Download Cardiorespiratory responses to exercise training

THERAPY AND PREVENTION
CARDIAC TRANSPLANTATION
Cardiorespiratory responses to exercise training
after orthotopic cardiac transplantation
TERENCE KAVANAGH, M.D., F.R.C.P.(C), MAGDI H. YACOUB, M.D., F.R.C.S.,
DONALD J. MERTENS, M.B., B.S., M.SC., JOHANNA KENNEDY, RN., ROBIN B. CAMPBELL, M.SC.,
AND PAUL SAWYER, B.P.H.E.
ABSTRACT We have tested the feasibility and effectiveness of a 2 year (average 16 7 months)
walk/jog exercise program on 36 male orthotopic cardiac transplant patients (21 to 57 years old) seen
initially 2 to 23 months after surgery. Comparison of initial exercise test results with those in 45
age-matched normal men showed the patients to have a lesser lean body mass (56 ± 7 vs 63 8 kg,
14 beats/min, p < .001) and systolic
p < .001), with a higher resting heart rate (104 ± 12 vs 77
14 vs 84 ± 10 mm Hg, p < .001)
(138 ± 16 vs 129 ± 17 mm Hg, p < .001) and diastolic (95
27 vs 219 ± 41 W, p < .001), as
blood pressures. Peak power output was less than normal (101
was peak heart rate (136 ± 15 vs 176 ± 13 beats/min, p < .001), peak oxygen intake (V02max) (22
+ 5 vs 34 ± 6 ml.kg.min -', p < .001), and absolute anaerobic threshold (1.18 ± 0.40 vs 2.04 +
0.40 liters-min- 1, p < .001). Peak ventilatory equivalent was higher (48 9 vs 37 ± 6 1.1- 1, p
< .001). Cardiac output (Q), as estimated by the CO2 rebreathing method, was slightly above normal
at rest (p < .0 1), but below normal at two submaximal work rates. The group's average weekly training
distance was 24 km, with eight highly compliant patients progressing to 32 km or more weekly. After
training, lean tissue increased ( + 2.4 + 3.1 kg, p < .001), and resting values were reduced for heart
11 beats/min, p < .05), systolic (-13 20 mm Hg, p < .001), and diastolic (9
rate (-4
17 mm Hg, p < .001) blood pressures. There were significant reductions in submaximal values for
minute ventilation (VE), ratings of perceived exertion, and diastolic blood pressure at equivalent
workloads. Peak values increased for power output ( + 49 + 34 W, p < .001), VO2max ( + 4.0 6.0
ml-kg.min- 1, p < .001), VE ( + 20 ± 20 1 *min- ', p < .001), and heart rate ( + 13 + 17 beats/min,
p < .001), and decreased for diastolic blood pressure (-8 ± 15 mm Hg, p < .001). In the eight highly
compliant patients a greater decrease occurred in resting heart rate (1 1 5 beats/min, p < .00 1)
and submaximal heart rate (range 5 to 10 beats/min less at each power output), with a greater increase
in peak power output (+ 68 + 42 W, p < .001), and V02max (+ 11
p < .001).
6 mlkgmin
The slope of the Q/V02 line was unchanged by training. There was no evidence of cardiac reinnervation
in any patient. We conclude that exercise rehabilitation is justified because of its ability to increase
working capacity and thus quality of life in cardiac transplant patients.
Circulation 77, No. 1, 162-171, 1988.
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CARDIAC TRANSPLANTATION is now an accepted
treatment for end-stage cardiac disease, with actuarial
survival rates of 78% for the first 2 years' and greater
than 60% for the first 5 years after operation.2 3 Nevertheless, to date there have not been any reports on the
effect of a long-term endurance-type exercise training
program on the cardiorespiratory function of a large
group of such patients.
From the Toronto Rehabilitation Centre, Toronto, Ontario, Canada,
and Harefield Hospital, Middlesex, England.
Address for correspondence: Terence Kavanagh, M.D., Medical
Director and Associate Professor of Rehabilitation Medicine, Toronto
Rehabilitation Centre, 345 Rumsey Rd., Toronto, Ontario, Canada M4G
1R7.
Received June 11, 1987; revision accepted Sept. 24. 1987.
162
Consequently, the functional status of 36 male orthotopic cardiac transplant recipients was assessed at entry
to and at the end of a 16 month training program. The
initial status of the patients was compared with the
findings in 45 age-matched male volunteers.
Methods
Because only 44 patients were entered into the study, and
because they were taking a variety of immunosuppressive and
other drugs, it was not feasible to randomize them into intervention and control cohorts. Averaged changes in measurements
for the entire group thus provided the basis for our conclusions.
To encourage compliance with a lengthy exercise training
program in patients already obligated to frequent invasive reassessments, only noninvasive testing was used.
