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Cardiac effects of exercise rehabilitation in hemodialysis patients
International
journal
of
cardiology ELSEVIER
International Journal of Cardiology 70 (1999) 253-266
Cardiac effects of exercise rehabilitation in hemodialysis patients Asterios Deligiannis”‘“, Evangelia Kouidi”, Elias Tassoulasb, Panagiotis Gigis”, Achilleas Tourkantonisd, Andrew Coatsb “National
“Laboratory of Sports Medicine, Aristotle University and Lung Institute, Imperial College School of Medicine, at ‘Laboratory of Human Anatomy, Aristotle University dFirst Internal Medicine Department, AHEPA Hospital, Aristotle
Heart
of Thessaloniki, Thessaloniki, Greece Royal Brompton Hospital, Sydney St., London SW3 6NP, UK of Thessaloniki, Thessaloniki, Greece University of Thessaloniki, Thessaloniki, Greece
Received 24 April 1999; accepted 17 May 1999
Abstract Exercise training has well documented beneficial effects in a variety of cardiac disorders. End stage renal disease patients present many cardiovascular complications and suffer from impaired exercise capacity. No study to date has adequately examined the cardiac responses to exercise training in renal patients on hemodialysis (HD). To determine the effects of an exercise rehabilitation program on the left ventricular function at rest and during submaximal effort, 38 end-stage renal disease patients on maintenance HD were randomised into three groups. Sixteen of them (group A - mean age 46.4213.9 years), without clinical features of heart failure, participated in a 6-month supervised exercise renal rehabilitation program consisting of three weekly sessions of aerobic training, 10 (group B - mean age 51.42125 years) followed a moderate exercise program at home, and the other 12 (group C - mean age 50.2k7.9 years) were not trained and remained as controls. The level of anemia and the HD prescription remained constant during the study. Fifteen sex- and age-matched sedentary individuals (group D - mean age 46.9t6.4 years) were the healthy controls. All subjects at the start and end of the program underwent physical examination, laboratory tests, treadmill exercise testing, M-mode and 2-D echocardiograms performed at rest and at peak of supine bicycle exercise. Left ventricular volumes (EDV, ESV) and mass (LVM) were measured and ejection fraction (EF), stroke volume index (SVI) and cardiac output index (COI) were calculated by standard formulae. The maximal oxygen consumption increased by 43% (P
Hemodialysis; End-stage renal disease; Left ventricular function; Exercise training
1. Introduction
*Corresponding author. Present address: 53 Mitropoleos Str, 546 23 Thessaloniki, Greece. Tel.: + 30-31-992-181; fax: + 30-31-992-183.
A high proportion of end-stage renal disease patients on hemodialysis (HD) are found to suffer from cardiovascular complications, including coro-
0167-5273/99/$ - see front matter 0 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: SO167-5273(99)00090-X
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nary artery disease, heart failure and hypertension. These complications are the main reason for death in up to 50% of these patients [1,2]. Most have left ventricular dysfunction due to factors which adversely affect cardiac pre-load and after-load such as hypertension, anaemia, and arterio-venous anastomoses, and/or contractility, as uremic toxins, acidosis etc. [3-51. A decreased cardiac response to exercise is likely to be one of the major causes responsible for the low physical capacity of these patients. Maximal oxygen uptake in HD patients ranges from 15 to 25 ml/kg/min (similar to moderate heart failure) and their maximal metabolic equivalents (METS) are frequently lower than 3.5 [6]. The effort of correcting their anemia by using human recombined erythropoietin over the last few years has improved physical capacity by 20%; it remains however, significantly limited [7]. Exercise training is now being used as a therapeutic modality in the medical management of patients with a variety of stable cardiac disorders, including chronic angina, myocardial infarction, hypertension, etc., as well as selected patients with chronic heart failure or after cardiac operation. In many of these settings training has had beneficial effects on physical fitness and quality of life [f&10]. These benefits, if achievable in HD patients, would be of considerable value. There have been a number of studies which have demonstrated that physical training, mainly of an aerobic mode, significantly improves the physical condition of end-stage renal disease patients on HD [6,11- 131. However, there are very few references as regards the effects of physical training on the cardiac function of these patients. The aim of this study was to explore the impact of a 6-month supervised exercise rehabilitation program on cardiac anatomy and systolic function in comparison with another 6-month home moderate physical training program in patients with end-stage renal disease on regular HD. 2. Methods
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to 65 years old. They were all undergoing regular HD with an artificial kidney, for three sessions a week, 4 h each session. Patients with unstable hypertension, congestive heart failure (grade211 according to New York Heart Association classification), cardiac arrhythmias (III according to Lown) [ 141, recent myocardial infarction or unstable angina, diabetes mellitus, active liver disease, serious anemia and peripheral vascular disease were excluded. The patients were randomized into three groups: in group A, 16 HD patients were included (11 men and five women, mean age 46.45 13.9 years old) and followed a 6-month supervised exercise training program. In group B, 10 patients were included (eight men and two women, mean age 51.4+- 12.5 years old) and followed a moderate exercise training program for 6 months at home. In group C, 12 patients were included (four men and eight women, mean age 50.2k7.9 years old), who continued their usual lifestyle and were used as ‘patient’ controls. In this study there were also included 15 healthy sedentary individuals (eight men and seven women, mean age 46.9k6.4 years old), who constituted the group D and were used as ‘healthy’ controls. 2.2. Study design
A baseline clinical assessment,spiroergometric and echocardiographic study, as well as blood tests were carried out on each patient, 24 h after an uncomplicated and effective hemodialysis session, as well as on the healthy controls. After a 6-month period the same measurements were repeated only in the three groups of patients. To exclude any impact of the changes in the status of anemia on the aerobic capacity of patients, we tried to keep the haematocrit level stable for all renal patients throughout the study by increasing or decreasing the dose of erythropoietin, whenever necessary. Twenty-three out of 32 patients were receiving erythropoietin regularly. HD parameters were kept stable throughout the 6-month period program (by using the same model of filter and a constant composition of the dialysis solution, and by keeping the HD session time constant throughout this period).
2.1. Study population 2.3. Cardiopulmonary
Thirty-eight end-stage renal disease patients were included in this study. Their age ranged from 21 up
exercise test
The cardiopulmonary exercise test was performed
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using an Ergometer Health Track II model with a manipulation system HT-7. The test was done according to modified Bruce protocol and was discontinued when the subjects complained of limiting fatigue, dyspnea or exhaustion [15,16]. During this test the ECG of each individual was monitored and recorded every 3 min. At the same time points blood pressure was measured by mercury sphygmomanometry. During the exercise test the VO,max was continuously monitored using a specific mobile telemetric device (Cosmed K, model). The following parameters were detected from the spiroergometric study: heart rate at peak exercise (HRmax), systolic (sBP) and diastolic (dBP) blood pressure at peak exercise, double product (heart rate maxX systolic blood pressure max), total exercise time, exercise as measured by estimation of metabolic equivalents using specific tables ( 1 MET= 3.5 ml O,/kg/min), maximal oxygen uptake (VO,max), as the highest recorded value of VO,, pulmonary ventilation (VE) and the relationship of VE/VO, as well as lactic acid. To measure lactic acid, blood samples were taken from the right ear before and 4 min after the end of the exercise test. Lactic acid measurement was carried out in a photometer (Dr Lange LP 400 model). Before each measurement, inspection of the spiroergometer and the photometer function and regulation were carried out according to their operating instructions. 2.4. Rest and stress echocardiography
The left ventricular anatomical and functional indices were measured at rest, as well as during supine exercise with M- and B-mode echocardiographic study. This study was carried out with a Sigma 44HVCD echocardiograph (Kontron Instruments). The echocardiographic study was made by putting the patient in the left lateral semi-erect position at 30” from the horizontal plane. A manufactured couch was used for this study, the incline of which could change from 0” to 45”. An ergometric bicycle (Monark 868 model) was adapted to this couch. The subject’s feet during the study were fixed on the pedals of the cycle-ergometer. During the measurements the chest was kept in a mid-expiratory phase in order to minimize the effects of breathing on them. The transducer (2.5/3.5 MHz) was placed in the 3rd or 4th left parastemal intercostal space in such a posi-
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tion as to give the best quality images of the intraventricular septum, left ventricular posterior wall and mitral valve or the cordae tendinae. The position at which the transducer was put during the initial measurements was defined in each individual by measuring the distance between the transducer and the sternal edge, as well as the distance from the lower edge to the left clavicle. At the 6-month follow-up measurements, the transducer was put again at the same position on each patient. The left ventricular end-diastolic diameter (LVIDd), the left ventricular end-systolic diameter (LVISd), the intra-ventricular septal thickness (IVS), the left ventricular posterior wall (PW) during systole and diastole, the right ventricular dimension (RV), the aorta (Ao), the left atrium (LA), as well as the aortic valve excursion (AV) were measured by Mmode echocardiography. The end diastolic point was defined as the point which coincides with the QRS complex onset on the simultaneously recorded ECG, whereas the end systolic point was determined as the point coinciding with the end of the T wave on the ECG. Each M-mode measurement was done on five sequential cardiac cycles on each individual and the average of all these measurements was used for analysis. Left ventricular mass (LVM) was calculated by the M-mode echocardiography study according to the formula of Devereux and Reichek [ 171: LVM = 0.8 X [ l.O4(IVS + PW + LVIDd)3 - (LVIDd)3] -i- 0.6 g.
The LVM change into mass index (LVMI) was done by dividing the LVM by the body surface area (BSA). The stress echo study was carried out both at rest and during submaximal exercise. Each subject underwent graded supine bicycle exercise in the left lateral semi-erect position. The exercise consisted of 2-min stages, beginning at a work rate of 25 W and increasing in 25 W increments, until 70 or 80% of each individual’s HRmax was achieved. Each HRmax was estimated in the preceding treadmill exercise test. This exercise level was chosen in order to have the best quality images during the stress echo study, as more vigorous exercise causes significant tachypnea, which gives rise to poor quality imaging.
