0.98), respectively.
DISCUSSION The loss of lean tissue is a prominent feature after heart transplantation. It results from antecedent chronic heart failure, bed rest following surgery, and the subsequent use of steFIGURE 1. Changes after training and over time in cardiac transplant patients and roids. The deficit is partially restored normal subjects. p Values for differences in measurements from initial to 16 months with exercise rehabilitation, but even and initial to 12 years in transplant patients (straight line arrows), initial to 12 after 12 years the lean mass of survivyears in normals (dotted line arrows), and differences in changes from initial to 12 years between transplant patients and normals (dashed line arrows). CT1 ⴝ cardiac ing patients remained 3.4 kg less than transplant survivors, initial; CT2 ⴝ cardiac transplant survivors at 16 months; CT3 the matched normal subjects. Possiⴝ cardiac transplant survivors at 12 years; N1 ⴝ normal subjects; N2 ⴝ normal bly, the resynthesis of muscle could subjects at 12 years. have been accelerated and made more complete by a program that included resistance training. In confirmation of previous studies, the surviving values of the transplant patients also decreased initially with training but had increased at 12 years; the patients showed little change in peak heart rate between the 16 months and 12 years after surgery.16,17 A final values were slightly less than in the controls. ˙ O2peak showed substantial decrease in heart rate of 5 to 6 beats/min would be Peak power output and V gains in the transplant group at 16 months. By 12 anticipated with 10 years of normal aging18,19; our years, however, values had regressed to only slightly normal subjects showed an effect of this magnitude. above their initial levels. A similar deterioration oc- The increase in peak heart rate of 5 beats/min seen in curred in the normal subjects over the 12-year period, the transplant patients thus represents a substantial suggesting that the decrease was attributable to aging. gain of 15 beats/min relative to the expected course of Changes in pertinent measurements, from initial to 16 aging, and possibly reflects some degree of cardiac months and to 12 years, from initial to 12 years in the reinnervation.20 –22 ˙ O2peak from At first inspection, the decrease in V transplant patients, and from initial to 12 years in the ⫺1 ⫺1 27.9 ⫾ 6.7 ml 䡠 kg 䡠 min at 16 months to 23.7 ⫾ controls are shown in Figure 1. Comparison between transplant survivors and de- 5.7 ml 䡠 kg⫺1 䡠 min⫺1 at 12 years seems disappointceased patients: Initial testing showed no significant ing. However, cross-sectional and longitudinal studies ˙ O2peak with differences in body composition or cardiopulmonary have demonstrated a decrease in V ⫺1 ⫺1 23,24 and the 0.39 ml 䡠 kg 䡠 min annual devariables between survivors and those who died (Ta- age, ble 2). However, over the 16 months of training, body crease in oxygen transport is similar to the 0.37 mass increased in survivors, but not in those who ml 䡠 kg⫺1 䡠 min⫺1 loss seen in the normal controls subsequently died. Survivors also achieved a greater over the same interval. The potential for slowing the reduction in diastolic blood pressure at rest and a aging of function by a continued program of rigorous ˙ O2peak than those who died. The exercise is controversial; even the high level of activlarger increase in V conclusions from univariate comparisons of initial ity undertaken by participants in Masters competitions data were confirmed by logistic regression testing of still leaves a healthy older adult with an annual dethe probability of death as a function of selected crease in peak aerobic power of as much as 0.3 to 0.4 variables, with the other variables held constant. The ml 䡠 kg⫺1 䡠 min⫺1.18 Furthermore, if we compare the only items of significance were LBM (p ⫽ 0.03) and 10 patients who continued to exercise conscientiously with the remaining 10 who failed to do so, we noted diastolic blood pressure at rest (p ⫽ 0.03). ˙ O2peak Applying a similar analysis to the changes over the that although the exercisers attained a higher V first 16 months of observation (Table 2) in anthropo- after training (30.2 ⫾ 6 vs 25.5 ⫾ 7, p ⫽ 0.1), and had metric and cardiorespiratory variables, univariate lo- a marginally higher fitness level at 12 years (25.5 ⫾ 7 gistic regression showed significant effects for LBM, vs 21.3 ⫾ 6, p ⫽ 0.06), their rate of decline was the ˙ O2peak. How- same (i.e., 39 ml 䡠 kg⫺1 䡠 min⫺1). Thus, although diastolic blood pressure at rest, and V 192 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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TABLE 2 Pre- and Post-training Anthropometric and Cardiorespiratory Variables Among Surviving and Deceased Cardiac Transplantation Patients Surviving Patients (n ⫽ 20) Variable
Pre-Training
Body mass (kg) Lean mass (kg) Heart rate at rest (beats/min) Peak heart rate (beats/min) Systolic blood pressure at rest (mm Hg) Peak systolic blood pressure (mm Hg) Diastolic blood pressure at rest (mm Hg) Peak diastolic blood pressure (mm Hg) Peak power output (W) V˙ O2peak (ml/kg 䡠 min)
70.1 56.7 103 133 137 173 96 100 107 22.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8 5 12 17 15 24 12 11 29 4
Deceased Patients (n ⫽ 13)
Post-Training 75.7 59.8 97 148 123 170 84 90 161 27.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 6 10 19 15 17 11 11 40 6
Pre-Training 70.9 57.6 103 137 138 189 93 102 100 21.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 7 13 12 19 27 14 14 18 4
Post-Training 73.7 57.7 100.3 146 130 187 93 100 138 24.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
14 8 14 13 16 20 9 9 23 6
Data are presented as means ⫾ SD.