Patients. A total of 44 patients (all but one male) were
initially enrolled. Two of the group died during the study, one
CIRCULATION
THERAPY AND PREVENTION-CARDIAC TRANSPLANTATION
TABLE 1
Initial physical characteristics of cardiac transplant patients and age-matched normal subjects (mean values ± SD)
Lean mass
Group
Age (yr)
Cardiac transplant
recipients (n=36)
Age-matched normal
subjects (n = 45)
Height (cm)
47.3±8.6 172.8+6.1
Body mass
(kg)
Excess massA
Skin folds
Body fat
(kg)
(average of 3, mm)
(%)
69.9± 11.5
45.4 ± 7.2 176.4 6.5B 80.7 + 10.9C
kg-cm-' of
kg
stature
56.2±7.3
0.325±0.06
3.1±10.4
15.4+6.8
19.1±5.0
10.1 ± 9.Oc
17.0 + 4.6c
22.1±3.5c 62.6±7.6C 0.355±0.07c
ASociety of actuaries (1959).
.0l; Cp < .001.
Bp <
after repeated bouts of allograft rejection, and
one
during
and suprailiac). Body fat and lean body mass were derived from
appropriate age-specific equations.7
Exercise testing. Assessment included two cycle ergometer
tests, performed approximately 24 hr apart. The first (stage I)
test habituated patients to the laboratory procedures, measured
peak heart rate, power output, and oxygen consumption (V02),
and provided guidelines for the exercise prescription; loadings
were increased by 16.7 W each minute until the patient could
no longer pedal at 60 rpm. At each load the patient indicated his
perception of effort with reference to the Borg scale.8 The
electrocardiogram (leads lII, V,, and CM5) was monitored
throughout, with the use of a computer-assisted system (Marquette case II). Blood pressures were taken by sphygmomanometer in the final 15 sec of each minute of exercise. Metabolic
data were analyzed by a SensorMedics Horizon II Metabolic
Cart. The ventilatory anaerobic threshold was determined from
the inflection of the minute ventilation (VE)/VO2 line, supplemented where necessary by information from the ventilatory
equivalent and excess CO2 production. Indications for halting
a test before the demonstration of an V02 plateau were as
follows:
(1) Adverse symptoms (recognizing that the transplanted
heart does not sense anginal pain); e.g., severe dyspnea, lightheadedness and faintness, confusion, severe fatigue.
(2) Adverse signs; e.g., facial pallor, heart rate or blood
pressure fall, or failing to rise with increasing effort, systolic
blood pressure exceeding 280 mm Hg, or diastolic blood pressure exceeding 140 mm Hg.
(3) Adverse electrocardiographic changes; e.g., frequent
complex ventricular extrasystoles, ventricular tachycardia, sustained supraventricular tachycardia, atrial fibrillation, secondor third-degree heart block, severe ST segment depression (horizontal or downsloping greater than 4 mm).9
an
acute rejection episode. Initial findings in these two individuals
were unremarkable. One underwent initial assessment, but never
started to exercise, dying 8 months after assessment and 31
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months after transplantation. The other was active in the exercise
when he died (4 months after the initial test, and 21
months after the transplantation), having attained an average
walking distance of 13 km/week.
Five men and one woman dropped out after the initial test, all
for nonmedical reasons that were typical of those encountered
in a long-term training program.4' 5 Their average age was 47.2
+ 8.0 years, the mean time from initial test to dropout was 8.2
3.3 months, and the initial findings were unremarkable. Our
data are therefore restricted to 36 men, tested an average of 7
months after transplantation, who exercised for 16.3 ± 6.9
months.
The age of the compliers at enrollment was 47.3 ± 8.6 years
(21 to 57 years). Before surgery, their clinical status had deteriorated to New York Heart Association functional classification
IV, with causes including cardiomyopathy, coronary artery disease, myocarditis, valvular disease, and bacterial endocarditis.
The time from transplantation to initial assessment was 7.4 ±
6.1 months; the distribution was slightly skewed (median 4.8,
range 2 to 23 months). All patients were taking cyclosporine and
azathioprine, with six on minimal quantities of oral steroids
initially, and five finally.6 None required P3-blocking agents,
initially or finally. Other medications included nifedipine, (three
initially, four finally), hydralazine (six initially, six finally), and
furosemide (nine initially, six finally). The 45 age-matched
volunteers were physically active, but not athletic individuals.
None were taking medications of any type.