2%
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The blood pressure was recorded every 3 mm during the submaximal exercise test. For the evaluation of left ventricular function from this stress echo study, B-mode echocardiograms at rest and during the last minute of submaximal exercise were obtained at held relaxed expiration. Apical four-chamber and long axis views were recorded according to standard methods [ 181. Images were stored in archives for later playback and analysis on the computer. The images in each phase were analyzed by computerized planimetry using a computer software incorporated in the Sigma 44HVCD echocardiograph system. The indices of left ventricular function assessedwere: left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), stroke volume (SV), cardiac output (CO) and ejection fraction (EF). These indices were corrected for BSA, where appropriate. 2.5. Exercise rehabilitation
programs
The patients who were included in group A followed a 6-month exercise rehabilitation program under the supervision of a physician and the responsibility of two physical education teachers, specialized in this field. The training sessions were performed three times a week, 90 min each time, on the non-dialysis days. The patients were divided into subgroups, each one consisting of three or four persons according to age, sex, and dialysis days. Each training session consisted of a lo-min warm up on a cycle-ergometer or treadmill, a 50-min intermittent aerobic exercise program, including calistenics, steps and flexibility exercises and a IO-mm cool down period. After the first 2 months of training, a IO-min stretching and low-weight resistance program was added to the program. Continuous monitoring of the HR and cardiac rhythm of each patient was performed with a specific telemetric device. The intensity of exercise was prescribed on an individual basis, so that during the first 2 months the heart rate remained within 60 to 70% of the HRmax achieved during the initial maximal exercise test. The blood pressure was also measured every 15 min. After the first 3 months the younger patients were playing basketball and football once a week, whereas the older patients were swimming. The 10 patients who were included in group B
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followed a moderate exercise training program at home. These patients were supplied with a mobile cycle-ergometer and they were given instructions regarding the performance of simple exercises. We kept close contact with these patients, to answer any questions they had and to become aware of their course. According to this exercise program the patients had to cycle at least five times a week, 30 min each time, at a heart rate of SO to 60% of the maximal heart rate each one had reached during the baseline treadmill test. After that, they performed simple flexibility and muscular extension exercises. Progress checks were carried out at each patient’s home every month to check physical adaptation and to modify the exercise program, if necessary. 2.6. Statistical
analysis
All data are expressed as mean values +S.D. Changes of variables within groups were evaluated by the Student’s t-test for paired data. One-way analysis of variance (ANOVA) was performed for the comparison of the quantitative measurements among groups. For statistical analysis the SPSS 7.0 for Windows was used (Statistical Package for the Social Sciences, Chicago, IL, USA). A P value less than 0.05 was regarded as statistically significant. 3. Results
The clinical features of the four groups who participated in this study are presented in Table 1. The three patient groups (A, B and C) did not differ significantly regarding age, months on HD, frequency and duration of each HD session, anthropometric data (height, weight and body surface), as well as resting heart rate and blood pressure. From the 38 end-stage renal disease patients who were included in this study, 24 were hypertensives controlled on medication, 10 suffered from coronary artery disease with no clinical manifestations and five had heart failure of class II of NYHA. The allocation of the above patients in the three groups was balanced. The healthy individuals in group D in comparison with group A had an increased body weight by an average of 16% (P
A. Deligiannis Table 1 Clinical features
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at the onset of the study (mean+S.D.)
Groups
A
B
C
D
Subjects (n =) Men/ women Age (years) Height (cm) Weight (kg) BSA (m’) Months on hemodialysis
16 11/s 46.4’13.9 166212 65.4% 12.4 1.7?0.2 78562
10 812 51.4k12.5 16656 64.4-e 12.5 1.750.2 62237
12 418 50.2-r-1.9 16428 64.7-t-11.6 1.720.2 79k86
1s 817 46.9k6.4 171?10 76.02 10.9* 1.920.2* -
Hypertension (n =) Coronary artery disease (n =) Heart failure (n=)
10 4 2
6 3 1
8 3 2
-
Heart rate (bpm) Systolic BP (mmHg) Diastolic BP (mmHg)
85.3-cl1.7 145517 8728
82.3511.1 145?18 87213
80.628.6 14327 82?5
70.4?8.4* 122-c11* 78t7*
* P
between
groups
D and A, B, C.
17% (P
2), before the onset of the study and after 6 months and the values indicate effective HD. Urea and creatinine levels in all three patient groups, as expected, were higher than the healthy controls (P< 0.01). Potassium in group A was increased in comparison with group D by 33% (P
data (meansL8.D.) Baseline
Follow-up
Groups
A
B
C
D
Hematocrit (%) WBC Urea (mg%) Creatinine (mg%) Uric acid (mg%) Glucose (mg%) K (meq/l) Na (meqll) Ca (mg%) P (mg%) Fe (mg%)
31.124.2 5.72 1.9 188L-30 12.8rt2.6 5.621.3 91.629.2 5.7-to.5 14Ok-3 8.720.8 6.421.6 93229
31.724.3 5.821.2 195528 13.121.7 5.4kO.6 91.526.9 5.8kO.6 139*3 8.920.3 6.121.1 104*21
30.822.8 5.851.3 187”20 11.522.4 5.7kl.l 93.5-r-6.7 5.4kO.5 14026 8.OkO.4 6.1~1.4 97?21
42.5?4.1* 7.3*0.7* 44.8t2.8* 1.0t0.1* 6.120.6 95.526.1 4.3?0.2* 14123 5.4zo.4* 5.0f0.6* 10527.2
WBC, white blood cell count (103/mm3). * PcO.05 between groups D and A, B, C.
A
B
C
31.1k4.3 5.6t2.0 191230 12.922.6 5.6tl.l 92.6k9.1 5.720.5 141?4 8.820.8 6.3t1.8 98232
31.924.4 5.721.1 201t19 12.721.2 5.720.9 91.927.6 5.520.7 141%3 8.9t0.6 6.4kl.l too+25
31.022.4 5.921.5 192517 11.122.5 5.420.9 93.9k6.2 5.420.4 14026 8.1IYO.8 6.02 1.3 95518
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(e.g. injuries) or other complications develop as a consequence of exercise training during the rehabilitation program. 3.1. Cardiopulmonary exercise testing results baseline measurements The baseline values during exercise testing on the treadmill were at the same level for all three patient groups (Table 3). In 24 out of 38 patients the exercise test was discontinued because of leg fatigue and the remainder because of shortness of breath or exhaustion. Only 12 of these patients (31.6%) attained 85% of the maximum predicted heart rate for their age. The healthy control group D achieved a longer exercise time on the treadmill by 68% in comparison with group A (P
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3.2. Follow-up measurements After the 6-month training program the repeated exercise test was discontinued because of leg fatigue only in two out of the 16 patients in group A and in three out of the 10 patients in group B. Resting HR decreased by 9% in group A (P CO.01 ) and by 5% in group B (P
results Baseline
Follow-up
Groups
A
B
C
D
A
B
C
Resting HR” (bpm) Resting sBP” (mmHg) Resting dBP” (mmHg) Exercise time (min) METS” HRmax (bpm) Exercise sBP (mmHg) Exercise dBP (mmHg) Double product (X 10’) VE” max (I/mitt) VE/VO,max VO,max” (m.l/kg/min) Lactic acid (mmol/l)
85.3k11.7 145217 87+8 16.Ok3.7 8.622.1 139222 188223 8929 26.125.7 42.1214.1 41.01r16.6 16.6?6.2 8.1k2.3
82.3-cll.l 145218 87213 16.3t2.8 9.221.3 13927 192214 84?11 26.8k2.6 42.928.2 49.7k16.2 16.2k5.0 8.521.7
80.628.6 14327 82t5 16.0+3.1 9.Ok1.6 140512 195t11 82”5 27.352.2 35.4211.5 44.5% 10.0 16.3k4.7 8.9k1.9
70.4*8.4* 122rt11* 78-c7* 26.8%4.1* 13.9*1.5* 179+11* 1692 15* 75+6* 30.3+2.6* 90.0t20.1* 27.8?5.3* 42.4+9.8* 11.5t1.1
77.3z9.o+$ 136t 14” 7928’ 21.2?3.6+s 11.4t1.7+$ 146?20* 179?29 78-r- 12’ 26.Ok6.0” 59.22 15.7’” 43.2& 17.6’ 23.7%7.7” 6.9+3.0+’
78.4% 10.5’ 143217 8358’ 18.6?3.3+’ 10.4t1.5’ 142?10 1892 14 83?9 26.7t2.1 44.3k8.6’ 45.2-c 15.7 19.0+5.3+S 8.4t2.2
81.8+8.5 144* 10” 8223 16.1-C3.1”n 9.0t1.5# 139212 2022 12*a 8325 28.1 t2.4 34.9t9.0+a 43.5% 10.2 15.8%4.8#’ 9.0?2.3#
a HR, heart rate; sBP, systolic blood pressure; dBP, diastolic blood pressure; METS, metabolic equivalents; VE, ventilation; consumption. *P
VO,max,
maximal
between
groups
oxygen A and B,
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(P
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RV, LA or Ao dimensions, or in the excursion of the aortic valve (Table 4). Group D had a lower value of RV size by 27% (PKO.01) and of LA by 9% (PC 0.05) in comparison with group A, by 32% (PC 0.002) and 11% (P cO.05) in comparison with group B and by 28% (P
data (meanskS.D.) Baseline
Follow-up
Groups
A
B
C
D
A
B
C
RV” (mm) Ao” (mm) AV” (mm) LA” (mm) LVIDd” (mm) LVISd” (mm) IVS (d)” (mm) PW (4” (=I 2 PW/LVIDd (mm) LVM” (g) LVMI” (g/m*)
17.8’-4.8 31.724.6 20.623.2 33.326.0 52.1 t-6.4 34.925.3 10.922.7 10.8Z1.6 0.4t0.1 226k70 133243
19.255.5 31.5t3.8 20.723.2 33.525.5 52.Ok4.9 34.824.7 ll.Ok1.8 10.9t1.6 0.420.9 226255 134235
18.024.6 30.3k4.7 19.623.0 34.525.9 52.1k5.2 35.024.1 10.9z2.1 11.252.0 0.4?0.1 234272 139t42
13.0?2.3* 30.0ir3.3 23.023.3 30.3?4.2* 46.1?4.0* 26.02X3* 9.5?1.6* 9.3t0.9* 0.4eo.1 151f29* 80?14*
21.Oe6.4 32.154.6 20.823.4 33.555.9 54.0?6.1+ 35.Ok5.1 10.9k2.8 10.7Z1.8 0.450.1 240%84+ 148248’
20.1 k6.0 31.61t3.5 20.723.2 33.8k4.6 53.124.6 35.125.3 11.021.3 10.9t1.3 0.450.6 234545 147?27+
18.4k5.1 30.324.6 20.0k3.4 34.525.7 52.125.0 35.124.4 11.0*1.9 11.021.7 0.4kO.l 231266 1372359
’ RV, right ventricle; Ao, aorta; AV, aortic valve excursion; LA, left atrium; LVIDd, left ventricular internal dimension at enddiastole; LVISd, left ventricular internal dimension at end-systole; IVS (d), intraventricular septal thickness at end-diastole; PW (d), left ventricular posterior wall thickness at end-diastole; LVM, left ventricular mass; LSMI, left ventricular mass index. *P
261)
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Table 5 LV functional data of group A during stress echo (means?S.D.) Baseline EDVI” (ml/m*) ESVI” (ml/m’) EF” (%) WI” (ml/m’) COI” (l/min/m2)
Follow up
Rest
Exercise
Rest
Exercise
78.4225.9 30.6k10.9 61.13-6.7 47.9216.4 4.221.4
78.9224.3 26.7t9.5* 66.4?7.3* 52.4?17.3* 6.22 1.8*
84.9%24.5+ 30.629.8 64.115.6+ 54.4Z16.5' 4.121.0
85.4223.6' 23.4?8.6"+ 73.1?5.6*" 62.2?17.1*+" 7.1*1.9”‘q
a EDVI, end-diastolic volume index; ESVI, end-systolic volume index; EF, ejection fraction; SVI, stroke volume index; COI, cardiac output index. * PCO.05 between rest and exercise. ’ PcO.05 between baseline and follow-up values. ’ PcO.05 between groups A and C (Table 7).
