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Section of Physiology, Istituto di Tecnologie Biomediche Avanzate, Consiglio Nazionale delle Ricerche, I-20131 Milan, Italy; Department of Physiology, Max Planck Institut für Experimentelle Medizin, D-37075 Göttingen, Germany; Laboratoire de Physiologie des Adaptations, Université de Paris V, 75014 Paris, France; and Department of Physiology, Centre Médicale Universitaire, Université de Genève, CH-1211 Geneva 4, Switzerland
ABSTRACT
INTRODUCTION
METHODS AND EXPERIMENTAL PROCEDURE
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Grassi, Bruno, Claudio Marconi, Michael Meyer, Michel Rieu,
and Paolo Cerretelli. Gas exchange and cardiovascular kinetics with different exercise protocols in heart transplant recipients. J. Appl. Physiol. 82(6): 1952-1962, 1997.
Metabolic
and cardiovascular adjustments to various submaximal exercises were
evaluated in 82 heart transplant recipients (HTR) and in 35 control
subjects (C). HTR were tested 21.5 ± 25.3 (SD) mo (range
1.0-137.1 mo) posttransplantation. Three protocols were used:
protocol A consisted of 5 min of rectangular 50-W load repeated
twice, 5 min apart [5 min rest, 5 min 50 W (Ex 1), 5 min
recovery, 5 min 50 W (Ex 2)]; protocol B consisted
of 5 min of rectangular load at 25, 50, or 75 W; protocol C
consisted of 15 min of rectangular load at 25 W. Breath-by-breath
pulmonary ventilation (
E),
O2 uptake (O2),
and CO2 output
(CO2) were determined.
During protocol A, beat-by-beat cardiac
output (
) was estimated by impedance cardiography. The half times (t1/2) of the on- and
off-kinetics of the variables were calculated. In all protocols,
t1/2 values for
O2 on-,
E on-, and
CO2 on-kinetics were higher
(i.e., the kinetics were slower) in HTR than in C, independently of
workload and of the time posttransplantation. Also,
t1/2 on- was higher in HTR
than in C. In protocol A, no significant difference of t1/2 O2
on- was observed in HTR between Ex 1 (48 ± 9 s) and Ex
2 (46 ± 8 s), whereas t1/2
on- was higher during Ex 1 (55 ± 24 s)
than during Ex 2 (47 ± 15 s). In all protocols and for all variables, the t1/2 off-values were higher in HTR
than in C. In protocol C, no differences of steady-state
E,
O2, and
CO2 were observed in both
groups between 5, 10, and 15 min of exercise. We conclude that
1) in HTR, a "priming" exercise, while effective in
speeding up the adjustment of convective O2 flow to muscle fibers during a second on-transition, did not affect the
O2 on-kinetics, suggesting
that the slower O2 on- in
HTR was attributable to peripheral (muscular) factors; 2) the
dissociation between on- and
O2 on-kinetics in HTR
indicates that an inertia of muscle metabolic machinery is the main
factor dictating the
O2 on-kinetics; and 3) the
O2 off-kinetics was slower
in HTR than in C, indicating a greater alactic O2 deficit
in HTR and, therefore, a sluggish muscle
O2 adjustment.
heart denervation; oxygen uptake kinetics; exercise transients
INTRODUCTION IT HAS BEEN KNOWN FOR SEVERAL YEARS that, with a
rectangular increase in workload (on-transition), heart transplant
recipients (HTR) show a sluggish heart rate (HR) adjustment
(on-kinetics), presumably attributable to surgical denervation of the
heart (23). More recently, Cerretelli et al. (5, 6) and Grassi et al. (12) showed that the slower HR on-kinetics of HTR was associated with a
slower adjustment of pulmonary ventilation
( A somewhat faster METHODS AND EXPERIMENTAL PROCEDURE
E), O2 uptake (O2), and CO2
output (CO2). In
HTR, also the on-kinetics of cardiac output
() was found to be somewhat slower than in
control subjects, despite the finding of a powerful Frank-Starling
mechanism at the very onset of work (6). Cerretelli et al.
(6) concluded that in HTR the slower
on-kinetics, by affecting the rate of adjustment of O2
delivery to the exercising muscles, could be, at least in part,
responsible for the slower gas-exchange on-kinetics. On the other hand,
Sinoway et al. (25) observed in HTR an impairment of the vasodilatory
response to exercise, which could also be responsible for the slower
gas-exchange readjustment. On the basis of all these observations,
Meyer et al. (21) reasoned that, if the cardiovascular system could be
"primed" by a preceding constant-load exercise, a subsequent
rest-to-work transition carried out shortly after the first (i.e., in
the presence of HR, , and blood catecholamine levels
presumably higher than in normal resting conditions and of muscle
vasodilation) should be characterized by a faster
O2 on-kinetics.