Body composition. Measurements were made of height,
body mass, and three standard skin folds (triceps, subscapular,
program
TABLE 2
Change in physical characteristics of cardiac transplant patients over the training period (mean values ± SD for entire group of eight highly
compliant and 28 moderately compliant patients)
Body fat (%)
Body mass (kg)
Group
Initial
All patients
(n = 36)
Final
Change
69.9 11.5 73.9 -+ 12.4 + 4.0 + 6.7A
Highly compliant
67.6± 11.6 68.9 ± 9.6 + 1.3 ±5.9
patients (n = 8)
Moderately compliant
70.3 11.6 75.3 ± 12.9 + 5.0 6.8A
patients (n = 28)
Ap
Lean mass (kg)
Initial
Final
20.2 5.9 + 1.2 4.4
56.2±+-7.4
58.2 + 7.5
+ 1.98
17.2 3.6 18.3 3.0 + 1.1 3.5
55.7±+ 8.0
56.1 +-6.9
+ 0.4
19.8 +5.3 20.7 6.5 + 0.9 4.8
56.4 +-7.2
Initial
19.1
±5.0
Final
Change
Change
3.31A
3.6
58.74±+ 7.74 +2.43-+ 3.1SA
< .001.
Vol. 77, No. 1,
January 1988
163
KAVANAGH et al.
TABLE 3
Initial cardiovascular status of cardiac transplant patients and age-matched normal subjects at stage I exercise test (mean values
Heart rate
Group
All patients
(n = 36)
Age-matched normal
subjects (n =45)
Highly compliant
patients (n = 8)
Moderately compliant
patients (n = 28)
+
Systolic pressure
Age
(yr)
Weeks
after surgery
Rest
Peak
Rest
Peak
(beats/min)
(beats/min)
(mm Hg)
(mm Hg)
47.3 8.6
29.4 24.4
103.9 ± 11.8
135.5 15.2
137.8
176.2+ 12.8A
128.6+ 16.5A
214.221-.2-
131.9+ 13.1
165.0+ 16.0
139.4 +26.9
181.9±+26.9
45.4+7.2
76.8+ 13.7A
SD)
42.1 + 11.5
25.5 25.7
116.6 ± 9.2
145.6
48.8 6.7A
30.5 24.5
100.3 + 9 9A
132.6 14.9A
12.2
15.7
178.2 -25.8
Ap < .001, all patients vs normal subjects and eight highly compliant patients vs 28 moderately compliant patients.
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In the second (stage II) test, steady-state cardiac output was
measured at rest and approximately one- and two-thirds of the
previously determined peak power output with the CO2 rebreathing technique of Jones and Campbell. 10 Arterial carbon
dioxide pressures were estimated from the end-tidal CO2 and
tidal volume and the standard downstream correction was
applied to the mixed venous figure, always based on a true
plateau.
Exercise training regimen. Workouts were preceded by a 20
min muscle-stretching routine. The main prescribed activity was
walking, initially 1.6 km five times weekly, at an intensity based
on the results of the stage I test with respect to 60% to 70% peak
oxygen intake (VO2max), the ventilatory anaerobic threshold,
and a perception of effort of 14 on the Borg scale. The initial
average pace varied between 1 1 and 14 min/km. The distance
was then increased by 1.6 km every 2 weeks, maintaining the
same pace until, by 6 weeks, the patient was walking 4.8 km
five times weekly. The pace was then quickened by 1 min per
1.6 km until the 4.8 km was accomplished in 45 min (typically
within 4 months of starting the program). Thereafter, 45 m bouts
of slow jogging paced at 7.5 min/km were introduced every 800
m, 400 m, 200 m, and so on until ultimately the entire 4.8 km
was completed in 36 min. The distance was then extended in
stages by 400 m, the aim being to have the patient jogging 6.4
km in 48 min five times weekly by the eighth month of the
program.11 12
The training regimen recognized that angina could not warn
of myocardial ischemia and that the sluggish response of the
denervated heart to effort rendered pulse counting less accurate
as a measure of exercise intensity. Thus, accurate pacing, thorough familiarity with the Borg concept of perceived exertion,
and correct interpretation of such symptoms as excessive dyspnea, unusual fatigue, lightheadedness, and extrasystoles were
of paramount importance. The possibility of episodes of rejection or infection retarding progress was an additional concern.
Statistical methods. Because the normal subjects were ageand sex-matched, differences in response to exercise between
them and the patients could be evaluated by t tests for groups
of unequal size. Training responses were evaluated by paired t
tests. Since our experience has shown differences in responses
between patients covering longer and shorter distances, 13-15 we
subdivided data for the 36 patients on this basis.
Results
Compliance. Few workouts were missed because of
injuries or other medical setbacks. The average length
164
of time on the program was 16 + 7 months. All patients
progressed to walk/jogging an average distance of 24
km/wk, at an average pace of 8.5 min/km. The eight
most highly motivated achieved 32 km or more a week,
at an average pace of 6.5 min/km. One of these entered
and finished the 42 km Boston marathon 12 months
after joining the program and 15 months after undergoing the transplantation procedure. 16 The findings for
the eight were compared with the results in the remaining 28 patients.