50% of our survivors continued to exercise, their level of physical activity was insufficient to retard normal aging. However, taking the aging process into account, there had been little loss of gains obtained from the initial 16 months of rehabilitation. Furthermore, 12 years after surgery, the patients retained a level of aerobic function well above the threshold of 18 ml 䡠 kg⫺1 䡠 min⫺1 that frail, elderly persons need to perform many of the activities of daily living.25 Factors influencing survival: The initial data provided few clues to prognosis. The trend to a higher peak systolic pressure in the deceased suggests that systemic hypertension may have had some influence on prognosis. In terms of the response to training, the 2 predic˙ O2peak and lean tissue. tors of survival were gains in V Braith and colleagues26 have reported a significant ˙ O2peak in heart correlation between leg strength and V transplantation recipients, and we have previously ˙ O2peak is an imnoted that in postcoronary patients V portant independent marker of prognosis.15 In the present sample, those who died entered our program ˙ O2peak to those who survived, but they with a similar V showed a smaller training response, with a final value of about 4 ml 䡠 kg⫺1 䡠 min⫺1 lower than the survivors. ˙ O2peak A recent study found a similar difference of V between those with and those without significant coronary vasculopathy.27 It should be noted that almost half of the deceased subjects succumbed to coronary artery disease. Study limitations: We recognize that a limitation of the study is the small sample size, which weakens the inferences drawn regarding markers for survival. Nevertheless, in keeping with our current understanding of physiology following cardiac transplantation, the numbers were adequate to demonstrate statistically ˙ Opeak in multivariate significant effects of LBM and V analysis. Previous studies have demonstrated that the effects of rehabilitation training are short-lived, but few, if any, to our knowledge have been able to compare the decrease with the same age-matched controls and over such a protracted period. In summary, this study shows that exercise-in˙ O2peak are lost over time but at a rate duced gains in V commensurate with normal aging. In our patients, the
˙ O2peak was equivalent to a reversal of the gain in V cumulative effects of 12 years’ aging. Loss of lean tissue is a key factor limiting oxygen transport, and rehabilitation should include a substantial component of resistance training. Smaller than anticipated train˙ O2peak heralds a ing-induced increases in LBM and V reduced survival and is possibly a marker for the future development of coronary vasculopathy. Acknowledgment: Our thanks to Salahddin Qureshi, MSc, and Edward Strohm, MSc, for cardiorespiratory exercise testing and data collection and to Janet Will and Doreen Flockhart for manuscript preparation.