O2
on-kinetics was indeed observed by Paterson et al. (22) during the
second of two rectangular workload steps, separated by a 6-min
interval. These authors examined a limited number of HTR
(n = 6), all tested shortly (1.9-2.5 mo) after
transplantation. This did not allow the authors to evaluate any effect
on the investigated variables of the time elapsed after surgery, which
could represent an important factor, particularly in the light of
recent indications of the possibility of reinnervation of the
transplanted heart (17, 34), or of heart 
2-adrenoceptors upregulation and increased sensitivity to epinephrine as a function of
time after transplantation (26). Moreover, to confirm the efficacy of
the priming exercise on the cardiovascular system, at least an indirect
determination of on-kinetics would be needed, which
would lend weight to the speculations about the rate of O2
delivery to the exercising muscles. Therefore, the present study was
carried out on a large number of HTR (n = 82), covering a
large time interval (between 1 and 137 mo) after surgery, thus allowing
an analysis of the O2
on-kinetics as a function of the time posttransplantation. The
sequential exercises protocol was different from that of Paterson et
al. (22) to circumvent some methodological limitations of that study
(see also DISCUSSION), and an indirect estimate of
beat-by-beat was also obtained. In addition to the
main working hypothesis, the following questions were addressed:
1) Are the E,
O2, and
CO2 on-kinetics in HTR
related to the intensity of exercise, as in normal subjects? 2) Are the E,
O2, and
CO2 off-kinetics (e.g.,
during a rectangular work-to-rest transition) in HTR different than in
control subjects? 3) Do HTR reach a steady state for gas
exchange during exercises lasting only 5 min? Thus, in the present
study, in addition to the sequential exercise protocol, HTR performed
also rectangular 5-min exercises at different workloads, as well as a
rectangular exercise lasting for 15 min, and both on- and off-kinetics
of ventilation and gas exchange were analyzed.
-blockers.
Table 1.
Some physical characteristics of subjects, pretransplant diagnosis, and
time elapsed between surgery and the present study
Gender
Age, yr
Height, m
Weight, kg
No. of
Months Postsurgery
Pretransplant Diagnosis
HTR
(n = 82) Range
70 M; 12 F
43.3 ± 11.3 17-66
1.70 ± 0.08 1.50-1.91
66.8 ± 10.3 40-100
21.5 ± 25.3 1.0-137.1
56 CCM; 13 IHD; 4 RHD; 4 O; 5 U
C (n = 35)
29 M; 6 F
36.3 ± 8.9
1.73 ± 0.16
69.4 ± 12.0
Range
25-61
1.57-1.85
49-106
Values are means ± SD; n, no. of subjects. HTR, heart
transplant recipients; C, controls; M, males; F, females; CCM,
congestive cardiomyopathy; IHD, ischemic heart disease; RHD, rheumatic
heart disease; O, others; U, unknown.
E (in BTPS), and gas
exchange (O2,
CO2; in STPD).
VT and E were calculated by
integration of the flow tracings recorded at the mouth of the subject
by a low-resistance turbine flowmeter. Volume calibration was performed before each experiment by means of a 3-liter syringe, at three different flow rates. Respiratory frequency (fr) was
calculated as E/VT.
O2
and CO2 were determined
by continuously monitoring PO2 and
PCO2 at the mouth of the subject throughout the
respiratory cycle and from established mass balance equations.
Calibration of the O2 and CO2 analyzers was
performed before each experiment by utilizing gas mixtures of known
composition.
HR was determined from the electrocardiogram, which was continuously
monitored throughout the tests. Beat-by-beat values of stroke volume
(SV) and were estimated noninvasively by impedance cardiography. Cardiograms were obtained by means of an impedance device
designed at the Department of Biomedical Engineering of the University
of Stuttgart (Germany). A constant current of 4 mA at a frequency of
100 kHz was introduced by two disposable self-adhesive electrodes. Two
separated electrodes were used to measure changes of voltage within the
segment under consideration. The four-spot electrode array was placed
according to the scheme by Kubicek et al. (19). Baseline thoracic
impedance (Z0), changes of impedance (dZ/dt), and
maximum of impedance derivative (dZ/dtmax) were
automatically derived along with estimates of the preejection period,
left-ventricular ejection time (LVET), and HR. SV was calculated
according to the formula of Kubicek et al. (19), with the known
distance (L) between the inner electrodes and the resistivity
(
) of blood at 100 kHz
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E,
O2, and
CO2 during the
on-transition do not follow the standard kinetics (5, 6, 12), no
attempts were made to characterize mathematically these time courses,
and the kinetics were evaluated by calculating the half times
(t1/2) of the responses. The
t1/2 was calculated as the time required for the
variable to reach 50% of the difference between the baseline and the
new asymptotic (or peak) value. Because we were mainly interested in
gas exchange occurring at the muscle level, t1/2
was calculated when it occurred during the phase II of the response
(32). In a small minority of subjects, 50% of the difference between
baseline and the new steady state was first reached during phase I,
i.e., during the so-called "cardiodynamic phase" of gas exchange
(33). Phase I is usually followed by a transient drop, and, therefore,
in these cases, the t1/2 was taken when the 50%
mark was reached again during the ensuing phase II (see e.g., the
second on-transition of Fig. 1); in the
rare occasions in which phase I was not followed by a drop,
t1/2 was taken along a line extrapolated between
the value at the beginning of phase II and the value at time 0 (i.e., just before exercise onset). By following this procedure,
t1/2 was in all cases calculated on the basis of
the phase II response, but the time elapsed during phase I was also
taken into consideration. The same procedures were applied to the
off-transition. Before the calculation of t1/2, a
"smoothing" of the curves was obtained by calculating a
five-breath moving average. A typical breath-by-breath
O2 vs. time tracing
obtained in a HTR during protocol A, together with the
calculated moving average and the t1/2 on- and
off-marks, is shown in Fig. 1.