Body composition. Body masses of the patients were
lighter than those of the age-matched controls, even
allowing for the latter's greater height (table 1). The
patients had a lower percentage of body fat, but the
differences in body mass were largely attributable to a
lesser lean mass.
After training, the patients had increased their body
mass by 4 kg without significant increase in body fat,
implying an increase in lean mass (table 2).
Exercise test results. A total of 250 exercise tests were
performed without incident; all stage I tests were continued to voluntary exhaustion.
Initial assessment (stage I test). Initial cardiorespiratory
responses before training were typical of the denervated
heart. 17- ' Resting heart rates were higher (p < .001)
and peak exercise heart rates lower (p < .001) than in
the age-matched normal subjects (table 3).
Resting systolic and diastolic pressures were higher
in the patients than in the normal subjects (p < .001),
although the resting pulse pressure was essentially
normal (41.7 + 12.7 vs 44.8 + 12.6 mm Hg in the
normal subjects). The patients terminated exercise at
a lower systolic pressure (p < .001) and double product
(p < .001) (table 3).
A breakdown of information on the eight highly
compliant and the 28 moderately compliant patients
CIRCULATION
THERAPY AND PREVENTION-CARDIAC TRANSPLANTATION
TABLE 3
(Continued)
200
product
(beats-mm Hg-1)
Peak
(mm Hg)
Rest
(mm Hg)
180
Peak
Double
Diastolic pressure
^160*
I;
.
23,542 4,866
100.4 ± 12.5
95.3 13.5
_
120
O
83.8+ 1.OA
95.6± 12.1
36,768 4,812A
86.3 15.7
93.3 ± 13.2
23,291 3,807
97.9 11.9
102.4 ± 11.7
23,614 5,187
*...
Initial (CT's)
---
Finoal
(C T's)
I-
( 100
X
So
O
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showed that the former were 6 years younger (p < .(00)1)
and had a higher average resting (p < .00 1) and peak
exercise (p < .001) heart rate. Nevertheless, their peak
heart rates were lower than those of the age-matched
normal subjects (p < .001), (table 3). No significant
correlations were found between cardiovascular function and either age of patient, age of donor, or time
elapsing between surgery and entry to program.
All exercise tests were terminated because of Ieg
fatigue. Three of the highly compliant and 15 of the
moderately compliant patients exercised to an oxygen
plateau as classically defined (an increment in V'02 of
less than 2 ml-kg.min- for a further increment of
power output), compared with 39 of the 45 agematched controls. The absolute V02max attained
before training was 70% of that for the age-matched
normal group (p < .001); there was no significant
difference between high compliant and moderately
compliant patients (table 4).
The average peak power output achieved by the
patients before training was less than one-half that
'
100
260
1S0
250
POWER OUTPUT (Watts)
FIGURE 2. Relationship of heart rate to power output in highly compliant patients before and after conditioning (n = 8, mean ± SD). *p
< .05; **p < .01; ***p < .001.
attained by the normal subjects (p < .001), showing that
they were unable or unwilling to undergo substantial
anaerobic metabolism. At peak effort, the patients also
had a lower rating of perceived exertion (p < .001),
respiratory exchange ratio (NS), and VE (p < .001). Peak
ventilatory equivalent was, however, higher (p < .001)
than in the normal subjects. The absolute ventilatory
threshold was lower (p < .001) in the patients (table 4).
Final assessment (stage I test). After training, most test
values approached those of healthy age-matched control subjects (table 5). There was no evidence of reinnervation, but the resting heart rate for all patients was
reduced (p < .05), with the greatest reduction occurring in those who were highly compliant (p < .001).
3.+
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22
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200
t42
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a t0
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CTas)
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130
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chblaInc *uccmlve
initial and final tests:
100-
minute
X a
4
* *
power
'1.2
oztputa at
g
(1s.i watt-min.)
7
9
-e
o 4
toX 11 12 13 14
25 33 25 15 a 2 2
26
31 34 3 a26 20 15
n-36 36
initial n.M 26 36
final
6
6
3
2
f
0
°
SO
~~10
m
15.0
1|
POWER
0
200
OUTPUT
250
1"
1---
ama
tWatta)
FIGURE 1. Relationship of heart rate to power output in total patient
before and after conditioning (n = 36).
group
Vol. 77, No. 1, January 1988
0
i50
0o
1b0
abo
POWER OUTPUT (Watts)
FIGURE 3. Relationship of oxygen intake to power output before and
after conditioning (n = 36).
165
KAVANAGH
et
al.