1. Squires RW, Arthur PR, Gau GT, Muri A, Lambert WB. Exercise after cardiac transplantation: a report of two cases. J Cardiac Rehabil 1983;3:570 –574. 2. Niset G, Coustry-Degre C, Degre S. Psychosocial and physical rehabilitation after heart transplantation: 1-year followup. Cardiology 1988;75:311–317. 3. Kavanagh T, Yacoub MH, Mertens DJ, Kennedy J, Campbell RB, Sawyer P. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulation 1988;77:162–171. 4. Keteyian S, Shepard R, Ehrman J, Fedel F, Glick C, Rhoads K, Levine BL. Cardiovascular responses of heart transplant patients to exercise training. J Appl Physiol 1991;70:2627–2631. 5. Ehrman J, Keteyian S, Fedel F, Rhoads K, Levine B, Shepard R. Ventilatory threshold after exercise training in orthotopic heart transplant recipients. J Cardiopulmon Rehabil 1992;12:126 –130. 6. Kobashigawa JA, Leaf DA, Lee N, Gleeson MP, Liu HH, Hamilton MA, Moriguchi JM, Kawata N, Einhorn K, Herlihy E, Laks H. A controlled trial of exercise rehabilitation after heart transplantation. N Engl J Med 1999;340:272– 277. 7. McGee HM, Horgan JH. Participation in the Cardiac Transplant Games: impact on health-related quality of life. Br J Health Psych 1996;1:245–252. 8. Golding LA, Mangus BC. Competing in varsity athletics after cardiac transplantation. J Cardiopulmon Rehabil 1989;9:486 –491. 9. Kavanagh T, Yacoub M, Campbell R, Mertens D. Marathon running after cardiac transplantation: a case report. J Cardiopulmon Rehabil 1986;6:16 –20. 10. Richard R, Verdier J-C, Duvallet A, Rosier S-P, Leger P, Nignan A, Rieu M. Chronotropic competence in endurance trained heart transplantation recipients: heart rate is not a limiting factor for exercise capacity. J Am Coll Cardiol 1999;33:192–197. 11. Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Report—2001. J Heart Lung Transplant 2001;20:805–815. 12. Borg G. The perception of physical performance. In: Shephard RJ, ed. Frontiers of Fitness. Springfield, IL: CC Thomas, 1971:280 –294. 13. Durnin JVGA, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J Nutr 1974;32:77–97. 14. American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription. Baltimore, MD: Lippincott Williams & Wilkins, 2000. 15. Kavanagh T, Mertens DJ, Hamm LF, Beyene J, Kennedy J, Corey P, Shephard RJ. Prediction of long-term prognosis in 12,169 men referred for cardiac rehabilitation. Circulation 2002;106:666 –671.
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16. Givertz MM, Hartley LH, Colucci WS. Long-term sequential changes in
22. Radaelli A, Valle F, Falcone C, Calciati A, Leuzzi S, Martinelli L, Goggi
exercise capacity and chronotropic responsiveness after cardiac transplantation. Circulation 1997;96:232–237. 17. Osada N, Chaitman BR, Donohue TJ, Wolford TL, Stelken AM, Miller LW. Long-term cardiopulmonary exercise performance after heart transplantation. Am J Cardiol 1997;79:451–456. 18. Kavanagh T, Mertens DJ, Matosevic V, Shephard RJ, Evans B. Health and aging of Masters athletes. Clin Sports Med 1989;1:72–88. 19. Shephard RJ. Aging, Physical Activity, and Health. Champaign, IL: Human Kinetics Publishers, 1997. 20. Wilson RF, Christensen BV, Olivari MT, Simon A, White CW, Laxson DD. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans. Circulation 1991;83:1210 –1220. 21. Kaye DM, Esler M, Kingwell B, McPherson G, Esmore D, Jennings G. Functional and neurochemical evidence for partial cardiac sympathetic reinnervation after cardiac transplantation in humans. Circulation 1993;88:1110 –1118.
C, Vigano M, Finardi G, Bernardi L. Determinants of heart rate variability in heart transplanted subjects during physical exercise. Eur Heart J 1996;17: 462–471. 23. Dehn MM, Bruce RA. Longitudinal variates in maximal oxygen uptake with age and activity. J Appl Physiol 1972;33:805–807. 24. Jackson AS, Beard EF, Wier LT, Ross RM, Stuteville JE, Blair SN. Changes in aerobic power of men, ages 25–70 yr. Med Sci Sports Exerc 1995;27:113–120. 25. Paterson DH, Cunningham DA, Koval JJ, St. Croix CM. Aerobic fitness in a population of independently living men and women aged 55– 86 years. Med Sci Sports Exerc 1999;31:1813–1820. 26. Braith RW, Limacher MC, Leggett SH, Pollock ML. Skeletal muscle strength in heart transplant recipients. J Heart Lung Transplant 1993;12:1018 –1023. 27. Schwaiblmair M, von Scheidt W, Uberfuhr P, Reichart B, Vogelmeier C. Lung function and cardiopulmonary exercise performance after heart transplantation: influence of cardiac allograft vasculopathy. Chest 1999;116:332–339.