O2) values in a typical
heart transplant recipient (HTR) during sequential exercises protocol. Calculated moving average is also shown (solid line), together with
half time (t1/2) on- and t1/2
off-marks. See text for further details.
Whereas HTR performed only one repetition of each protocol, most of the control subjects performed multiple (2-5) repetitions of protocols A and B. Breath-by-breath data obtained in each repetition were superimposed for each subject, and the moving average and the t1/2 were calculated as described above. Statistics. Data were expressed as means ± SD. To check the statistical significance of differences between two means, paired or unpaired Student's t-test (two-sided) was performed as indicated. To check the statistical significance of differences between more than two means, a one-way analysis of variance was performed. A Tukey's test was utilized to discriminate where significant differences occurred. Regression analysis and analysis of variance were performed as indicated. The level of significance was set at P = 0.05.
RESULTS
E was higher in HTR than in C
subjects, as a consequence of a higher fr. In HTR, the
hyperventilation was responsible for the observed higher gas-exchange
ratio, higher end-tidal PO2
(PETO2) and lower end-tidal
PCO2
(PETCO2) as compared with
C. Whereas at rest hyperventilation in HTR might be
attributable to emotional factors, during exercise it is more likely a
reflection of a lower exercise capacity. No significant
O2 differences were observed,
both at rest and during exercise, between HTR and C groups. HR was
higher in HTR than in C both at rest (as a typical manifestation of
heart denervation) and during exercise. The HR increase from rest to
steady-state exercise was about the same (~20 beats/min) in the two
groups. The higher HR in HTR at Rest 1 was compensated by a
lower SV, so that the values were not significantly
different in the two groups. On the other hand, during both Ex
1 and Ex 2, the higher HR in HTR compared with C, in the
presence of only slightly lower SV values, determined higher
in the first group. In HTR the priming exercise
elicited significantly higher during Rest 2 (i.e., the last minute of Rec 1) than during Rest 1, whereas no significant difference was observed between Ex 1 and
Ex 2. In C, priming exercise determined only a slightly higher
(no significant difference) at Rec 1 compared with Rest 1. Blood lactate concentration ([La]b) values in HTR were moderately elevated during
Ex 1 and Ex 2, compared with normal resting
values, and they were higher during Rec 1 compared with
Rest 1. [La]b values in C were not affected
by exercise.
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E,
O2, and
CO2 during the sequential
50-W exercises are shown for HTR and C in Fig.
2. For both Ex 1 and Ex 2, the values of t1/2 on- and t1/2
off- were for all investigated variables significantly higher (i.e.,
the kinetics were slower) in HTR than in C. No significant differences
were observed, for both HTR and C, between the t1/2 O2 on- and the
t1/2 O2
off-values, whereas for E and
CO2 the
t1/2 on-values were higher than the corresponding
t1/2 off-values. No significant differences were
observed for any of the investigated values, between the values
obtained during Ex 1 and Ex 2, for both HTR and C.
The t1/2 on- and off-kinetics of
during the sequential 50-W exercises are shown for HTR and C in Fig. 3.
The t1/2 on-values during Ex
1 were significantly higher in HTR
compared with C, whereas no significant difference between the two
groups was observed during Ex 2. Such absence of a significant
difference can be attributed both to faster
on-kinetics in HTR (at the limit of statistical significance,
P = 0.05), and to slightly slower (no significant difference)
on-kinetics in C, during Ex 2 compared with
Ex 1. The t1/2
off-values were slightly higher in HTR than in C, during both Rec
1 and Rec 2, even though a statistically significant difference was observed only for Rec 2. In both groups,
t1/2 on-values were not
significantly different from t1/2
O2 on-, and
t1/2 off-values were not
significantly different from t1/2 O2 off-values.
Protocol B. Steady-state values obtained in HTR and C at rest and during the 5-min rectangular exercises at different workloads are presented in Table 3. The hyperventilation described above (see protocol A), in HTR compared with C, was confirmed by this set of data as well, both at rest and during exercises at the indicated loads. Steady-state
O2 values are plotted as a
function of workload in Fig. 4. No
differences were observed between HTR and C at rest and at 25 or 50 W,
whereas O2 values were
slightly but significantly higher in HTR at 75 W.