TABLE 4
Initial cardiorespiratory responses of cardiac transplant patients and age-matched normal subjects at stage I exercise test (mean values ± SD)
Ratin
VOmax
V02
max
Group
All patients
(n =36)
Age-matched normal
subjects (n = 45)
Highly compliant
patients (n = 8)
Moderately compliant
patients (n =28)
STPD
Ap <
=
I min
STPD
ml kg min
STPD
1.51+0.33
21.7+4.5
Peak
Peak
power
ventilation
VE/VO2
(W) (Imin 1 BTPS) (1 I1')
101+27
70.5±16.6
48.1+9.3
Ventilatory threshold
Resp.
g
perceived
exchange
ratio
exertion
(units)
1 minSTPD
% of VO,
max
1.14+-0.11
18.3+2.1
1 18-0.38
78
2.74 + 0.56A 34.0 ± 5.9A 2r9±41A 101.4 ± 23.8A 37.3 6.4A 1.18 ±0.10
19.4 ±1.A 2.04 ±0.44A
75
1.44 0.40
21.3 ± 4.9
105 34
70.7 ± 19.9
49.5 9.5
1.14 ± 0.15
17.8
1.7
1.18 ± 0.33
82
1.53+0.32
21.8±4.4
100+25
70.4±15.9
47.6+9.4
1.13±0.08
18.4+2.2
1.19+0.27
78
standard temperature, pressure, dry. BTPS
=
body temperature, pressure, saturated.
.001.
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At the same time, the peak heart rate was significantly
increased in both highly compliant (p < .001) and
moderately compliant patients (p < .001; table 5). Nevertheless, the final resting heart rates remained higher (p
< .001), and the final peak heart rates lower (p < .001),
than in the age-matched normal subjects (table 5).
Resting systolic and diastolic blood pressures for all
patients were significantly reduced (p < .001), as were
peak diastolic pressures (p < .001), so that at the end
of the conditioning program differences from normal
were no longer significant. However, the peak systolic
pressure and the peak double product did not change
significantly, remaining less than in the normal subjects
(p < .001; table 5).
At the final assessment, the average relationship of
submaximal heart rates to midrange power outputs
showed a small reduction in the group as a whole
(figure 1). However, there was no change in the 28
moderately compliant patients, whereas in the eight
highly compliant patients the effect was quite large
(average, 7 beats/min, range 5 to 10; figure 2). Interestingly, the patient who completed the Boston marathon, averaging 65 km weekly in the final months of
training, showed the response closest to a true training
bradycardia.16 Since the relationship of V02 to power
output in all patients, including the highly compliant
eight, was unchanged during submaximal effort
(figure 3), this reduction in submaximal heart rate
could not have been due to an improvement in mechanical efficiency on the ergometer. There was also an
overall and significant marked reduction in the rating
of perceived exertion (figure 4), VE (figure 5), and diastolic blood pressure (figure 6) at equivalent power
outputs.
TABLE 5
Final cardiovascular status of cardiac transplant patients (total group, highly compliant, and moderately compliant), with differences from
initial values (stage I exercise test, mean values ± SD)
Systolic pressure
Heart rate
Group
All patients
(n 36)
Change from
initial value
Highly compliant
patients (n =8)
Change from
initial value
Moderately compliant
patients (n = 28)
Change from
initial value
Ap < .05; Bp <
166
Peak
Diastolic pressure
Peak
double
Rest
(beats/min)
(beats/min)
Rest
(mm Hg)
Peak
(mm Hg)
Rest
(mm Hg)
Peak
(mm Hg)
(beats-mm Hg )
100.3 13.4
148.2 17.2
125.2 14.9
174.4±20.1
86.3± 11.6
92.5±12.1
25,336+4,823
-7.9 ± 15.4B
+ 1,794 ± 6,611
8.59+10.8
91.0±6.7
27,210+4,331
-0.4 ± 17.8
-2.3 ± 12.3
+ 3,919 ± 5.1 JOA
86.4 ± 12.0
93.3 ± 13.1
24,801 ± 4,894
11.5± 15.5B
-9.1 ± 15.9
+ 1,187±6,940
-
3.6
10.7A
106.1±8.7
-10.5 +4.9B
98.6
-
14.2
1.7 11.1
+ 12.7
16.7B
157.8+15.8
+
12.1 13.2B
145.5
16.9
+ 12.7± 17.8B
-
12.6 20.2B
125.9±16.8
-
6.0 ± 21.1
124.9 ± 14.6
-
14.5+ 19.9B
-3.8 30.9
-
175.0+17.7
+ 10.0 ±2.2
174.3 21.1
-7.7±32.3
-
9g0 ± 16.5B
product
.001.
CIRCULATION
THERAPY AND PREVENTION-CARDIAC TRANSPLANTATION
S
20
E 120E
18W
c
0
3
T
to
16i
Co
W
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(CT's)
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Final (CT.s)
Initial (CT'.)
(CT'.)
Normal.