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after training and decreased 0.39 ml 䡠 kgⴚ1 䡠 minⴚ1 per year (27.9 ⴞ 7 to 23.7 ⴞ 6), which was a similar rate as the controls (0.37 ml 䡠 kgⴚ1 䡠 minⴚ1 per year; 33.7 ⴞ 7 to 29.2 ⴞ 7). Lean body mass (LBM) increased 3 kg by 16 months and a further 2.5 kg by 12 years, but ultimately was 3 kg below the controls. Although there was no difference in entry data between deceased patients and survivors, the latter attained greater gains in ˙ O2peak and LBM over the 16 months of training. Thus, V in heart transplantation patients who undergo training, gains in exercise capacity are lost over 12 years at a rate commensurate with normal aging. A reduced train˙ O2peak and LBM contributes to a poorer ing response in V prognosis. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;91:190 –194)
revious studies have established that exercise training after cardiac transplantation accelerates P recovery and maximizes the benefit of surgery.
study provides data collected on 20 of 23 survivors (3 were unavailable for final assessment) after 12 years.
1– 6
Substantial gains are made in cardiorespiratory fitness and muscle strength, and although, on average, posttraining maximum peak exercise values do not achieve those of healthy subjects, some rehabilitated patients have been able to compete regularly in the World Transplant Games,7 return to playing intercollegiate soccer,8 or finish grueling road races.9,10 What is unclear, however, is whether the training benefits and exercise habits imparted by a successful exercise program are sustained long-term. With 40% of heart transplantation recipients now surviving as long as 12 years, we believed that it was important to address this question.11 Accordingly, we report the long-term findings in 36 men who underwent successful exercise rehabilitation after orthotopic heart transplantation. All patients achieved a substantial gain in peak power ˙ O2peak) when they output and peak oxygen intake (V were tested on a cycle ergometer after training. This From the Toronto Rehabilitation Institute, Faculty of Medicine, Faculty of Physical Education and Health, and Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada; and Imperial School of Science Technology and Medicine at Heart Science Centre, Harefield, Middlesex, United Kingdom. This study was supported by a grant from Canadian Cardiac Rehabilitation Foundation, Toronto, Ontario, Canada. Manuscript received April 17, 2002; revised manuscript received and accepted August 26, 2002. Address for reprints: Terence Kavanagh, MD, Canadian Cardiac Rehabilitation Foundation, Columbus Centre, 901 Lawrence Avenue W, Toronto, Ontario M6A IC3, Canada. E-mail: terence.kavanagh @utoronto.ca.
190
©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 91 January 15, 2003
METHODS
Patient sample: This study is based on 36 men, initially aged 47 ⫾ 9 years (range 21 to 57) at time of transplantation. Presurgical diagnoses included cardiomyopathy, coronary artery disease, myocarditis, valvular disease, and bacterial endocarditis. They entered the outpatient rehabilitation program 7 ⫾ 6 months (median 4.8, range 2 to 23) after surgery. Medications remained the responsibility of the patient’s physician, in consultation with the transplantation team. Drugs given to patients included cyclosporine and azathioprine (all cases), minimal quantities of oral steroids (6 cases initially, 5 finally), nifedipine (3 initially, 4 finally), hydralazine (6 initially, 6 finally), and furosemide (9 initially, 6 finally). None were taking a -blocker drug, initially or finally. After completion of the 16-month training program, the patients were advised to continue with their final exercise prescription, and apart from a simple annual questionnaire enquiring as to their state of health, no monitoring was carried out. The final assessment was undertaken an average of 11.6 ⫾ 0.4 years after the program. At this stage, we were able to evaluate 20 of 23 surviving patients; 13 had died an average of 7.3 ⫾ 2.9 years after surgery. The causes of death were coronary artery disease (n ⫽ 6), malignancy (n ⫽ 4), and infection (n ⫽ 3). Three survivors were awaiting kidney transplantation and were unable to attend the final assessment. 0002-9149/03/$–see front matter PII S0002-9149(02)03108-9
TABLE 1 Changes in Anthropometric and Cardiorespiratory Variables in Surviving Cardiac Transplantation Patients Over 16 Months and 12 Years, and Comparison With Changes in Age-matched Normal Subjects Over the Same 12-year Interval Surviving Patients (n ⫽ 20) Variable
Pre-Training
Body mass (kg) Lean mass (kg) Heart rate at rest (beats/min) Peak heart rate (beats/min) Systolic blood pressure at rest (mm Hg) Peak systolic blood pressure (mm Hg) Diastolic blood pressure at rest (mm Hg) Peak diastolic blood pressure (mm Hg) Peak power output (W) V˙O2peak (ml 䡠 kg⫺1 䡠 min⫺1) V˙O2peak (ml 䡠 min⫺1)
70 56.7 103 133 137 173 96 100 107 22.2 1,550
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8 5 11 17 15 24 12 11 29 4 30
Post-Training 75.7 59.8 97 148 123 170 84 90 161 27.9 2,080
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 5 10 19 15 17 11 11 40 7 42
Normal Subjects (n ⫽ 20) 12 Yrs
78.7 62.3 101 153 137 185 89 95 145 23.7 1,864
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13 8 11 19 20 41 15 14 40 6 39
Initial 83.2 65.8 78 172 128 221 86 97 229 33.7 2,811
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 Yrs 11 8 16 12 16 23 8 11 47 6 65
83.6 65.7 73 164 148 229 89 99 219 29.2 2,435
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 7 16 20 25 27 13 16 53 7 66
Data are presented as means ⫾ SD.