Table 6 LV functional measurements of group B during stress echo (means2S.D.) Baseline EDVI (ml/m’) ESVI (ml/m’) EF (%) SVI (ml/m*) CO1 (l/min/m2)
Follow up
Rest
Exercise
Rest
Exercise
77.4217.4 30.4t 10.0 61.424.8 47.Ok9.3 3.9r0.7
77.6Zl7.0 27.4%11.8* 65.7t7.2* 50.2%8.3* 5.721.3*
81.1Z16.7 31.4k11.8 61.8k9.6 48.6+10.1 4.OLO.8
81.5t17.8 26.1+11.2*+ 68.8%8.1*+ 55.4t10.5*+ 6.3?1.4*+
* P~0.05 between rest and exercise. ’ PcO.05
between baseline and follow-up values.
Table 7 LV functional measurements of group C during stress echo (mean&SD.) Baseline EDVI (ml/m*) ESVI (ml/m’) EF (%) SVI (ml/m2) CO1 (llmin/m2) * PcO.05
Follow up
Rest
Exercise
Rest
Exercise
78.8219.7 30.7k10.6 60.825.4 48.1?11.3 3.921.0
79.2219.0 27.6f8.1* 64.8f5.4* 51.6?12.1* 5.9-+1.3*
78.3217.8 31.6211.4 60.259.3 46.7t11.2 3.950.9
78.3k17.2 27.7?10.3* 65.3?8.1* 50.6+10.3* 5.921.4*
between rest and exercise.
during exercise by 5% (NS), whereas the ESVI decreased by 10% (P
Table 8 LV functional measurements of group D during stress echo (means?S.D.) Baseline EDVI (ml/m*) ESVI (ml/m2) EF (%) SVI (ml/m’) CO1 (l/mm/m*)
*P
Rest
Exercise
52.9?9.2* 14.1 -t7.0* 74.12 10.8* 38.828.3* 2.8%0.7*
61.9)10.6*+ 9.3?5.6*+ 83.1?8.9*+ 44.6%8.2+ 5.81trl.l+
between D and A, B, C. between rest and exercise.
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those of groups A, B and C. At rest group A showed a 15% higher HR (P
measurements
After the (j-month period, no significant change was seen regarding the RV, LA and Ao dimensions in the three patient groups. After the end of the exercise training program in group A the LVIDd was increased by 4% (P
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with the respective values seen before training. So, the ESVI decreased by 85% (P
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malities [3-51. The resting HR of our patients is increased compared to healthy sedentary controls. This increase can be attributed to the combined effects of anemia and sympathetic nervous system over-activity as well as to the decreased physical capacity of these patients [ 19-211. On the contrary, the decreased HR response during exercise may be a sign of cardiac autonomic nervous system and/or atria1 pacemaker myocyte dysfunction, which is common in HD patients [22,23]. One third of our patients reached 85% of the maximum predicted HR, a fact that confirms previous observations [24,25]. Increased left ventricular end-diastolic and endsystolic volumes, interventricular septal and posterior wall thickness and myocardial mass were found in our HD patients compared to the healthy controls. They also had higher values of right ventricular and left atria1 dimensions. These anatomical changes were associated with LV functional abnormalities both at rest and during submaximal exercise. The ejection fraction was found to be decreased and the stroke volume and cardiac output increased in comparison with the healthy controls. These changes could be considered as a form of high output systolic dysfunction of the left ventricle, which is common in dialysis patients [26-301. Some of our patients (63%) were hypertensive, whose blood pressure was well controlled, others (26%) suffered from ischaemic heart disease without clinical manifestations and a small proportion ( 13%) of our patients had heart failure symptoms (grade>11 according to NYHA). The coexistence of remarkable LV dilatation and LV hypertrophy and the decrease in the systolic function in some of our patients indicate the existence of cardiomyopathy, too [l]. Similar anatomical and functional changes in chronic renal failure patients have been described by others under the title ‘uremic cardiomyopathy’ and the reasons have been attributed to several causes [20,3 l-331. This may in part relate to the effects of anemia, hypertension, intravenous anastamosis etc. or factors which decrease the myocardial contractility and perfusion, such as coronary artery disease, valvular disease, endocarditis, pericarditis, uremic toxins and the influence of the I-ID itself [2,34-361. Left ventricular hypertrophy is the most common finding in ‘uremic cardiomyopathy’ and one of the causes of the increased mortality in these patients even if coronary artery
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disease or hypertension do not exist [4,5,37]. This hypertrophy is followed by left ventricular dilatation (eccentric-dilated hypertrophy) and causes left ventricular systolic and diastolic dysfunction [ 1,38-401. Left ventricular dysfunction is not mainly due to the increased myocardial mass itself, but also to other factors, such as myocardial fibrosis and biochemical abnormalities amongst others, which are present with this ‘pathological’ type of hypertrophy [41,42]. On the contrary, in the ‘physiological’ left ventricular hypertrophy, as a result of regular training, no diastolic or systolic LV dysfunction is detected, as a rule [43-451. 4.1. Training
effects on cardiovascular
system
We have noticed that the resting HR, as well as the systolic and diastolic blood pressure were decreased after exercise training. This beneficial effect on the arterial pressure was detected in a large number of HD patients, even in the hypertensives with a 24-h ambulatory blood pressure monitoring (unpublished observations). Due to this decrease of the blood pressure the dose of anti-hypertensive agents in some patients had to be decreased. These results were in agreement with previous reports of Goldberg et al., Hagberg et al. and Painter and Zimmerman [6,11,46,47]. These authors consider that the blood pressure decrease seen in the uremic hypertensives after a regular training program may be due to a blood volume decrease, because of favorable effects of exercise on the peripheral vascular resistance, sympathetic nervous system activity and also possibly to the renin-angiotensin system. A beneficial effect of exercise training on cardiac autonomic nervous system in I-ID patients has also been indicated [48]; we found that physical training significantly enhanced the reduced heart rate variability in HD patients. Similar effects of training on heart rate variability in healthy and cardiac patients, as a result of enhanced vagal and reduced sympathetic tone, were previously reported [49,50]. Another finding was the left ventricular end diastolic volume and left ventricular mass increase only in group A after the 6-month training program. Similar left ventricular anatomical adaptations due to chronic regular exercise are also described with echocardiographic and nuclear studies on healthy
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subjects and cardiac patients [51-541. Ehsani et al. made the allegation that the left ventricular enddiastolic volume increases adaptively, whereas the left ventricular end-systolic volume remains stable after a 12-month aerobic exercise program in postinfarct patients [55]. It is possible that cardiac myocyte adaptations, due to regular exercise, may lead in some patients to an increase of the left ventricular end-diastolic dimension and the inter-ventricular septum, as well as the left ventricular posterior wall thickness, even in coronary artery disease patients [56]. The same mechanism may be present in the HD patients following intense exercise training, in spite of the fact that these patients already have an increased left ventricular volume and mass, compared to the healthy controls. On the contrary, there was no increase found either in the left ventricular enddiastolic diameter or mass in our patients, who followed a moderate exercise training program at their home. Demopoulos et al. suggested a moderate aerobic exercise training program ((50% of the peak VO,max) in patients with congestive heart failure, because, compared with the intense exercise (7080% of the peak VO,max), it does not significantly affect the size of the left ventricular and the ventricular wall stress, although it improves the aerobic capacity similarly [57]. However, the left ventricular remodeling due to regular training was associated with an improvement of cardiac function as detected by the stress echo study. So, in the patients of group A, who followed the supervised intense training program, the ejection fraction, stroke volume and cardiac output were significantly increased both at rest and during submaximal supine exercise. On the contrary, in the patients who followed the moderate training program at home (group B), these improvements were only seen during sub-maximal exercise. Very few observations regarding the effects of physical training on cardiac function in chronic renal failure patients have previously been reported. Roseler et al., who studied the cardiac silhouette from the chest X-ray in patients on hemodialysis after a training program, supported that during sub-maximal exercise in the upright position cardiac output and stroke volume were decreased, whereas at maximal exercise these factors are not changed [58]. Shalom et al. have not detected any changes regarding the left ventricular ejection
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fraction estimated using a radionuclear ventriculography at maximal exercise on a cycle-ergometer after a 12-week training program in end-stage renal disease patients [ 121. The fact that different results have been detected in these cases may be due to the different position of the patients during the exercise test. It is supported that during exercise in the supine position and especially when the lower limbs are elevated (e.g. feet fixed on the cycle-ergometer), the left ventricular end-diastolic volume increases and so the Frank-Starling mechanism is operative in this setting, whereas in an upright or sitting position no specific changes have been seen [43,59,60]. The left ventricular functional improvement not only at rest (group A), but also during exercise in our patients is attributed to the left ventricular end-diastolic increase and to the end-systolic volume decrease, suggesting an increase in the myocardial contractility. The extent of left ventricular systolic functional improvement in the end-stage renal disease patients, that is ejection fraction, stroke volume and cardiac output is similar to that seen in healthy individuals after an aerobic training period [52]. It is also believed, relying on experimental and clinical studies, that regular training can cause an improvement in the left ventricular function in patients with coronary artery disease and in those with heart failure (grade II according to NYHA) [61-641. As already mentioned, the patients of our study had decreased cardiac function, and border-line left ventricular hypertrophy, while a considerable number of them were hypertensive and suffered from stable ischaemic heart disease. For the healthy sedentary individuals there are conflicting views, if these improvements are only due to the Frank-Starling mechanism improvement or also due to an increase in the myocardial contractility, whereas in trained patients, who suffer from cardiovascular disease, it is believed that both these mechanisms are taking part during exercise [65-671. The enhancement of the left ventricular function, especially in patients with coronary artery disease, probably results from an increased oxygen supply to the myocardium with exercise [61,68,69]. Moreover, the improvement in LV systolic function in HD patients following exercise training may be due to the reduction in the cardiac load, which leads to a depression in the arterial pressure. It is also supported, that another mechanism responsible for this