__ Final
jI
0
0
0
-Normal*
0 120
100-
---
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I.~~~~~~~~~
0
O 0
10-
I:
Co
#c
1i0
100
SO
0
150
100
so
0
200
200
250
OUTPUT (Watt.)
POWER
250
FIGURE 6. Relationship of diastolic blood pressure responses to
power output before and after conditioning (n = 36, mean + SD). *p
POWER OUTPUT (Watts)
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FIGURE 4. Relationship of rating of perceived exertion to power
output before and after conditioning (n = 36, mean ± SD). *p < .05;
**p < .01; ***p < .001.
While six of the highly compliant patients reached
an oxygen plateau after training, only 15 of the remaining 28 patients did so. Nevertheless, there was a notable overall increase of 27% in VO2max (change of
+4.2 ± 5.9 ml.kg.min-1, p < .001), which was
again larger (54%) in the eight highly compliant
patients (change of + 10.9 ± 5.6 mlkg.min- 1, p <
.001) than in the remaining 28 patients (change of
+2.7 ± 5.1 ml.kg.min- 1or 20%, p < .001) (table
6). Gains in peak power output were even more marked,
64% and 43% for the subgroups, respectively (changes
of +68 ± 42W,p< .001; and +43 ± 30W,p<
.001), with all patients exercising to a larger respiratory
VE and a higher maximum heart rate after training.
< .05; **p < .01; ***p < .001.
Since change in respiratory gas exchange ratio (NS),
and peak rating of perceived exertion (p < .05) were
quite small, it is unlikely that greater voluntary effort
was responsible for improved performance (table 6).
Stage II test (initial and final). The initial resting cardiac
outputs of the transplant patients (average cardiac index
of 2.94 + 0.73 liters.min- "im2), were slightly larger
than those of the age-matched control subjects (2.55
0.48 liters.min- 'lm2; change of 0.39, SE of change
0.14; p < .01). At the two submaximal workloads, the
patients' average cardiac outputs were less than those for
the normal subjects (table 7).
For the whole patient group, the initial linear
regression relating cardiac output (Q0) to V02 was Qt
= 6.1 (V02) + 3.29 (r = .88), with no difference
between highly and moderately compliant groups. The
E
* 10014.
-
_J
Z 80'
1t
0
.J
',
'
i
I.
*b
CO-
10.
2
z
*
Initial (CT's)
...0
> 40'
__ Final
W
(CT.s)
.
~~~~~~~0
20-
^
0
Normal*
-*
4
.** Aut *^
I-
.
a
O
2
9
0
gO
1
100
1
1iO
POWER OUTPUT
1
200
1
250
(Watt.)
FIGURE 5. Relationship of VE responses to power output before and
after conditioning (n = 36, mean + SD). *p < .05; **p < .01; ***p
< .001.
Vol. 77, No. 1, January 1988
.
.2
.
.4
.A
.
.
.5
.
.
.
1.0
1.2
1*4
OXYGEN INTAKE
1.5
1.A
2.0
{itrto.min1)
FIGURE 7. Relationship of individual cardiac output responses to VO2
before and after conditioning (n = 36).
167
KAVANAGH
et al.
TABLE 6
Final cardiorespiratory responses of cardiac transplant patients (total group, highly compliant, and moderately compliant), with differences
from initial values (stage I exercise test, mean values + SD)
VO, max
1 min-1
STPD
Group
All patients
(n=36)
Change from
initial value
Highly compliant
patients (n = 8)
Change from
initial value
Moderately compliant
patients (n = 28)
Change from
initial value
Peak
ml kg min
STPD
Peak
power
ventilation
(W)
(lmin-m BTPS)
VE'VO
(11 '1
1.92±0.47
25.8±6.4
150±40
90.9±23.4
48.1 9.2
+0.41 ±0.44B
+4.2± 59B
+49±34B
+20.4±20.8B
0.0Q9.6
2.22 ± 0.46
32.3 + 5.2
173 ± 43
93.8 27.5
42.6+ 11.3
+ 0.77 0.43B
10 9 ± 5.6B
+ 68 42
+ 23.1
1.83 0.45
24.5 ± 6.1
143 37
90.1
+ 0.31
0.39
+ 2.7 5.
+ 43
30B
20.9B
- 6.9 +
22.6
12.6
49.8- 7.8
+ 19.6 +21.1
+ 2.2
7.4
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
Abbreviations as in table 4.
Ap < .05; Bp < .001.
corresponding equation for the age-matched normal
subjects was Qt 6.0 (V02) + 3.87 (r - .94). After
training, the line for the patients remained essentially
unchanged (Q1 5.9 (V02) + 3.17, r = .94; figures
7 and 8).