Exercise program: The primary element was walking, progressing to jogging, initially covering a distance of 1.6 km 5 times weekly, at a pace that required ˙ O2peak, cou60% to 70% of the patient’s measured V pled with a perception of effort equivalent to 13 to 14 on the original Borg scale.12 The objective was to progress to jogging 4.8 km in 36 minutes (8.0 km/ hour) by 6 to 8 months. The average length of time on the program was 16 ⫾ 7 months; few workouts were missed because of injuries or other medical setbacks. All patients progressed to walking and/or jogging an average distance of 24 km/week at an average pace of 8.5 min/km (7.1 km/hour). The 8 most highly motivated patients achieved ⱖ32 km/week at an average pace of 6.5 min/km (9.2 km/hour). Anthropometric measurements: In addition to height and body mass, body fat was calculated from skinfolds13 and LBM was estimated from total body mass and percent body fat. Cardiopulmonary exercise testing: The peak power ˙ O2peak were determined by a progressive output and V cycle ergometry test, using a MedGraphics Metabolic Cart (St. Paul, Minnesota). The power output was increased stepwise by 16.7 W every minute until: (1) voluntary fatigue or indications to halt the test, or (2) an oxygen plateau was attained.3,14 The electrocardiogram (leads V1, CM5, III) was monitored continuously, blood pressure was recorded every 2 minutes, and the rating of perceived exertion was measured at 1-minute intervals. Anthropometric measurements, peak power output, ˙ O2peak were completed on entry, after 16 ⫾ 7 and V months of conditioning, and 11.6 ⫾ 0.4 years after surgery. The initial and final status of the surviving patients was compared with the same age-matched healthy men. Finally, patients were questioned at the 12-year assessment as to their current level of physical activity. Statistical analyses: Primary analysis was based on prospective data, using paired t tests to examine and compare 16-month and 12-year changes in anthropometric and physiologic characteristics between the patients and a group of healthy men matched for age
and occupation (blue-collar, white-collar, professional and/or managerial), none of whom were regular exercisers and none gave a history of athleticism. Independent sample t tests were used to compare 16-month changes for the 20 survivors with findings for the 13 subjects who died. Moreover, the changes within each group were analyzed using paired t tests, and a Bonferroni correction was applied to allow for multiple comparisons. Finally, univariate and multivariate logistic regression analyses were developed to predict the risk of death.
RESULTS
Current exercise habits: Eight of the 20 survivors admitted to abandoning their prescribed exercise an average of 3 years (1 to 7) after discharge from the program and for a variety of reasons, such as “too tired,” back or knee problems, or “other interests.” The remaining 12 patients reported that they were continuing with some form of regular physical activity an average of 3.5 times weekly. Ten of the 12 were continuing with their exercise prescription and believed they were doing enough to keep healthy, whereas 2 believed they should be doing more.