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improvement in HD patients is the restoration of the cardiac autonomic nervous balance [48]. In a recent study we have noticed that regular exercise training improves lower limb muscular atrophy considerably in HD patients [70]; this favorable peripheral effect of exercise, similar to that seen in heart failure patients, may be one of the most important factors, that in combination with the cardiac function improvement, brings about a significant increase in the aerobic capacity of these patients [6,10]. Similar beneficial effects of exercise training on aerobic capacity, work capacity and quality of life index in end-stage renal patients on HD have also been reported [6,1 l- 131. Although widely used, the mechanisms of training-induced benefits are not known, and may include muscular, autonomic cardiac and vascular components. The description recently of reduced oxygen free radical stress with training may also be relevant to these patients [71]. In conclusion, a long-term, intense exercise rehabilitation program improves the left ventricular performance, both at rest and during sub-maximal exercise in HD patients. Similar favorable changes at effort, but to a lesser degree, is seen after moderate aerobic exercise training at home. Physical training could be used as a therapeutic modality in the management of end-stage renal disease, because of the beneficial effects in cardiac function, aerobic capacity and work capacity of the dialysis patients. This is another group which is only rarely considered for cardiac rehabilitation programmes because of frequent entry restrictions against complicated or elderly patients [72]. References (11 Lundin AP, Stein RA, Frank F, LaBelle P, Berlyne G, Krasnow N, Friedman E. Cardiovascular status in long-term hemodialysis patients: an exercise and echocardiographic study. Nephron 1981;28:234-7. [2] Kenny A, Sutters M, Evans D, Shapiro L. Effects of hemodialysis on coronary blood flow. Am J Cardiol 1994;74:291-4. [3] Lewis BS, Milne FJ, Goldberg B. Left ventricular function in chronic renal failure. Br Heart J 1976;38:1229-39. [4] Deligiannis A, Paschalidou E, Sakellariou G, Vargemezis V, Geleris P, Kontopoulos A, Papadimitriou M. Changes in left ventricular anatomy during haemodialysis, continuous ambulatory peritoneal dialysis and after renal transplantation. Proc EDTA-ERA 1984;21:185-9. [5] London G, Fabiani F, Marchais S, De Vemejoul M, Guerin AP, Safar ME, Metivier F, Llach F. Uremic cardiomyopathy: an inadequate LV hypertruphy. Kidney Int 1987;31:973-80.
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[6] Painter PL, Zimmerman SW. Exercise in end-stage renal diseast, Am .I Kidney Dis 1986;7:386-94. [7] Robertson H. Haley N, Guthrie M. Gardenns D, Eschbach J. Adamson J. Recombinant erythropoietin improves exercise capacity in anemic hemodialysis patients. Am J Kidney Dis 1990;15:325-32. [8] 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. [9] Kavanagh T, Myers MG, Baigrie RS, Mertens DJ, Sawyer P, Shephard RJ. Quality of life and cardiorespiratory function in chronic heart failure: effects of 12 months aerobic training. Heart 1996;76:42-9. [lo] Coats A, Adamopoulos S, Radaelli A, McCane A, Meyer T, Bemedi L. Controlled trial of physical training in chronic heart failure. Circulation 1992;95:2119-31. [ll] Goldberg AP, Hagberg JM, Delmez JA, Haymes ME, Harter HR. The metabolic and psychological effect of exercise training in hemodialysis patients. Am J Clin Nutr 1980;33: 1620-8. [12] Shalom R, Blumenthal JA, Williams SR, McMurray RG, Dennis VW. Feasibility and benefits of exercise training in patients on maintenance dialysis. Kidney Int 1984;25:958-63. [13] Kouidi E, Iacovides A, Iordanidis P, Vassiliou S, Deligiannis A, Ierodiakonou C, Tourkantonis A. Exercise renal rehabilitation program (ERRP): psychosocial effects. Nephron 1997;77: 152-8. [14] Lown B, Podrid PJ, De Silva RA, Graboys TB. Sudden cardiac death - management of the patient at risk. Curr Prob Cardiol 1980;4:7-62. [15] Ross DL, Crabeau GM, Smith S, Seymour M, Knierim N, Pitetti K. Efficacy of exercise for end-stage renal disease patients immediately following high-efficiency hemodialysis: a pilot study. Am J Nephrol 1989;9:376-83. [16] McInnis K, Balady G. Comparison of submaximal exercise responses using the Bruce vs. modified Bruce protocols. Med Sci Sports Exert 1994;26:103-7. [17] Devereux R, Reichek N. Echocardiographic estimation of LV mass in man: anatomic validation of the method. Circulation 1977;55:613-8. [18] Feigenbaum H. In: 5th ed, Echocardiography, Philadelphia: Lea and Febiger, 1993. [ 191 Kersch ES, Kronfield SJ, Unger A, Popper RW, Cantor S, Cohn K. Autonomic insufficiency in uremia as a cause of hemodialysisinduced hypotension. N Eugl J Med 1974;290:650-3. [20] Lazarus JM, Lowrie EG, Hampers CL, Merill JP. Cardiovascular disease in uremic patients on hemodialysis. Kidney Int 1975;7(Suppl 2):167-75. [21] Clyne N, Jogestrand T, Lins LE, Pehrsson SK. Factors limiting physical working capacity in predialytic uremic patients. Acta Med Stand 1987;222: 183-90. [22] Pickering TG, Gribbin B, Strange-Petersen E, Cunningham DJC, Sleight l? Effects of autonomic blockage on the baroreflex in man and during exercise. Circ Res 1972;30:177-85. [23] Kettner A, Goldberg A, Hagberg J, Delmez J, Harter H. Cardiovascular and metabolic responses to submaximal exercise in hemodialysis patients. Kidney Int 1984;26:66-71. [24] Morrow CE, Schwartz JS, Sutherland DE, Simmons RL, Ferguson RM, Kjellstrand CM, Najarian JS. Predictive value of thallium stress testing for coronary ani cxdiovascular events in uremic diabetic patients before renal transplantation. Am J Surg 1983;146:331-5. [25] Philipson JD, Carpenter BJ, Itzkoff J, Hakala TK, Rosenthal JT, Taylor RJ, Puschett JB. Evaluation of cardiovascular risk for renal transplantation in diabetic patients. Am J Med 1986;81:630-4. [26] Feild BJ, Basley WA, Russel RO. Left ventricular function and
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hypertrophy in cardiomyopathy with depressed ejection. Circulation 1973;47:1022-31. ~271 Capelli JP, Kasparian H. Cardiac work demands and left ventricular function in end-stage renal disease. Ann Intern Med 1977;86:261-7. ml Riley Jr. SM, Blackstone EH, Sterling WA, Diethelm AG. Echocardiographic assessment of cardiac performance in patients with arteriovenous fistulas. Surgery Gynecol Obstet 1978;146:203-8. 1291 Pehrsson SK. Jonasson R, Lins LE. Cardiac performance in various stages of renal failure. Br Heart J 1984;52:667-73. [301 Lai KN, Whitford J, Buttfield I, Fassett RG, Mathew TH. Left ventricular function in uremia: echocardiographic and radionuclide assessment in patients on maintenance hemodialysis. Clin Nephrol 1985;23:125-33. [311 Daniel J, Ahearn MD, Maher JF. Heart failure as a complication of hemodialysis arteriovenous fistula. Arch Intern Med 1972;77:201-5. ~321 Schott CR, Le Sar JF, Kotler MN, Parry WR, Segal BL. The spectrum of echocardiographic findings in chronic renal failure. Cardiovasc Med 1978;3:217-27. I331 Von Bibra H, Castro L, Autenrieth G, McLeod A, Gurland HT. The effects of arteriovenous shunts on cardiac function in renal dialysis patients an echocardiographic evaluation. Clin Nephrol 1978;9:205-9. in endstage renal t341 Vertes V, Cangiano JL, Berman LB. Hypertension disease. N Engl J Med 1969;280:978-81. [351 Lindner A, Charra B, Sherrard DJ, Scribner BH. Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974;290:697. [361 London G, De Vemejoul M, Fabiani F, Marchais SJ, Guerin AP, Metivier F, London AM, Llach F. Secondary hyperparathyroidism and cardiac hypertrophy in haemodialysis patients. Kidney Int 1987;32:900-7. [371 Sibelberg DJ, Rahal D, Patton R, Sniderman A. Role of anemia in the pathogenesis of left ventricular hypertrophy in end-stage renal disease. Am J Cardiol 1989;64:222-4. assessment of left [381 Cohen MV, Diaz l? Scheuer J. Echocardiographic ventricular function in patients with chronic uremia. Clin Nephrol 1979;12:156-62. [391 D’Cruz IA, Bhatt GR, Cohen HC, Glick G. Echocardiographic detection of cardiac involvement in patients with chronic renal failure. Arch Intern Med 1979;138:720-4. [401 Miach PJ, Dawbom JK, Louis WJ, McDonald IG. Left ventricular function in uremia: echocardiographic assessment in patients on maintenance dialysis. Clin Nephrol 1981;15:259-63. septal hyper1411 Abbasi AS, Slaughter JC, Allen MW. Asymmetric trophy in patients on long-term hemodialysis. Chest 1978;74:54851. 1421 Drueke T, Le Pailleur C, Sigal-Saglier M, Zingraff J, Crosnier J, DiMatteo J. Left ventricular function in hemodialyzed patients with cardiomegaly. Nephron 1981;28:80-7. [43] Froelicher V In: 2nd ed, Exercise and the heart. Clinical concepts, Chicago: Year Book Medical Publishers, 1987. [44] Deligiannis A, Mandroukas K. Non-invasive cardiac evaluation of weight lifters using anabolic steroids. Stand J Med Sci Sports 1992;3:37-41. [45] Shapiro L. Cardiac adaptations. In: Harries M, Williams C, Stanish W, Micheli L, editors, Oxford textbook of sports medicine, Oxford: Oxford Medical Publications, 1994, pp. 257-67. 1461 Hagberg JM, Ehsani A, Heath GW, Goldring D, Hemandez T, Holloszy JO. Beneficial effects of endurance exercise training in adolescent hypertension. Am J Cardiol 1980;45:489-95. 1471 Hagberg JM, Goldberg AP, Ehsani A, Heath G, Dehnez J, Harter H. Exercise training improves hypertension in hemodialysis patients. Am J Nephrol 1983;3:209-12.