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O2) obtained at rest and at
steady state during 5-min rectangular exercises at different workloads
in HTR and in C subjects. * Significantly different from corresponding
value in C.
The calculated t1/2 for the on- and off-responses of
E,
O2, and
CO2, at the three
investigated workloads, are shown in Fig. 5A
(t1/2 on-) and 5B (t1/2
off-). With regard to the
t1/2 on-values, for all variables and at all
workloads the values were significantly higher in HTR than in C. The
t1/2 on-values in C were progressively higher with
increasing workload, whereas such behavior was not observed in HTR
(there were no significant differences, in this group, among the
E,
O2, and
CO2 values obtained at 25, 50, or 75 W). The differences between HTR and C became, therefore,
progressively smaller at heavier workloads, although they were
statistically significant at all workloads. Also, for t1/2 off-, the values in HTR were significantly
higher than those in C, for all variables and at all workloads, with
the exception of E and
CO2 at 75 W, in which cases
the differences did not reach statistical significance. At all
workloads, no significant differences were observed, for both HTR and
C, between the t1/2 O2 on- and the
t1/2
O2 off-values.
E),
O2, and CO2 output (CO2) in HTR and in
C during 5-min rectangular exercises at different workloads. See text
for further details. * Significantly different from corresponding
value in C; § significantly different from value corresponding to 50 W in C; # significantly different from value corresponding to 75 W in
C.
The t1/2
O2 on- and off-values
obtained in HTR at 25 and 50 W are plotted as a function of the time
elapsed between surgery and the tests in Fig. 6, A and B,
respectively. Both t1/2
O2 on- and off-values did not
bear a significant relationship to the time elapsed after
transplantation. This analysis was not performed for the 75-W
exercises, as a consequence of the relatively small number of HTR
subjects who carried out the exercise at this load.
O2 on (A, left) and
t1/2 O2
off (B, right) calculated in HTR for the 25-W and 50-W
exercises, expressed as a function of time elapsed between
transplantation and tests. Linear regression lines (solid) and 95%
confidence intervals lines (broken) are also shown. See text for
further details.
Protocol C. Steady-state values at rest and at 5, 10, and 15 min of the 15-min 25-W rectangular exercise are shown in Fig. 7. Also, for this protocol,
E,
fr, gas-exchange ratio, and
PETO2 were higher, whereas
PETCO2 was lower, in HTR than in C. Both in HTR and in C, no differences were observed for any of the
investigated variables between the values obtained at 5, 10, and 15 min
of exercise. In HTR, SaO2 was not affected by exercise
(98 ± 2% at rest, 98 ± 1% at 5-min exercise, 98 ± 2% at
10-min exercise, 98 ± 1% at 15-min exercise).
E,
tidal volume (VT), respiratory frequency (fr),
O2, CO2,
gas exchange ratio (R), end-tidal pressures of O2
(PETO2) and CO2
(PETCO2), and heart rate (HR) at rest and at 5, 10, and 15 min of exercise at 25 W. See
text for further details. * Statistically significant difference.
DISCUSSION
O2 adjustment to a
higher steady state (5, 6, 12, 22). This slower
O2 on-kinetics has been
attributed, at least in part, to the slower HR (5, 23) and
(6) on-kinetics, as a consequence of the denervation
of the transplanted heart. Alternative explanations could be an
impairment of the vasodilatatory response to exercise (25), muscle
deterioration attributable to physical deconditioning, chronic
corticosteroid (15) or cyclosporine A (20) therapy, or to chronic
bioenergetic abnormalities of skeletal muscle associated with the
congestive heart failure preceding the transplantation (27). On such
premises, Meyer et al. (21) and, subsequently, Paterson et al. (22) hypothesized that, if the factors responsible for the slower
O2 on-kinetics in HTR were,
indeed, related to a limitation in the rate of adjustment of
O2 delivery to the exercising muscles, a priming of the
cardiovascular system obtained by a preceding exercise would determine,
on a second on-transition carried out a few minutes later, a faster
O2 on-kinetics. Before the
second on-transition was performed, HTR would in fact present higher HR
(5, 23) and, presumably, also higher and muscle
blood flow, higher blood catecholamine levels (5), and a more favorable
situation as far as blood flow distribution to the exercising muscles,
compared with the scenario immediately preceding the first
on-transition. Moreover, lactic acid accumulation in blood during the
recovery after the first exercise would likely determine by itself
vasodilation and an increased blood flow at the muscle level, together
with a rightward shift of the hemoglobin-O2 dissociation
curve, thereby favoring O2 delivery to muscle fibers at the
onset of the second exercise (29).