=
Discussion
Human physical work performance is impaired after
cardiac transplantation,20 in contrast to the performance of the denervated dog heart.2' Improvement by
exercise training seems a reasonable approach. However, correct interpretation of any improvement apparently associated with training must be viewed in the
light of initial baseline responses of the transplanted
human heart to exercise, as well as the possibility that
any such changes are due to spontaneous recovery.
Initial pretraining exercise responses. Several investigators have commented on the high resting heart rate
after transplantation, 17, 18, 22 attributing this to a revelation of the intrinsic rate of the sinoatrial node. In the
absence of autonomic reinnervation, the resting rate
has remained quite high, with figures from the literature
ranging from an average of 107 beats/min at age 29 to
80 beats/min at age 52 years.23? 24 Given that the average age of the donors in this study was 24 years, and
that care was taken to familiarize our patients with the
exercise test protocol, it seems reasonable to assume
that the high resting heart rates we observed are nodal
and not due to anxiety. Assuming a normal peripheral
demand for blood flow, the resting tachycardia implies
a small stroke volume, and therefore during light exercise the Frank-Starling mechanism can produce a substantial increase of cardiac output. However, during
more vigorous activity any further increase in cardiac
output depends on circulating catecholamine-induced
chronotropic and inotropic responses.'8 21.25 This
TABLE 7
Responses of cardiac transplant patients and age-matched normal subjects to stage II testing before and after conditioning
Group
cardiac
transplant
recipients
(n=36)
Initial
Final
Age-matched
normal subjects (n =45)
SV
168
Load I
Rest
VO,2
(1 min
STPD)
Cd
VO2
output
__________output
1.min m2
lmin-m
SV
AVD
( min'
(ml)
(ml 1'-)
STPD)
0.34+0.06 5.4±1.3 2.94±0.73 52.0+14.0 65.8+16.5
0.29±0.04 4.8+0.74 2.54+0.44 48.1±+ 11.1 63.1±11.3
0.85+0.16
0.87±0.15
2.55±0.48 69.2±13.5 61.8+10.5
1.16+0.19
0.30±0.04 5.0±0.84
-stroke volume; AVD
arteriovenous difference; STPD
=
Cardiac
output
(1min- 1)
sv
(ml)
8.6+1.9
74.0±21.0
8.6±1.4
77.4±16.0
100.6+18.5
103.0± 13.8
11.3±1.6 106.0+24.0
103.0± 14.0
AVD
(mil
1)
standard temperature, pressure, dry.
CIRCULATION
THERAPY AND PREVENTION-CARDIAC TRANSPLANTATION
TABLE 6
(Continued)
Resp.
exchange
ratio
Rating of
perceived
exertion
(units)
1.16±0.19
Ventilation threshold
1 minm1
STPD
% of V02
max
19.1 ± 1.5
1.56±0.38
62
+0.7±0.2A
+0.37+0.35B
18.8±2.2
1.75±0.46
+ 1.0± 1.4A
+0.57+0.45B
1.19±0.11
19.1 ± 1.4
1.50±0.35
82
+0.06±0.09
+0.7±2.1
+0.32±0.31B
-
+0.02±0.19
1.17±0.15
+0.03±0.12
79
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
explains the sluggish heart rate response and delayed
recovery rates seen on the incremental exercise test.
Both cardiac and peripheral vascular components
probably contribute to changes in resting and exercise
blood pressure responses. The resting hypertension
may reflect preoperative congestive heart failure and a
resultant chronic elevation of plasma norepinephrine,26
or it may be a side effect of cyclosporine.27 Loss of
sympathetic stimulation and resultant impairment of
myocardial contractility could account for the low peak
exercise systolic pressure.28 Chronically elevated levels of serum catecholamines may also induce downregulation of the peripheral arterial a-receptors.19 This
blunted systolic blood pressure response to exercise
may compound the peripheral limitations described
below.
Our previous exercise radionuclide studies have also
noted that the transplanted heart develops impairment
of diastolic function at moderate levels of supine exercise (45 W). 30 Contributing factors here could include
impaired myocardial compliance,30 ischemia from
accelerated coronary artery narrowing,3' or the side
effects of immunosuppressive drugs.28
The patients had 6 kg less lean tissue mass than
the age-matched normal subjects, which was likely
the result of prolonged preoperative physical inactivity. This reduction in muscle mass undoubtedly
plays a major role in limiting maximum exercise performance. Partly because of this peripheral limitation
and partly because of low peak heart rate and peak
blood pressure, the V02max of our patients was only
about two-thirds of that in the normal age-matched
population. Consequently, early fatigue is experienced
during exercise, thus discouraging future effort and
leading to a vicious circle of further loss of lean tissue
and more fatigue.
Exercise responses after training. Since the incidence
of rejection episodes or coronary atherosclerosis was
minimal or absent in our group, we believe we are
justified in disregarding these factors as playing any
significant part in our findings.