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A, Kouidi E, Tourkantonis A. The effects of physical training on heart rate variability in hemodialysis patients. Am J Cardiol 1998;submitted. S, Meyer T, Conway J, Sleight P. Physical [491 Coats A, Adamopoulos training in chronic heart failure. Lancet 1990;335:63-6. [501 Goldsmith R, Bigger T, Steinman R, Fleiss J. Comparison of 24-h parasympathetic activity in endurance-trained and untrained young men. JACC 1992;20:552-8. adaptations to physical 1511 Scheuer JS, Tipton CM. Cardiovascular training. Annu Rev Physiol 1977;39:221-5 1. ~521 DeMaria A, Neumann A, Lee G, Fowler W, Mason D. Alterations in ventricular mass and performance induced by exercise training in man evaluated by echocardiography. Circulation 1978;57:237-43. 1531 Sold G, Zwehl W, Neuhaus KL, Kreuzer H. Echokardiographische Dimensionen des linken Ventrikels unter Ergometerbelastung: Untersuchungen an gesunden Probanden. Z Kardiol 1979;68:802-9. [541 Maron B. Structural features of the athlete heart as defined by echocardiography. J Am Co11 Cardiol 1986;7:190-203. [551 Ehsani AA, Heath GW, Hagberg JM, Sobel BE, Hollszy JO. Effects of 12 months of intense exercise training on ischemic ST-segment depression in patients with coronary artery disease. Circulation 1981;64:1116-24. to 1561 Moore R, Korzick D. Cellular adaptations of the myocardium chronic exercise. Prog Cardiovasc Dis 1995;37:371-96. [571 Demopoulos L, Bijou R, Fergus I, Jones M, Strom J. LeJemtel T. Exercise training in patients with severe congestive heart failure: enhancing peak aerobic capacity while minimizing the increase in ventricular wall stress. J Am Co11 Cardiol 1977;29:597-603. [581 Roseler E, Aurisch R, Precht K, Strangfeld D, Priem F, Siewert H, Lindenau K. Haemodynamic and metabolic responses to physical training in chronic renal failure. Proc Eur Dial Transplant Assoc 1980;17:702-6. [591 Gorlin R, Cohen LS, Elliot WC, Klein MD, Lane FJ. Effect of supine exercise on left ventricular volume and oxygen consumption in man. Circulation 1965;32:361-71. [601 Poliner LR, Dehmer GJ, Lewis SE, Parkey RW, Blomqvist GG, Willerson JT. Left ventricular performance in healthy subjects: a comparison of the responses to exercise in the upright and supine positions. Circulation 1980;62:528-33. [‘311Letac B, Cribier A, Desplanches JF. A study of left ventricular function in coronary patients before and after physical training. Circulation 1977;56:375-9. effects of [621 Lee AP, Ice R, Blessey R, Samnarco ME. Long-term physical training on coronary patients with impaired LV function. Circulation 1979;60:1519-26. t631 Ehsani AA, Martin III WH, Heath GW, Coyle EF. Cardiac effects of prolonged and intense exercise training in patients with coronary artery disease. Am J Cardiol 1982;50:246-51. 1641 Hagberg JM, Ehsani AA, Hollszy JO. Effect of 12 months of intense exercise training on stroke volume in patients with coronary artery disease. Circulation 1983;67:1194-9. [651 Weiss JL, Weisfeldt ML, Mason SJ, Garrison JB, Livengood SV, Fortuin NJ. Evidence of Frank-Starling effect in man during severe semisupine exercise. Circulation 1979;59:655-61. 1661 Ehsani A, Biello D, Seals DR, Austin MB, Schultz J. The effect of left ventricular systolic function on maximal aerobic exercise capacity in asymptomatic patients with coronary artery disease. Circulation 1984;70:552-8. [67] Ehsani A, Biello D, Schultz J, Sobel B, Holloszy J. Improvement of left ventricular contractile function by exercise training in patients with coronary artery disease. Circulation 1986;74:350-8. [68] Detry JMR, Rousseau M,Vanderbroucke G, Kusumi F, Brasseur LA, Bruce RA. Increased arteriovenous oxygen difference after physical training in coronary heart disease. Circulation 1971;44: 109-204.
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journal
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cardiology ELSEVIER
International Journal of Cardiology 70 (1999) 253-266
Cardiac effects of exercise rehabilitation in hemodialysis patients Asterios Deligiannis”‘“, Evangelia Kouidi”, Elias Tassoulasb, Panagiotis Gigis”, Achilleas Tourkantonisd, Andrew Coatsb “National
“Laboratory of Sports Medicine, Aristotle University and Lung Institute, Imperial College School of Medicine, at ‘Laboratory of Human Anatomy, Aristotle University dFirst Internal Medicine Department, AHEPA Hospital, Aristotle
Heart
of Thessaloniki, Thessaloniki, Greece Royal Brompton Hospital, Sydney St., London SW3 6NP, UK of Thessaloniki, Thessaloniki, Greece University of Thessaloniki, Thessaloniki, Greece
Received 24 April 1999; accepted 17 May 1999
Abstract Exercise training has well documented beneficial effects in a variety of cardiac disorders. End stage renal disease patients present many cardiovascular complications and suffer from impaired exercise capacity. No study to date has adequately examined the cardiac responses to exercise training in renal patients on hemodialysis (HD). To determine the effects of an exercise rehabilitation program on the left ventricular function at rest and during submaximal effort, 38 end-stage renal disease patients on maintenance HD were randomised into three groups. Sixteen of them (group A - mean age 46.4213.9 years), without clinical features of heart failure, participated in a 6-month supervised exercise renal rehabilitation program consisting of three weekly sessions of aerobic training, 10 (group B - mean age 51.42125 years) followed a moderate exercise program at home, and the other 12 (group C - mean age 50.2k7.9 years) were not trained and remained as controls. The level of anemia and the HD prescription remained constant during the study. Fifteen sex- and age-matched sedentary individuals (group D - mean age 46.9t6.4 years) were the healthy controls. All subjects at the start and end of the program underwent physical examination, laboratory tests, treadmill exercise testing, M-mode and 2-D echocardiograms performed at rest and at peak of supine bicycle exercise. Left ventricular volumes (EDV, ESV) and mass (LVM) were measured and ejection fraction (EF), stroke volume index (SVI) and cardiac output index (COI) were calculated by standard formulae. The maximal oxygen consumption increased by 43% (P
Hemodialysis; End-stage renal disease; Left ventricular function; Exercise training
1. Introduction
*Corresponding author. Present address: 53 Mitropoleos Str, 546 23 Thessaloniki, Greece. Tel.: + 30-31-992-181; fax: + 30-31-992-183.