The validity of this hypothesis was not confirmed by the results of the
present study, which showed in HTR no differences in
t1/2 O2
on- between the first and the second on-transition of the sequential
exercises (see Fig. 2). To interpret these results correctly, the
question should be raised whether the priming exercise was indeed
effective in determining in HTR more favorable conditions with regard
to the rate of adjustment of O2 delivery to muscle fibers.
The measurements carried out in the present study allow at least a
partial answer to such question. Indeed, during the 30-s resting period
preceding the second on-transition (Rest 2), HR and
values were significantly higher compared with the
homologous period before the first on-transition (Rest 1)
(see Table 2). The on-kinetics were faster during
Ex 2 compared with Ex 1 (see Fig. 3). No data are
available for blood catecholamines or muscle blood flow, which,
however, should have been higher during Rest 2 compared with
Rest 1, for the reasons discussed above. [La]b
values were moderately but significantly higher during Rest 2 compared with Rest 1. Even a low degree of metabolic acidosis should determine some vasodilatation, some increase in blood flow, and
some degree of rightward shift of the hemoglobin-O2
dissociation curve, favoring O2 delivery to muscle fibers.
Five minutes of recovery were allowed between the two exercises, so
that blood, tissue, and lung O2 stores, which might have
been depleted during the first exercise (a depletion could influence
the following O2 on-kinetics)
were presumably fully reestablished when the second exercise was
carried out (10).
Considering the very particular set of subjects, all measurements of
the present study were supposed to be noninvasive; thus, muscle blood
flow, arterial PO2
(PaO2), and arterial O2
concentration (CaO2) could not be determined.
Inferences on convective O2 delivery to muscles must,
therefore, rely on two assumptions: 1) the time course of
blood flow to the active muscles could be reasonably estimated on the
basis of time course; 2) no significant
arterial desaturation occurred during exercise. The first assumption
holds if perfusion to active skeletal muscles accounts for most of the increase in at the on-transition. Although this
would appear to be reasonable, it could not be directly tested. In this
context, however, it may be noteworthy that previous work by our group showed a rapid adjustment (not different from that of controls) of
muscle blood flow at exercise onset in a limited number of HTR (6). As
far as the second assumption, whereas it appears obvious for the
control subjects, it might be slightly more controversial in HTR.
Indeed, whereas Degre et al. (9) showed no significant decreases in
PaO2 during exercise in HTR, Braith et al. (4) showed
some reduction in PaO2 (to ~85-92 Torr) during
submaximal exercises in ~50% of their HTR. In any case, even if
it occurred in some of the HTR of the present study, a
PaO2 reduction similar to that described above
would not significantly influence CaO2 (the
important variable when dealing with O2 delivery), since PaO2 would still be on the flat portion of the
O2-hemoglobin dissociation curve. In some HTR of the
present study, arterialized SaO2 was, indeed, monitored
during the tests by earlobe pulse oximetry, and no
SaO2 decreases were observed. Moreover, even if some
CaO2 decrease occurred during Ex 1, it appears
reasonable to assume that during the following recovery
CaO2 would resume its resting values, so that
at the onset of Ex 2 CaO2 would be the same
as at the onset of Ex 1. Therefore, the most important aspect
of the present study would be, from this point of view, flawless.
From the above considerations, it would appear reasonable to conclude
that the priming exercise was effective in determining more favorable
conditions for the adjustment of O2 delivery to the
increased metabolic demand. Despite this, the
O2 on-kinetics was unchanged.
Thus it would appear that the slower
O2 on-kinetics in HTR was not
attributable to a slower adjustment of convective O2
transfer, confirming what was previously hypothesized by our group (5,
6, 12). Other factors, likely involving muscle metabolism [e.g.,
chronic deconditioning, effects of chronic corticosteroid (15) or
cyclosporine A (20) therapy, or chronic bioenergetic abnormalities
attributable to the congestive heart failure preceeding the
transplantation (27)] would appear to play a determinant role.
Considered in broader terms from the standpoint of metabolic control
mechanisms, the dissociation between the rate of adjustment of
and O2 delivery (faster during Ex
2 compared with Ex 1) and the rate of adjustment of
O2 (unchanged during Ex
2 compared with Ex 1) in HTR appears in favor of the
hypothesis that the O2
on-kinetics in humans are mainly determined by an inertia of the
intramuscular oxidative machinery (7, 31) and not by the rate of
O2 delivery to the exercising muscles (16). This conclusion, which on the basis of the present results can, of course,
be drawn only for the transition from rest to an exercise presumably
lower than the lactate threshold, appears in agreement with recent
studies on muscle metabolism carried out in exercising humans by
nuclear magnetic resonance spectroscopy (3) as well as with studies
analyzing the O2 on-kinetics
in the human quadriceps muscle (13).
The results of the present study do not confirm the data obtained by
Paterson et al. (22) by utilizing a similar protocol of sequential
exercises. Indeed, these authors described faster O2 on-kinetics in HTR during
the second on-transition, with time constant (
) values
that were not different from those of control subjects.