Long-term responses of survivors and healthy controls (Table 1): The body composition of the control
subjects remained relatively stable over the 12 years of observation. In contrast, the cardiac transplantation recipients entered the study with a low body mass; this showed a substantial increase at 16 months, with a further increase at 12 years. The gain was due largely to an increase in lean tissue. As is typical of the denervated state, heart rates at rest were initially higher and peak heart rates lower in the transplant patients than in the controls. Similarly, systolic pressures at rest were higher and peak systolic pressures were initially lower in the transplant group than in the controls. After 12 years, pressures at rest were lower in the transplant patients than in the controls; the discrepancy in peak values was unchanged. Diastolic pressure at rest decreased significantly in the transplant patients at 16 months and increased only slightly at 12 years, by which time it was similar to the values of the controls. The average peak diastolic
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ever, based on our previous experience,15 we decided to force the rela˙ O2peak into a multivariate equative V tion, along with diastolic blood pressure at rest, and LBM. As a result, no significant effect was seen for diastolic blood pressure at rest, but effects were detected for LBM (p ⫽ ˙ O2peak (p ⫽ 0.009) and relative V 0.03), with hazard ratios of 0.57 (95% confidence interval 0.38 to 0.87) and 0.79 (95% confidence interval 0.64 to 0.98), respectively.
DISCUSSION The loss of lean tissue is a prominent feature after heart transplantation. It results from antecedent chronic heart failure, bed rest following surgery, and the subsequent use of steFIGURE 1. Changes after training and over time in cardiac transplant patients and roids. The deficit is partially restored normal subjects. p Values for differences in measurements from initial to 16 months with exercise rehabilitation, but even and initial to 12 years in transplant patients (straight line arrows), initial to 12 after 12 years the lean mass of survivyears in normals (dotted line arrows), and differences in changes from initial to 12 years between transplant patients and normals (dashed line arrows). CT1 ⴝ cardiac ing patients remained 3.4 kg less than transplant survivors, initial; CT2 ⴝ cardiac transplant survivors at 16 months; CT3 the matched normal subjects. Possiⴝ cardiac transplant survivors at 12 years; N1 ⴝ normal subjects; N2 ⴝ normal bly, the resynthesis of muscle could subjects at 12 years. have been accelerated and made more complete by a program that included resistance training. In confirmation of previous studies, the surviving values of the transplant patients also decreased initially with training but had increased at 12 years; the patients showed little change in peak heart rate between the 16 months and 12 years after surgery.16,17 A final values were slightly less than in the controls. ˙ O2peak showed substantial decrease in heart rate of 5 to 6 beats/min would be Peak power output and V gains in the transplant group at 16 months. By 12 anticipated with 10 years of normal aging18,19; our years, however, values had regressed to only slightly normal subjects showed an effect of this magnitude. above their initial levels. A similar deterioration oc- The increase in peak heart rate of 5 beats/min seen in curred in the normal subjects over the 12-year period, the transplant patients thus represents a substantial suggesting that the decrease was attributable to aging. gain of 15 beats/min relative to the expected course of Changes in pertinent measurements, from initial to 16 aging, and possibly reflects some degree of cardiac months and to 12 years, from initial to 12 years in the reinnervation.20 –22 ˙ O2peak from At first inspection, the decrease in V transplant patients, and from initial to 12 years in the ⫺1 ⫺1 27.9 ⫾ 6.7 ml 䡠 kg 䡠 min at 16 months to 23.7 ⫾ controls are shown in Figure 1. Comparison between transplant survivors and de- 5.7 ml 䡠 kg⫺1 䡠 min⫺1 at 12 years seems disappointceased patients: Initial testing showed no significant ing. However, cross-sectional and longitudinal studies ˙ O2peak with differences in body composition or cardiopulmonary have demonstrated a decrease in V ⫺1 ⫺1 23,24 and the 0.39 ml 䡠 kg 䡠 min annual devariables between survivors and those who died (Ta- age, ble 2). However, over the 16 months of training, body crease in oxygen transport is similar to the 0.37 mass increased in survivors, but not in those who ml 䡠 kg⫺1 䡠 min⫺1 loss seen in the normal controls subsequently died. Survivors also achieved a greater over the same interval. The potential for slowing the reduction in diastolic blood pressure at rest and a aging of function by a continued program of rigorous ˙ O2peak than those who died. The exercise is controversial; even the high level of activlarger increase in V conclusions from univariate comparisons of initial ity undertaken by participants in Masters competitions data were confirmed by logistic regression testing of still leaves a