A high proportion of end-stage renal disease patients on hemodialysis (HD) are found to suffer from cardiovascular complications, including coro-
0167-5273/99/$ - see front matter 0 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: SO167-5273(99)00090-X
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nary artery disease, heart failure and hypertension. These complications are the main reason for death in up to 50% of these patients [1,2]. Most have left ventricular dysfunction due to factors which adversely affect cardiac pre-load and after-load such as hypertension, anaemia, and arterio-venous anastomoses, and/or contractility, as uremic toxins, acidosis etc. [3-51. A decreased cardiac response to exercise is likely to be one of the major causes responsible for the low physical capacity of these patients. Maximal oxygen uptake in HD patients ranges from 15 to 25 ml/kg/min (similar to moderate heart failure) and their maximal metabolic equivalents (METS) are frequently lower than 3.5 [6]. The effort of correcting their anemia by using human recombined erythropoietin over the last few years has improved physical capacity by 20%; it remains however, significantly limited [7]. Exercise training is now being used as a therapeutic modality in the medical management of patients with a variety of stable cardiac disorders, including chronic angina, myocardial infarction, hypertension, etc., as well as selected patients with chronic heart failure or after cardiac operation. In many of these settings training has had beneficial effects on physical fitness and quality of life [f&10]. These benefits, if achievable in HD patients, would be of considerable value. There have been a number of studies which have demonstrated that physical training, mainly of an aerobic mode, significantly improves the physical condition of end-stage renal disease patients on HD [6,11- 131. However, there are very few references as regards the effects of physical training on the cardiac function of these patients. The aim of this study was to explore the impact of a 6-month supervised exercise rehabilitation program on cardiac anatomy and systolic function in comparison with another 6-month home moderate physical training program in patients with end-stage renal disease on regular HD. 2. Methods
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to 65 years old. They were all undergoing regular HD with an artificial kidney, for three sessions a week, 4 h each session. Patients with unstable hypertension, congestive heart failure (grade211 according to New York Heart Association classification), cardiac arrhythmias (III according to Lown) [ 141, recent myocardial infarction or unstable angina, diabetes mellitus, active liver disease, serious anemia and peripheral vascular disease were excluded. The patients were randomized into three groups: in group A, 16 HD patients were included (11 men and five women, mean age 46.45 13.9 years old) and followed a 6-month supervised exercise training program. In group B, 10 patients were included (eight men and two women, mean age 51.4+- 12.5 years old) and followed a moderate exercise training program for 6 months at home. In group C, 12 patients were included (four men and eight women, mean age 50.2k7.9 years old), who continued their usual lifestyle and were used as ‘patient’ controls. In this study there were also included 15 healthy sedentary individuals (eight men and seven women, mean age 46.9k6.4 years old), who constituted the group D and were used as ‘healthy’ controls. 2.2. Study design
A baseline clinical assessment,spiroergometric and echocardiographic study, as well as blood tests were carried out on each patient, 24 h after an uncomplicated and effective hemodialysis session, as well as on the healthy controls. After a 6-month period the same measurements were repeated only in the three groups of patients. To exclude any impact of the changes in the status of anemia on the aerobic capacity of patients, we tried to keep the haematocrit level stable for all renal patients throughout the study by increasing or decreasing the dose of erythropoietin, whenever necessary. Twenty-three out of 32 patients were receiving erythropoietin regularly. HD parameters were kept stable throughout the 6-month period program (by using the same model of filter and a constant composition of the dialysis solution, and by keeping the HD session time constant throughout this period).
2.1. Study population 2.3. Cardiopulmonary
Thirty-eight end-stage renal disease patients were included in this study. Their age ranged from 21 up
exercise test
The cardiopulmonary exercise test was performed
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using an Ergometer Health Track II model with a manipulation system HT-7. The test was done according to modified Bruce protocol and was discontinued when the subjects complained of limiting fatigue, dyspnea or exhaustion [15,16]. During this test the ECG of each individual was monitored and recorded every 3 min. At the same time points blood pressure was measured by mercury sphygmomanometry. During the exercise test the VO,max was continuously monitored using a specific mobile telemetric device (Cosmed K, model). The following parameters were detected from the spiroergometric study: heart rate at peak exercise (HRmax), systolic (sBP) and diastolic (dBP) blood pressure at peak exercise, double product (heart rate maxX systolic blood pressure max), total exercise time, exercise as measured by estimation of metabolic equivalents using specific tables ( 1 MET= 3.5 ml O,/kg/min), maximal oxygen uptake (VO,max), as the highest recorded value of VO,, pulmonary ventilation (VE) and the relationship of VE/VO, as well as lactic acid. To measure lactic acid, blood samples were taken from the right ear before and 4 min after the end of the exercise test. Lactic acid measurement was carried out in a photometer (Dr Lange LP 400 model). Before each measurement, inspection of the spiroergometer and the photometer function and regulation were carried out according to their operating instructions. 2.4. Rest and stress echocardiography
The left ventricular anatomical and functional indices were measured at rest, as well as during supine exercise with M- and B-mode echocardiographic study. This study was carried out with a Sigma 44HVCD echocardiograph (Kontron Instruments). The echocardiographic study was made by putting the patient in the left lateral semi-erect position at 30” from the horizontal plane. A manufactured couch was used for this study, the incline of which could change from 0” to 45”. An ergometric bicycle (Monark 868 model) was adapted to this couch. The subject’s feet during the study were fixed on the pedals of the cycle-ergometer. During the measurements the chest was kept in a mid-expiratory phase in order to minimize the effects of breathing on them. The transducer (2.5/3.5 MHz) was placed in the 3rd or 4th left parastemal intercostal space in such a posi-
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tion as to give the best quality images of the intraventricular septum, left ventricular posterior wall and mitral valve or the cordae tendinae. The position at which the transducer was put during the initial measurements was defined in each individual by measuring the distance between the transducer and the sternal edge, as well as the distance from the lower edge to the left clavicle. At the 6-month follow-up measurements, the transducer was put again at the same position on each patient. The left ventricular end-diastolic diameter (LVIDd), the left ventricular end-systolic diameter (LVISd), the intra-ventricular septal thickness (IVS), the left ventricular posterior wall (PW) during systole and diastole, the right ventricular dimension (RV), the aorta (Ao), the left atrium (LA), as well as the aortic valve excursion (AV) were measured by Mmode echocardiography. The end diastolic point was defined as the point which coincides with the QRS complex onset on the simultaneously recorded ECG, whereas the end systolic point was determined as the point coinciding with the end of the T wave on the ECG. Each M-mode measurement was done on five sequential cardiac cycles on each individual and the average of all these measurements was used for analysis. Left ventricular mass (LVM) was calculated by the M-mode echocardiography study according to the formula of Devereux and Reichek [ 171: LVM = 0.8 X [ l.O4(IVS + PW + LVIDd)3 - (LVIDd)3] -i- 0.6 g.
The LVM change into mass index (LVMI) was done by dividing the LVM by the body surface area (BSA). The stress echo study was carried out both at rest and during submaximal exercise. Each subject underwent graded supine bicycle exercise in the left lateral semi-erect position. The exercise consisted of 2-min stages, beginning at a work rate of 25 W and increasing in 25 W increments, until 70 or 80% of each individual’s HRmax was achieved. Each HRmax was estimated in the preceding treadmill exercise test. This exercise level was chosen in order to have the best quality images during the stress echo study, as more vigorous exercise causes significant tachypnea, which gives rise to poor quality imaging.
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The blood pressure was recorded every 3 mm during the submaximal exercise test. For the evaluation of left ventricular function from this stress echo study, B-mode echocardiograms at rest and during the last minute of submaximal exercise were obtained at held relaxed expiration. Apical four-chamber and long axis views were recorded according to standard methods [ 181. Images were stored in archives for later playback and analysis on the computer. The images in each phase were analyzed by computerized planimetry using a computer software incorporated in the Sigma 44HVCD echocardiograph system. The indices of left ventricular function assessedwere: left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), stroke volume (SV), cardiac output (CO) and ejection fraction (EF). These indices were corrected for BSA, where appropriate. 2.5. Exercise rehabilitation
programs
The patients who were included in group A followed a 6-month exercise rehabilitation program under the supervision of a physician and the responsibility of two physical education teachers, specialized in this field. The training sessions were performed three times a week, 90 min each time, on the non-dialysis days. The patients were divided into subgroups, each one consisting of three or four persons according to age, sex, and dialysis days. Each training session consisted of a lo-min warm up on a cycle-ergometer or treadmill, a 50-min intermittent aerobic exercise program, including calistenics, steps and flexibility exercises and a IO-mm cool down period. After the first 2 months of training, a IO-min stretching and low-weight resistance program was added to the program. Continuous monitoring of the HR and cardiac rhythm of each patient was performed with a specific telemetric device. The intensity of exercise was prescribed on an individual basis, so that during the first 2 months the heart rate remained within 60 to 70% of the HRmax achieved during the initial maximal exercise test. The blood pressure was also measured every 15 min. After the first 3 months the younger patients were playing basketball and football once a week, whereas the older patients were swimming. The 10 patients who were included in group B
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followed a moderate exercise training program at home. These patients were supplied with a mobile cycle-ergometer and they were given instructions regarding the performance of simple exercises. We kept close contact with these patients, to answer any questions they had and to become aware of their course. According to this exercise program the patients had to cycle at least five times a week, 30 min each time, at a heart rate of SO to 60% of the maximal heart rate each one had reached during the baseline treadmill test. After that, they performed simple flexibility and muscular extension exercises. Progress checks were carried out at each patient’s home every month to check physical adaptation and to modify the exercise program, if necessary. 2.6. Statistical
analysis
All data are expressed as mean values +S.D. Changes of variables within groups were evaluated by the Student’s t-test for paired data. One-way analysis of variance (ANOVA) was performed for the comparison of the quantitative measurements among groups. For statistical analysis the SPSS 7.0 for Windows was used (Statistical Package for the Social Sciences, Chicago, IL, USA). A P value less than 0.05 was regarded as statistically significant. 3. Results
The clinical features of the four groups who participated in this study are presented in Table 1. The three patient groups (A, B and C) did not differ significantly regarding age, months on HD, frequency and duration of each HD session, anthropometric data (height, weight and body surface), as well as resting heart rate and blood pressure. From the 38 end-stage renal disease patients who were included in this study, 24 were hypertensives controlled on medication, 10 suffered from coronary artery disease with no clinical manifestations and five had heart failure of class II of NYHA. The allocation of the above patients in the three groups was balanced. The healthy individuals in group D in comparison with group A had an increased body weight by an average of 16% (P
A. Deligiannis Table 1 Clinical features
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at the onset of the study (mean+S.D.)
Groups
A
B
C
D
Subjects (n =) Men/ women Age (years) Height (cm) Weight (kg) BSA (m’) Months on hemodialysis
16 11/s 46.4’13.9 166212 65.4% 12.4 1.7?0.2 78562
10 812 51.4k12.5 16656 64.4-e 12.5 1.750.2 62237
12 418 50.2-r-1.9 16428 64.7-t-11.6 1.720.2 79k86
1s 817 46.9k6.4 171?10 76.02 10.9* 1.920.2* -
Hypertension (n =) Coronary artery disease (n =) Heart failure (n=)
10 4 2
6 3 1
8 3 2
-
Heart rate (bpm) Systolic BP (mmHg) Diastolic BP (mmHg)
85.3-cl1.7 145517 8728
82.3511.1 145?18 87213
80.628.6 14327 82?5
70.4?8.4* 122-c11* 78t7*
* P
between
groups
D and A, B, C.