The on-transition studied by Paterson et al. (22) was from unloaded
pedaling to a workload lower than the subjects' anaerobic threshold.
Considering the limited exercise capacity of HTR, the amplitude of the
O2 response was, therefore, very small (change in O2
above the baseline = 0.21 l/min), with a signal-to-noise
ratio, during breath-by-breath analysis of gas exchange, which was
inevitably rather poor. The limited amplitude of the
O2 response, together with
the small number of investigated subjects (n = 6), was such
that the estimated 95% confidence intervals of the data obtained
by Paterson et al. (22) were, by their own admission, "wide"
(~40 s). Moreover, by utilizing an unloaded pedaling baseline, the
cardiovascular system was somewhat primed even before the first
on-transition, making the difference between the two sequential
transitions rather small.
The priming exercise did not affect t1/2
O2 on- in C subjects as well.
This is not surprising, considered that in this group values during Rest 2 were only slightly
higher (no significant difference) than during Rest 1, and the
t1/2 on- during Ex 2 were slightly higher (no significant difference) than during Ex
1. Moreover, no [La]b changes were described in C
during this protocol, so that the acidosis-induced effects described
above for HTR could not occur. Finally, no significant increases in blood catecholamine levels should occur in normal subjects at this low
workload (2). Thus the priming exercise could not significantly affect
the rate of adjustment of O2 delivery to muscle fibers in
C. The results of the present study, as far as C subjects are
concerned, confirm those obtained by Gerbino et al. (11), according to
whom in normal subjects a prior sublactic threshold exercise is not
effective in speeding up O2
kinetics during a second on-transient.
In the present study, the CO2
and E on-kinetics were significantly
slower than the O2
on-kinetics, as previously shown in normal subjects (28) as well as in
HTR (5, 6) and in heart and lung transplant recipients (12). The slower
CO2 on-kinetics, compared
with O2 on-, are presumably
attributable to the CO2 storage capacity of body tissues,
whereas the mechanisms responsible for the tight coupling of the
CO2 and
E on-kinetics are not firmly established
(30). In the present study, the E on- and
CO2 on-kinetics were
significantly slower in HTR compared with C, confirming previous
results by our group (5, 6, 12). On the basis of the present data, no
inferences can be made as far as any cause-effect relationships between
the delayed gas-exchange and ventilatory kinetics. It seems reasonable
to hypothesize, however, that a delayed
CO2 on-kinetics would follow the delayed O2 on-kinetics
and that a delayed E on-kinetics would
then strictly follow the delayed
CO2 on-kinetics. HTR slightly
hyperventilated at rest, compared with C (see Tables 2 and 3). The
influence of such modest hyperventilation on the E on-kinetics was presumably negligible.
Gas-exchange on-kinetics as a function of workload and of time
posttransplantation.
The results of the present study showed in C an increase in
t1/2 O2
on- (i.e., a slower O2
on-kinetics) with increasing workload (see Fig. 5), even if the latter
was moderate, i.e., was presumably lower than the lactic threshold.
These data confirm previous observations by Cerretelli et al. (8) and
di Prampero et al. (10). The slowing of the
O2 on-kinetics with
increasing exercise intensity, even in the moderate-exercise domain,
was associated by the above-mentioned authors with a transient
("early") lactate increase occurring during the first minutes of
exercise, before the attainment of a steady state for
O2. The present results, on the other hand, do not confirm those by Whipp and Ward
(32), according to whom, for moderate-intensity exercise, the
of the O2
on-response is relatively independent of work rate. No insights to
explain these discrepancies can be obtained from the present study. In
any case, the slowing of the on-kinetics with increasing workload was
not observed in HTR. No clear-cut explanation can be offered for this
finding, which appears rather surprising, considering that in some HTR
the higher investigated workloads might have corresponded to (or even
exceeded) the lactate threshold and that there is substantial agreement
among authors that at or above this threshold the
O2 on-kinetics is
significantly slower than during moderate exercise. A possible
explanation is that in HTR intrinsic metabolic factors at the muscle
level impose a slow kinetics already at low workloads. An alternative
partial explanation may lie in the fact that the method utilized in the present study to calculate the t1/2
O2 on- does not take into account the presence of a "slow component" of the
O2 on-kinetics (31), which
occurred in some HTR at 75 W, as also manifested by the steady-state
O2 values (see below).
At all investigated workloads (i.e., 25, 50, and 75 W), the ventilatory
and gas-exchange on-kinetics were significantly slower in HTR than in C
subjects. Slower on-kinetics in HTR were also described when HTR and C
were examined at the same relative (with respect to their
O2 max workload (12). The
slower on-kinetics in HTR appear, therefore, to be independent of
workload, either absolute or relative.