healthy older adult with an annual dethe probability of death as a function of selected crease in peak aerobic power of as much as 0.3 to 0.4 variables, with the other variables held constant. The ml 䡠 kg⫺1 䡠 min⫺1.18 Furthermore, if we compare the only items of significance were LBM (p ⫽ 0.03) and 10 patients who continued to exercise conscientiously with the remaining 10 who failed to do so, we noted diastolic blood pressure at rest (p ⫽ 0.03). ˙ O2peak Applying a similar analysis to the changes over the that although the exercisers attained a higher V first 16 months of observation (Table 2) in anthropo- after training (30.2 ⫾ 6 vs 25.5 ⫾ 7, p ⫽ 0.1), and had metric and cardiorespiratory variables, univariate lo- a marginally higher fitness level at 12 years (25.5 ⫾ 7 gistic regression showed significant effects for LBM, vs 21.3 ⫾ 6, p ⫽ 0.06), their rate of decline was the ˙ O2peak. How- same (i.e., 39 ml 䡠 kg⫺1 䡠 min⫺1). Thus, although diastolic blood pressure at rest, and V 192 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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TABLE 2 Pre- and Post-training Anthropometric and Cardiorespiratory Variables Among Surviving and Deceased Cardiac Transplantation Patients Surviving Patients (n ⫽ 20) Variable
Pre-Training
Body mass (kg) Lean mass (kg) Heart rate at rest (beats/min) Peak heart rate (beats/min) Systolic blood pressure at rest (mm Hg) Peak systolic blood pressure (mm Hg) Diastolic blood pressure at rest (mm Hg) Peak diastolic blood pressure (mm Hg) Peak power output (W) V˙ O2peak (ml/kg 䡠 min)
70.1 56.7 103 133 137 173 96 100 107 22.2
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8 5 12 17 15 24 12 11 29 4
Deceased Patients (n ⫽ 13)
Post-Training 75.7 59.8 97 148 123 170 84 90 161 27.9
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
10 6 10 19 15 17 11 11 40 6
Pre-Training 70.9 57.6 103 137 138 189 93 102 100 21.7
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
12 7 13 12 19 27 14 14 18 4
Post-Training 73.7 57.7 100.3 146 130 187 93 100 138 24.3
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
14 8 14 13 16 20 9 9 23 6
Data are presented as means ⫾ SD.
50% of our survivors continued to exercise, their level of physical activity was insufficient to retard normal aging. However, taking the aging process into account, there had been little loss of gains obtained from the initial 16 months of rehabilitation. Furthermore, 12 years after surgery, the patients retained a level of aerobic function well above the threshold of 18 ml 䡠 kg⫺1 䡠 min⫺1 that frail, elderly persons need to perform many of the activities of daily living.25 Factors influencing survival: The initial data provided few clues to prognosis. The trend to a higher peak systolic pressure in the deceased suggests that systemic hypertension may have had some influence on prognosis. In terms of the response to training, the 2 predic˙ O2peak and lean tissue. tors of survival were gains in V Braith and colleagues26 have reported a significant ˙ O2peak in heart correlation between leg strength and V transplantation recipients, and we have previously ˙ O2peak is an imnoted that in postcoronary patients V portant independent marker of prognosis.15 In the present sample, those who died entered our program ˙ O2peak to those who survived, but they with a similar V showed a smaller training response, with a final value of about 4 ml 䡠 kg⫺1 䡠 min⫺1 lower than the survivors. ˙ O2peak A recent study found a similar difference of V between those with and those without significant coronary vasculopathy.27 It should be noted that almost half of the deceased subjects succumbed to coronary artery disease. Study limitations: We recognize that a limitation of the study is the small sample size, which weakens the inferences drawn regarding markers for survival. Nevertheless, in keeping with our current understanding of physiology following cardiac transplantation, the numbers were adequate to demonstrate statistically ˙ Opeak in multivariate significant effects of LBM and V analysis. Previous studies have demonstrated that the effects of rehabilitation training are short-lived, but few, if any, to our knowledge have been able to compare the decrease with the same age-matched controls and over such a protracted period. In summary, this study shows that exercise-in˙ O2peak are lost over time but at a rate duced gains in V commensurate with normal aging. In our patients, the
˙ O2peak was equivalent to a reversal of the gain in V cumulative effects of 12 years’ aging. Loss of lean tissue is a key factor limiting oxygen transport, and rehabilitation should include a substantial component of resistance training. Smaller than anticipated train˙ O2peak heralds a ing-induced increases in LBM and V reduced survival and is possibly a marker for the future development of coronary vasculopathy. Acknowledgment: Our thanks to Salahddin Qureshi, MSc, and Edward Strohm, MSc, for cardiorespiratory exercise testing and data collection and to Janet Will and Doreen Flockhart for manuscript preparation.
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