17% (P
2), before the onset of the study and after 6 months and the values indicate effective HD. Urea and creatinine levels in all three patient groups, as expected, were higher than the healthy controls (P< 0.01). Potassium in group A was increased in comparison with group D by 33% (P
data (meansL8.D.) Baseline
Follow-up
Groups
A
B
C
D
Hematocrit (%) WBC Urea (mg%) Creatinine (mg%) Uric acid (mg%) Glucose (mg%) K (meq/l) Na (meqll) Ca (mg%) P (mg%) Fe (mg%)
31.124.2 5.72 1.9 188L-30 12.8rt2.6 5.621.3 91.629.2 5.7-to.5 14Ok-3 8.720.8 6.421.6 93229
31.724.3 5.821.2 195528 13.121.7 5.4kO.6 91.526.9 5.8kO.6 139*3 8.920.3 6.121.1 104*21
30.822.8 5.851.3 187”20 11.522.4 5.7kl.l 93.5-r-6.7 5.4kO.5 14026 8.OkO.4 6.1~1.4 97?21
42.5?4.1* 7.3*0.7* 44.8t2.8* 1.0t0.1* 6.120.6 95.526.1 4.3?0.2* 14123 5.4zo.4* 5.0f0.6* 10527.2
WBC, white blood cell count (103/mm3). * PcO.05 between groups D and A, B, C.
A
B
C
31.1k4.3 5.6t2.0 191230 12.922.6 5.6tl.l 92.6k9.1 5.720.5 141?4 8.820.8 6.3t1.8 98232
31.924.4 5.721.1 201t19 12.721.2 5.720.9 91.927.6 5.520.7 141%3 8.9t0.6 6.4kl.l too+25
31.022.4 5.921.5 192517 11.122.5 5.420.9 93.9k6.2 5.420.4 14026 8.1IYO.8 6.02 1.3 95518
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(e.g. injuries) or other complications develop as a consequence of exercise training during the rehabilitation program. 3.1. Cardiopulmonary exercise testing results baseline measurements The baseline values during exercise testing on the treadmill were at the same level for all three patient groups (Table 3). In 24 out of 38 patients the exercise test was discontinued because of leg fatigue and the remainder because of shortness of breath or exhaustion. Only 12 of these patients (31.6%) attained 85% of the maximum predicted heart rate for their age. The healthy control group D achieved a longer exercise time on the treadmill by 68% in comparison with group A (P
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3.2. Follow-up measurements After the 6-month training program the repeated exercise test was discontinued because of leg fatigue only in two out of the 16 patients in group A and in three out of the 10 patients in group B. Resting HR decreased by 9% in group A (P CO.01 ) and by 5% in group B (P
results Baseline
Follow-up
Groups
A
B
C
D
A
B
C
Resting HR” (bpm) Resting sBP” (mmHg) Resting dBP” (mmHg) Exercise time (min) METS” HRmax (bpm) Exercise sBP (mmHg) Exercise dBP (mmHg) Double product (X 10’) VE” max (I/mitt) VE/VO,max VO,max” (m.l/kg/min) Lactic acid (mmol/l)
85.3k11.7 145217 87+8 16.Ok3.7 8.622.1 139222 188223 8929 26.125.7 42.1214.1 41.01r16.6 16.6?6.2 8.1k2.3
82.3-cll.l 145218 87213 16.3t2.8 9.221.3 13927 192214 84?11 26.8k2.6 42.928.2 49.7k16.2 16.2k5.0 8.521.7
80.628.6 14327 82t5 16.0+3.1 9.Ok1.6 140512 195t11 82”5 27.352.2 35.4211.5 44.5% 10.0 16.3k4.7 8.9k1.9
70.4*8.4* 122rt11* 78-c7* 26.8%4.1* 13.9*1.5* 179+11* 1692 15* 75+6* 30.3+2.6* 90.0t20.1* 27.8?5.3* 42.4+9.8* 11.5t1.1
77.3z9.o+$ 136t 14” 7928’ 21.2?3.6+s 11.4t1.7+$ 146?20* 179?29 78-r- 12’ 26.Ok6.0” 59.22 15.7’” 43.2& 17.6’ 23.7%7.7” 6.9+3.0+’
78.4% 10.5’ 143217 8358’ 18.6?3.3+’ 10.4t1.5’ 142?10 1892 14 83?9 26.7t2.1 44.3k8.6’ 45.2-c 15.7 19.0+5.3+S 8.4t2.2
81.8+8.5 144* 10” 8223 16.1-C3.1”n 9.0t1.5# 139212 2022 12*a 8325 28.1 t2.4 34.9t9.0+a 43.5% 10.2 15.8%4.8#’ 9.0?2.3#
a HR, heart rate; sBP, systolic blood pressure; dBP, diastolic blood pressure; METS, metabolic equivalents; VE, ventilation; consumption. *P
VO,max,
maximal
between
groups
oxygen A and B,
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RV, LA or Ao dimensions, or in the excursion of the aortic valve (Table 4). Group D had a lower value of RV size by 27% (PKO.01) and of LA by 9% (PC 0.05) in comparison with group A, by 32% (PC 0.002) and 11% (P cO.05) in comparison with group B and by 28% (P
data (meanskS.D.) Baseline
Follow-up
Groups
A
B
C
D
A
B
C
RV” (mm) Ao” (mm) AV” (mm) LA” (mm) LVIDd” (mm) LVISd” (mm) IVS (d)” (mm) PW (4” (=I 2 PW/LVIDd (mm) LVM” (g) LVMI” (g/m*)
17.8’-4.8 31.724.6 20.623.2 33.326.0 52.1 t-6.4 34.925.3 10.922.7 10.8Z1.6 0.4t0.1 226k70 133243
19.255.5 31.5t3.8 20.723.2 33.525.5 52.Ok4.9 34.824.7 ll.Ok1.8 10.9t1.6 0.420.9 226255 134235
18.024.6 30.3k4.7 19.623.0 34.525.9 52.1k5.2 35.024.1 10.9z2.1 11.252.0 0.4?0.1 234272 139t42
13.0?2.3* 30.0ir3.3 23.023.3 30.3?4.2* 46.1?4.0* 26.02X3* 9.5?1.6* 9.3t0.9* 0.4eo.1 151f29* 80?14*
21.Oe6.4 32.154.6 20.823.4 33.555.9 54.0?6.1+ 35.Ok5.1 10.9k2.8 10.7Z1.8 0.450.1 240%84+ 148248’
20.1 k6.0 31.61t3.5 20.723.2 33.8k4.6 53.124.6 35.125.3 11.021.3 10.9t1.3 0.450.6 234545 147?27+
18.4k5.1 30.324.6 20.0k3.4 34.525.7 52.125.0 35.124.4 11.0*1.9 11.021.7 0.4kO.l 231266 1372359
’ RV, right ventricle; Ao, aorta; AV, aortic valve excursion; LA, left atrium; LVIDd, left ventricular internal dimension at enddiastole; LVISd, left ventricular internal dimension at end-systole; IVS (d), intraventricular septal thickness at end-diastole; PW (d), left ventricular posterior wall thickness at end-diastole; LVM, left ventricular mass; LSMI, left ventricular mass index. *P
261)
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Table 5 LV functional data of group A during stress echo (means?S.D.) Baseline EDVI” (ml/m*) ESVI” (ml/m’) EF” (%) WI” (ml/m’) COI” (l/min/m2)
Follow up
Rest
Exercise
Rest
Exercise
78.4225.9 30.6k10.9 61.13-6.7 47.9216.4 4.221.4
78.9224.3 26.7t9.5* 66.4?7.3* 52.4?17.3* 6.22 1.8*
84.9%24.5+ 30.629.8 64.115.6+ 54.4Z16.5' 4.121.0
85.4223.6' 23.4?8.6"+ 73.1?5.6*" 62.2?17.1*+" 7.1*1.9”‘q
a EDVI, end-diastolic volume index; ESVI, end-systolic volume index; EF, ejection fraction; SVI, stroke volume index; COI, cardiac output index. * PCO.05 between rest and exercise. ’ PcO.05 between baseline and follow-up values. ’ PcO.05 between groups A and C (Table 7).
Table 6 LV functional measurements of group B during stress echo (means2S.D.) Baseline EDVI (ml/m’) ESVI (ml/m’) EF (%) SVI (ml/m*) CO1 (l/min/m2)
Follow up
Rest
Exercise
Rest
Exercise
77.4217.4 30.4t 10.0 61.424.8 47.Ok9.3 3.9r0.7
77.6Zl7.0 27.4%11.8* 65.7t7.2* 50.2%8.3* 5.721.3*
81.1Z16.7 31.4k11.8 61.8k9.6 48.6+10.1 4.OLO.8
81.5t17.8 26.1+11.2*+ 68.8%8.1*+ 55.4t10.5*+ 6.3?1.4*+
* P~0.05 between rest and exercise. ’ PcO.05
between baseline and follow-up values.
Table 7 LV functional measurements of group C during stress echo (mean&SD.) Baseline EDVI (ml/m*) ESVI (ml/m’) EF (%) SVI (ml/m2) CO1 (llmin/m2) * PcO.05
Follow up
Rest
Exercise
Rest
Exercise
78.8219.7 30.7k10.6 60.825.4 48.1?11.3 3.921.0
79.2219.0 27.6f8.1* 64.8f5.4* 51.6?12.1* 5.9-+1.3*
78.3217.8 31.6211.4 60.259.3 46.7t11.2 3.950.9
78.3k17.2 27.7?10.3* 65.3?8.1* 50.6+10.3* 5.921.4*
between rest and exercise.
during exercise by 5% (NS), whereas the ESVI decreased by 10% (P
Table 8 LV functional measurements of group D during stress echo (means?S.D.) Baseline EDVI (ml/m*) ESVI (ml/m2) EF (%) SVI (ml/m’) CO1 (l/mm/m*)
*P
Rest
Exercise
52.9?9.2* 14.1 -t7.0* 74.12 10.8* 38.828.3* 2.8%0.7*
61.9)10.6*+ 9.3?5.6*+ 83.1?8.9*+ 44.6%8.2+ 5.81trl.l+
between D and A, B, C. between rest and exercise.