The changes observed in association with training included an increase of lean tissue, peak power
output, peak heart rate, peak VE, and V02max, together with a reduction in resting systolic and diastolic blood pressures and resting heart rates, the latter
more marked in those patients who attained a regular
weekly training distance of 32 km or more. There was
also a significant reduction in peak diastolic blood
pressure.
At all levels of submaximal effort, there was an
overall reduction in diastolic blood pressure, VE, and
rating of perceived exertion, but no change in mechanical efficiency or submaximal cardiac output. Submax-
.
141
- 12*
TABLE 7
(Continued)
.
J 10
I-
Load 2
VO2
(1min 1
STPD)
1.26+0.26
1.41±+ 0.27
SV
AVD
(1 mi1)
(ml)
(mi l)
10.8+2.2
84.3 16.0
86.8 ±16.7
118.1 ± 17.8
11.4±+-2.1
14.2 ± 2.8
Vol. 77, No. 1, January 1988
102.4± 24.0
(CT's)
-Final
0
_
mels
2.
124.9±+17.3
0
1.93 ± 0.32
.,Initial (CTs)
0
( a
,
Cardiac
output
129.0±+25.0
0.4
0.6
1.2
OXYGEN INTAKE (Ltres.minw1)
1
1.
2.0
FIGURE 8. Relationship of cardiac output responses to V02 before
and after conditioning (n = 36).
169
KAVANAGH et al.
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
imal heart rates were reduced only in those who attained
the greatest training distances.
Since it was not possible to organize a matchedcontrol series, it could be argued that part of the
changes were due to natural recovery. However, we do
not believe this to be the case. Previously published
reports17 18 have not shown any spontaneous change
in cardiac function after cardiac transplantation. Moreover, our initial and final data do not show any significant correlation with the interval between operation
and entry into the study.
There are several possible explanations for these
responses. In normal subjects, training increases vagal
inhibitory tone at rest, while sympathetic tone is
decreased at submaximal elfort.32 Such a mechanism
for bradycardia cannot occur in the denervated heart,
as substantiated by observations in the trained cardiac
denervated dog33 and in exercise-trained human cardiac transplant patients.22' 34 Reinnervation has not
been reported to occur in association with the human
orthotopic transplant, and there was no evidence of
reinnervation in our patients. It has been shown, however, that the denervated heart develops an increased
sensitivity to circulating catecholamines . The mechanism seems to be an increase in myocardial /-receptor
density and/or affinity.36-38 There is also evidence that
vigorously exercise-trained normal subjects and even
postmyocardial infarction patients develop a significant reduction in effort-induced levels of serum
norepinephrine.394 Measurements of circulating
catecholamines were not made in the present study, but
if such a reduction occurred as a result of our training
regimen, it could explain the training bradycardia seen
in the eight highly compliant subjects. Another possibility is that the high compliers experienced a "downregulation" in sensitivity of cardiac /3-adrenoreceptors.
This occurs in both rats and humans exposed to vigorous training,41-43 and correlates closely with increases in V02max.
The entire group's increase in peak exercise heart
rate could largely be due to a strengthening of the leg
muscles. This peripheral adaptation would account for
the improved power output, and because of a later onset
of anaerobiosis, the reduced perception of effort and VE
during submaximal exercise. The lack of change in
cardiac outputs over the period of training argues
against any central improvement, although it is tempting to infer that the reduction in peak and submaximal
diastolic blood pressures toward normal values is an
indication of improved myocardial compliance.
In conclusion, while it seems that a number of mechanisms interacted to varying degrees in bringing about
170
a training effect in our transplant patients, strengthening of the peripheral muscles appeared to play the major
role, and it achieved this by allowing the healthy transplanted heart to realize its full physiologic and functional potential. In the final analysis, the ability of the
cardiac transplant patients to attain jogging distances
of between 24 and 32 km/week and power outputs of
up to 170 W on the cycle ergometer implies that exercise training has considerable potential for improving
the quality of life of such patients.
We gratefully acknowledge the invaluable assistance of Salah
Qureshi, Chief Cardio-Respiratorv Technician, Rawlins Mohammed, Cardio-Respiratory Technician, and Manuscript Secretary Anna Ceci, all from the Toronto Rehabilitation Centre.
and Fiona Robinson, Exercise Program Liaison Secretary from
Harefield Hospital. We also thank Ken Lee of Cardiokinetics for
the loan of the MMC Horizon Metabolic Measurement Cart, and
Ian Eddy of Marquette Electronics (GB) for the loan of the
Marquette ECG system.
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171
Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation.
T Kavanagh, M H Yacoub, D J Mertens, J Kennedy, R B Campbell and P Sawyer
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Circulation. 1988;77:162-171
doi: 10.1161/01.CIR.77.1.162
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1988 American Heart Association, Inc. All rights reserved.
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