No statistically significant relationship was observed, either at
25 or at 50 W, between the t1/2
O2 on-response and the time
elapsed between the test and the heart transplantation, although a trend toward slightly lower t1/2 with time was
observed. This observation appears of some interest, considering the
wide range (between 1 and 137 mo) of time elapsed after surgery
encompassed by the present study and recent observations by some
authors indicating the possibility of some kind of reinnervation of the
transplanted heart (17, 34) or of heart 2-adrenoceptors
upregulation and increased sensitivity to epinephrine as a
function of time after transplantation (26). On the basis of the
present results, it can be concluded that, even if some reinnervation
or increased sensitivity to catecholamines occurs with time, it
does not appear to have any significant effect on the
O2 on-kinetics, which remain significantly slower in HTR compared with C subjects even more
than 10 yr after surgery. The slightly faster
O2 on-kinetics as a
function of time after surgery might, in fact, be well accounted for by some improvement of the muscle function of HTR.
Off-transients.
During the recovery after a moderate-intensity exercise, an analysis of
the O2 time course in normal
subjects indentifies a fast, workload-independent exponential component
with a t1/2 of 25-30 s, associated with the
resynthesis of muscle phosphocreatine and the replenishment of the
O2 stores of the body (8, 10). This fast component is
followed by a second, slow exponential component
(t1/2 of several minutes), which has been
attributed to the repayment of the fraction of the O2
deficit associated with early lactate accumulation (8, 10). Because, in
the present study, the t1/2
O2 off-values were calculated
over the first 4-5 min of recovery, the obtained values mainly
reflect the fast ("alactic") component mentioned above. The fact
that the t1/2
O2 off-values were
significantly higher in HTR than in C indicates that in the former
group the alactic O2 deficit was greater than in C, thereby
reinforcing the notion of a sluggish O2 adjustment at the muscle
level (on the assumption of an equal contribution of O2
stores to the O2 deficit in the two groups). In the present
study, t1/2
O2 off-values were, in both
groups, independent of workload, confirming previous observations by
others in normal subjects (8).
In HTR, the slower O2
off-kinetics, as compared with C, were associated with slower
CO2 off- and
E off-kinetics. As discussed above for
the on-response, on the basis of the present data, no inference can be
made as to any cause-effect relationships between the delayed
gas-exchange and ventilatory kinetics. Also for the off-phase, however,
it seems reasonable to hypothesize that a delayed
CO2 kinetics would follow the
delayed O2 kinetics and that
a delayed E kinetics would then
strictly follow the delayed
CO2 kinetics.
Steady-state values during prolonged exercise.
As mentioned above, with a rectangular increase in workload, HR follows
in HTR a time course that is distinctly different from that of healthy
subjects (5, 23). Indeed, after an initial delay during which HR does
not increase appreciably, an almost linear increase as a function of
the time of exercise is observed, and a new steady state is not reached
before the fourth or fifth minute of exercise, and sometimes even later
(5, 23). Thus it might be questioned whether during a standard 5-min
rectangular exercise protocol HTR do, indeed, reach a "steady
state" as far as the main cardiovascular, ventilatory, and
gas-exchange parameters are concerned. Therefore, a prolonged (15-min)
rectangular exercise protocol was carried out in the present study. The
workload chosen for this protocol was low (25 W) to prevent the
subjects from developing signs of fatigue, which could influence the
investigated variables. The obtained results indicate that, even in the
presence of HR values that kept slightly (although statistically not
significantly) increasing from the fifth to the fifteenth minute of
exercise, no changes were observed for the ventilatory and gas-exchange parameters between the fifth, the tenth, and the fifteenth minute of
exercise (see Fig. 7). Therefore, after 5 min of
moderate-intensity exercises, HTR appear in a situation of steady state
with regard to E,
O2, and
CO2, indicating that also
in HTR the ventilatory and gas-exchange kinetics can be
reliably evaluated by standard means and protocols. More caution
is probably needed for the cardiovascular parameters.
Steady-state O2 values were
substantially the same in HTR and in C subjects at rest and at 25 and
50 W (see Fig. 4). This indicates that despite the pharmacological
treatment the mechanical efficiency of exercise was unaltered in HTR,
confirming previous observations (5, 6). However,
O2 values were slightly but
significantly higher in HTR than in C subjects at 75 W. This presumably
indicates that at this load in HTR the "slow component" of
O2 kinetics was superimposed
on the O2 time course for moderate exercise (31). Such slow component could, indeed, be responsible for the higher O2
values that were attained in HTR between the fourth and the fifth
minute of exercise at 75 W, compared with those expected according to
an extrapolation of the O2 vs. workload relationship obtained at lower workloads. Some caution is,
therefore, warranted in the analysis of the gas-exchange kinetics in
HTR at 75 W.
Methodological considerations.