A. Deligiannis et al. I International Journal of Cardiology
those of groups A, B and C. At rest group A showed a 15% higher HR (P
measurements
After the (j-month period, no significant change was seen regarding the RV, LA and Ao dimensions in the three patient groups. After the end of the exercise training program in group A the LVIDd was increased by 4% (P
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with the respective values seen before training. So, the ESVI decreased by 85% (P
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malities [3-51. The resting HR of our patients is increased compared to healthy sedentary controls. This increase can be attributed to the combined effects of anemia and sympathetic nervous system over-activity as well as to the decreased physical capacity of these patients [ 19-211. On the contrary, the decreased HR response during exercise may be a sign of cardiac autonomic nervous system and/or atria1 pacemaker myocyte dysfunction, which is common in HD patients [22,23]. One third of our patients reached 85% of the maximum predicted HR, a fact that confirms previous observations [24,25]. Increased left ventricular end-diastolic and endsystolic volumes, interventricular septal and posterior wall thickness and myocardial mass were found in our HD patients compared to the healthy controls. They also had higher values of right ventricular and left atria1 dimensions. These anatomical changes were associated with LV functional abnormalities both at rest and during submaximal exercise. The ejection fraction was found to be decreased and the stroke volume and cardiac output increased in comparison with the healthy controls. These changes could be considered as a form of high output systolic dysfunction of the left ventricle, which is common in dialysis patients [26-301. Some of our patients (63%) were hypertensive, whose blood pressure was well controlled, others (26%) suffered from ischaemic heart disease without clinical manifestations and a small proportion ( 13%) of our patients had heart failure symptoms (grade>11 according to NYHA). The coexistence of remarkable LV dilatation and LV hypertrophy and the decrease in the systolic function in some of our patients indicate the existence of cardiomyopathy, too [l]. Similar anatomical and functional changes in chronic renal failure patients have been described by others under the title ‘uremic cardiomyopathy’ and the reasons have been attributed to several causes [20,3 l-331. This may in part relate to the effects of anemia, hypertension, intravenous anastamosis etc. or factors which decrease the myocardial contractility and perfusion, such as coronary artery disease, valvular disease, endocarditis, pericarditis, uremic toxins and the influence of the I-ID itself [2,34-361. Left ventricular hypertrophy is the most common finding in ‘uremic cardiomyopathy’ and one of the causes of the increased mortality in these patients even if coronary artery
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disease or hypertension do not exist [4,5,37]. This hypertrophy is followed by left ventricular dilatation (eccentric-dilated hypertrophy) and causes left ventricular systolic and diastolic dysfunction [ 1,38-401. Left ventricular dysfunction is not mainly due to the increased myocardial mass itself, but also to other factors, such as myocardial fibrosis and biochemical abnormalities amongst others, which are present with this ‘pathological’ type of hypertrophy [41,42]. On the contrary, in the ‘physiological’ left ventricular hypertrophy, as a result of regular training, no diastolic or systolic LV dysfunction is detected, as a rule [43-451. 4.1. Training
effects on cardiovascular
system
We have noticed that the resting HR, as well as the systolic and diastolic blood pressure were decreased after exercise training. This beneficial effect on the arterial pressure was detected in a large number of HD patients, even in the hypertensives with a 24-h ambulatory blood pressure monitoring (unpublished observations). Due to this decrease of the blood pressure the dose of anti-hypertensive agents in some patients had to be decreased. These results were in agreement with previous reports of Goldberg et al., Hagberg et al. and Painter and Zimmerman [6,11,46,47]. These authors consider that the blood pressure decrease seen in the uremic hypertensives after a regular training program may be due to a blood volume decrease, because of favorable effects of exercise on the peripheral vascular resistance, sympathetic nervous system activity and also possibly to the renin-angiotensin system. A beneficial effect of exercise training on cardiac autonomic nervous system in I-ID patients has also been indicated [48]; we found that physical training significantly enhanced the reduced heart rate variability in HD patients. Similar effects of training on heart rate variability in healthy and cardiac patients, as a result of enhanced vagal and reduced sympathetic tone, were previously reported [49,50]. Another finding was the left ventricular end diastolic volume and left ventricular mass increase only in group A after the 6-month training program. Similar left ventricular anatomical adaptations due to chronic regular exercise are also described with echocardiographic and nuclear studies on healthy
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subjects and cardiac patients [51-541. Ehsani et al. made the allegation that the left ventricular enddiastolic volume increases adaptively, whereas the left ventricular end-systolic volume remains stable after a 12-month aerobic exercise program in postinfarct patients [55]. It is possible that cardiac myocyte adaptations, due to regular exercise, may lead in some patients to an increase of the left ventricular end-diastolic dimension and the inter-ventricular septum, as well as the left ventricular posterior wall thickness, even in coronary artery disease patients [56]. The same mechanism may be present in the HD patients following intense exercise training, in spite of the fact that these patients already have an increased left ventricular volume and mass, compared to the healthy controls. On the contrary, there was no increase found either in the left ventricular enddiastolic diameter or mass in our patients, who followed a moderate exercise training program at their home. Demopoulos et al. suggested a moderate aerobic exercise training program ((50% of the peak VO,max) in patients with congestive heart failure, because, compared with the intense exercise (7080% of the peak VO,max), it does not significantly affect the size of the left ventricular and the ventricular wall stress, although it improves the aerobic capacity similarly [57]. However, the left ventricular remodeling due to regular training was associated with an improvement of cardiac function as detected by the stress echo study. So, in the patients of group A, who followed the supervised intense training program, the ejection fraction, stroke volume and cardiac output were significantly increased both at rest and during submaximal supine exercise. On the contrary, in the patients who followed the moderate training program at home (group B), these improvements were only seen during sub-maximal exercise. Very few observations regarding the effects of physical training on cardiac function in chronic renal failure patients have previously been reported. Roseler et al., who studied the cardiac silhouette from the chest X-ray in patients on hemodialysis after a training program, supported that during sub-maximal exercise in the upright position cardiac output and stroke volume were decreased, whereas at maximal exercise these factors are not changed [58]. Shalom et al. have not detected any changes regarding the left ventricular ejection
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263
fraction estimated using a radionuclear ventriculography at maximal exercise on a cycle-ergometer after a 12-week training program in end-stage renal disease patients [ 121. The fact that different results have been detected in these cases may be due to the different position of the patients during the exercise test. It is supported that during exercise in the supine position and especially when the lower limbs are elevated (e.g. feet fixed on the cycle-ergometer), the left ventricular end-diastolic volume increases and so the Frank-Starling mechanism is operative in this setting, whereas in an upright or sitting position no specific changes have been seen [43,59,60]. The left ventricular functional improvement not only at rest (group A), but also during exercise in our patients is attributed to the left ventricular end-diastolic increase and to the end-systolic volume decrease, suggesting an increase in the myocardial contractility. The extent of left ventricular systolic functional improvement in the end-stage renal disease patients, that is ejection fraction, stroke volume and cardiac output is similar to that seen in healthy individuals after an aerobic training period [52]. It is also believed, relying on experimental and clinical studies, that regular training can cause an improvement in the left ventricular function in patients with coronary artery disease and in those with heart failure (grade II according to NYHA) [61-641. As already mentioned, the patients of our study had decreased cardiac function, and border-line left ventricular hypertrophy, while a considerable number of them were hypertensive and suffered from stable ischaemic heart disease. For the healthy sedentary individuals there are conflicting views, if these improvements are only due to the Frank-Starling mechanism improvement or also due to an increase in the myocardial contractility, whereas in trained patients, who suffer from cardiovascular disease, it is believed that both these mechanisms are taking part during exercise [65-671. The enhancement of the left ventricular function, especially in patients with coronary artery disease, probably results from an increased oxygen supply to the myocardium with exercise [61,68,69]. Moreover, the improvement in LV systolic function in HD patients following exercise training may be due to the reduction in the cardiac load, which leads to a depression in the arterial pressure. It is also supported, that another mechanism responsible for this
163
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improvement in HD patients is the restoration of the cardiac autonomic nervous balance [48]. In a recent study we have noticed that regular exercise training improves lower limb muscular atrophy considerably in HD patients [70]; this favorable peripheral effect of exercise, similar to that seen in heart failure patients, may be one of the most important factors, that in combination with the cardiac function improvement, brings about a significant increase in the aerobic capacity of these patients [6,10]. Similar beneficial effects of exercise training on aerobic capacity, work capacity and quality of life index in end-stage renal patients on HD have also been reported [6,1 l- 131. Although widely used, the mechanisms of training-induced benefits are not known, and may include muscular, autonomic cardiac and vascular components. The description recently of reduced oxygen free radical stress with training may also be relevant to these patients [71]. In conclusion, a long-term, intense exercise rehabilitation program improves the left ventricular performance, both at rest and during sub-maximal exercise in HD patients. Similar favorable changes at effort, but to a lesser degree, is seen after moderate aerobic exercise training at home. Physical training could be used as a therapeutic modality in the management of end-stage renal disease, because of the beneficial effects in cardiac function, aerobic capacity and work capacity of the dialysis patients. This is another group which is only rarely considered for cardiac rehabilitation programmes because of frequent entry restrictions against complicated or elderly patients [72]. References (11 Lundin AP, Stein RA, Frank F, LaBelle P, Berlyne G, Krasnow N, Friedman E. Cardiovascular status in long-term hemodialysis patients: an exercise and echocardiographic study. Nephron 1981;28:234-7. [2] Kenny A, Sutters M, Evans D, Shapiro L. Effects of hemodialysis on coronary blood flow. Am J Cardiol 1994;74:291-4. [3] Lewis BS, Milne FJ, Goldberg B. Left ventricular function in chronic renal failure. Br Heart J 1976;38:1229-39. [4] Deligiannis A, Paschalidou E, Sakellariou G, Vargemezis V, Geleris P, Kontopoulos A, Papadimitriou M. Changes in left ventricular anatomy during haemodialysis, continuous ambulatory peritoneal dialysis and after renal transplantation. Proc EDTA-ERA 1984;21:185-9. [5] London G, Fabiani F, Marchais S, De Vemejoul M, Guerin AP, Safar ME, Metivier F, Llach F. Uremic cardiomyopathy: an inadequate LV hypertruphy. Kidney Int 1987;31:973-80.
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