Only two techniques can provide noninvasive estimates of
or SV on a beat-by-beat basis (i.e., with the time
resolution necessary for kinetics studies): impedance cardiography and
Doppler ultrasound. Both techniques are indirect, as a result of the
underlying principles, and thus in this respect there is not a clear
advantage of one over the other. Indeed, there are common problems for
both techniques, which may not be relevant for measurements at rest but
which may become important during exercise, mainly as a consequence of
movements of the chest and the upper body. As far as impedance cardiography is concerned, artifacts may derive from the movement of
the electrodes, whereas for the Doppler ultrasound technique placement
and stability of the Doppler probe becomes increasingly difficult at
higher workloads. measurements in the present study
were, therefore, mainly restricted to moderate exercise, in which
movements of the upper part of the body are limited. In any case, the
reliability of thoracic impedance as an indirect index of
, even during exercise, has been supported by several studies [see e.g., Hatcher and Srb (14) and Kobayashi et al. (18)].
Moreover, what really mattered for the present study were the relative
changes (compared with the resting baseline) of , the
absolute changes being much less important. Indeed, the obtained
results would have been essentially the same if the changes in thoracic
Z, rather than the calculated SV, were utilized as an indirect index of
.
Breath-by-breath determinations of E, as
well as beat-by-beat estimations of , are inherently
noisy. To improve accuracy and precision of kinetic analysis of these
parameters, several repetitions of the same experiment, with subsequent
superimposition of the results, are usually recommended. In the present
study, practical reasons mainly related to the rigid schedules of the hospital wards in which the experiments were conducted prevented us
from examining each patient for longer than ~45-60 min. In most
cases, it was therefore impossible for the patients to perform several
repetitions of the experimental protocols. On the other hand, in the
present study, we could examine a particularly elevated number (82) of
HTR, thereby reducing intersubject variability. Multiple (2-5)
repetitions of the rectangular exercises were, however, performed by
some of the C subjects. The same practical reasons mentioned above did
not allow determination of
O2 max in every HTR. An
incremental exercise protocol to determine
O2 max was,
however, carried out by a limited number (n = 8) of our HTR, and the obtained results (maximal workload 97 ± 25 W,
O2 max 1.60 ± 0.36
l/min, peak HR 128 ± 17 beats/min) appear fully in agreement with
those obtained by previous authors (1, 22, 24). Thus the workloads
chosen for the present study were clearly submaximal, and, in most
cases, they were also presumably lower than the subjects' lactate
threshold, i.e., they were suitable for standard gas-exchange kinetics
analysis. As mentioned above, some caution is probably warranted for
the 75-W protocol.
Conclusions.
Main results of the present study were as follows. 1) In HTR,
a priming exercise, while at least in part effective in speeding up the
rate of adjustment of and of the convective
O2 flow to muscle fibers during a second on-transition, did
not affect the O2
on-kinetics, which was still significantly slower than in C. The slower
O2 on- in HTR was, therefore,
presumably attributable to "peripheral" (i.e., muscular) factors.
2) In HTR, the
O2 on-kinetics did not change
as a function of workload, possibly indicating that intrinsic metabolic
factors were already imposing a slower kinetics at low workloads.
3) No relationship was observed between the
O2 on-kinetics and the time
elapsed after transplantation, indicating that, even if some
reinnervation or increased sensitivity to catecholamines of the
transplanted heart occurred with time, it did not affect these
kinetics. 4) The O2
off-kinetics were significantly slower in HTR than in C, indicating a
greater alactic O2 deficit in the former group, thereby
reinforcing the notion of a sluggish
O2 adjustment at the muscle
level. 5) After 5 min of low-intensity exercise, HTR were in
a situation of steady state as far as E,
O2, and
CO2, indicating that also in these patients kinetic analysis of these variables can be performed by
standard protocols.
Besides providing basic information regarding the exercise response of
HTR, the results of the present study allow the physiologist to gain
insight into some basic mechanisms of muscle metabolic control, i.e.,
into the long-lasting dispute about the mechanisms dictating the
O2 on-kinetics. Indeed, the
dissociation observed in HTR, during the on-transitions of the
sequential exercise protocol, between the rate of adjustment of
and presumably also of O2 delivery to
muscles, and the rate of adjustment of
O2, appears in favor of the
hypothesis that an inertia of muscle metabolic machinery is the main
factor dictating the O2
on-kinetics (7, 31) (at least during the transition from rest to an
exercise lower than the lactate threshold). This conclusion is in
agreement with recent studies on muscle metabolism carried out in
exercising humans by nuclear magnetic resonance spectroscopy (3) as
well as with studies analyzing
O2 on-kinetics in the human
quadriceps muscle (13).
ACKNOWLEDGEMENTS
The authors are grateful to all the patients and control subjects who willingly collaborated in this study. The authors are also indebted to Prof. C. Cabrol, Prof. B. Carù, and Prof. I. Brambilla for the clinical supervision of the patients during the experiments, and to A. Colombini and M. Pellegrini for technical assistance.
FOOTNOTES
Address for reprint requests: B. Grassi, Fisiologia ITBA, CNR, Via Ampere 56, I-20131 Milan, Italy (E-mail: grassi{at}itba.mi.cnr.it).
Received 12 June 1996; accepted in final form 4 March 1997.
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