Download Spontaneous baroreflex control of cardiac output during dynamic

Am J Physiol Heart Circ Physiol 294: H1310–H1316, 2008.
First published January 11, 2008; doi:10.1152/ajpheart.01187.2007.
Spontaneous baroreflex control of cardiac output during dynamic exercise,
muscle metaboreflex activation, and heart failure
Masashi Ichinose,1,3 Javier A. Sala-Mercado,1 Donal S. O’Leary,1 Robert L. Hammond,1,2
Matthew Coutsos,1 Tomoko Ichinose,1,4 Marco Pallante,5 and Ferdinando Iellamo5,6
Departments of 1Physiology and 2Surgery, Wayne State University School of Medicine, Detroit, Michigan; 3Laboratory
for Applied Human Physiology, Faculty of Human Development, Kobe University, Kobe, Japan; 4Laboratory for Human
Performance Research, Osaka International University, Osaka, Japan; and 5Dipartimento Medicina Interna, Universita
di Roma Tor Vergata, and 6Instituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Roma, Italy
Submitted 11 October 2007; accepted in final form 16 December 2007
THE ARTERIAL BAROREFLEX is considered the main mechanism of
arterial blood pressure regulation in the short-term control of
the cardiovascular system (30). Changes in arterial pressure
result in baroreflex-mediated reciprocal changes in heart rate
(HR) and sympathetic activity. During exercise, the baroreflex
is reset to operate around the higher-prevailing blood pressure
and HR (7, 13, 26, 28). In addition to resetting during exercise,
arterial baroreflex sensitivity in the control of HR during
rapid spontaneous changes in blood pressure decreases during exercise as workload rises (3, 14, 23, 31). The reduction
of baroreflex HR sensitivity during exercise is thought to be
associated with vagal withdrawal, inasmuch as these rapid
baroreflex changes in HR are mediated by changes in
parasympathetic tone (23). Recently, it has been demonstrated (31) in dogs that imposed muscle metaboreflex
activation during dynamic exercise also reduces spontaneous baroreflex HR sensitivity, which is even further suppressed in these settings in subjects with congestive heart
failure (HF) (16).
Although the spontaneous baroreflex HR technique has often
been used to study baroreflex control of HR (2, 3, 14, 23, 29),
Sala-Mercado et al. (33a) in the accompanying article have
shown that these baroreflex-mediated changes in HR do not
always cause changes in cardiac output (CO) due to changes in
stroke volume (SV). This study showed that in the normal dog
at rest, ⬃44% of the changes in HR caused changes in CO
(HR-CO translation or coupling). In addition, HF significantly
decreased this coupling such that changes in CO were more
related to changes in SV than to changes in HR. Whether
dynamic exercise with and without muscle metaboreflex activation alters the ability of spontaneous baroreflex-mediated
changes in HR to cause changes in CO is unknown, as is
whether these relationships are affected by HF. Since exercise
changes cardiac autonomic balance, markedly increasing baseline HR and decreasing spontaneous baroreflex HR sensitivity
(15), we hypothesized that the ability of the baroreflex HR
responses to elicit compensatory changes in CO would also be
decreased. Although spontaneous baroreflex HR sensitivity
decreases further with metaboreflex activation (31), substantial
increases in ventricular contractility also occur (6, 21, 33),
which could attenuate any further loss of coupling between the
HR and CO responses. However, in subjects with HF, muscle
metaboreflex-induced increases in ventricular contractility are
severely impaired (5, 32). Therefore, we also hypothesized that
muscle metaboreflex activation would not decrease the coupling between changes in HR and CO in normal subjects, but
with the impaired ventricular performance in HF, we hypothesized that metaboreflex activation in this setting would induce
further decreases in the ability of changes in HR to elicit
changes in CO.
Address for reprint requests and other correspondence: D. S. O’Leary, Dept.
of Physiology, Wayne State Univ. School of Medicine, 540 E. Canfield Ave.,
Detroit, MI 48201 (e-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
arterial baroreflex sensitivity; exercise reflexes; pressor response;
impaired cardiac performance
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Ichinose M, Sala-Mercado JA, O’Leary DS, Hammond RL,
Coutsos M, Ichinose T, Pallante M, Iellamo F. Spontaneous baroreflex control of cardiac output during dynamic exercise, muscle
metaboreflex activation, and heart failure. Am J Physiol Heart Circ
Physiol 294: H1310–H1316, 2008. First published January 11, 2008;
doi:10.1152/ajpheart.01187.2007.—We have previously shown that
spontaneous baroreflex-induced changes in heart rate (HR) do not
always translate into changes in cardiac output (CO) at rest. We have
also shown that heart failure (HF) decreases this linkage between
changes in HR and CO. Whether dynamic exercise and muscle
metaboreflex activation (via imposed reductions in hindlimb blood
flow) further alter this translation in normal and HF conditions is
unknown. We examined these questions using conscious, chronically
instrumented dogs before and after pacing-induced HF during mild
and moderate dynamic exercise with and without muscle metaboreflex
activation. We measured left ventricular systolic pressure (LVSP),
CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP
relationships. In normal animals, mild exercise significantly decreased
HR-LVSP (⫺3.08 ⫾ 0.5 vs. ⫺5.14 ⫾ 0.6 beats 䡠 min⫺1 䡠 mmHg⫺1;
P ⬍ 0.05) and CO-LVSP (⫺134.74 ⫾ 24.5 vs. ⫺208.6 ⫾ 22.2
ml 䡠 min⫺1 䡠 mmHg⫺1; P ⬍ 0.05). Moderate exercise further decreased
both and, in addition, significantly reduced HR-CO translation
(25.9 ⫾ 2.8% vs. 52.3 ⫾ 4.2%; P ⬍ 0.05). Muscle metaboreflex
activation at both workloads decreased HR-LVSP, whereas it had no
significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR
responses do not always cause changes in CO during exercise.
Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF
the HR-CO translation also significantly decreases during both
workloads and decreases even further with muscle metaboreflex
activation.
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BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
Table 1. Hemodynamic values at rest, during mild exercise and MRA at mild exercise, in N and in the same animals after
induction of HF
Condition, Setting
HLBF, l/min
LVSP, mmHg
CO, l/min
SV, ml
N, rest
N, mild free-flow exercise
N, mild exercise ⫹ MRA
HF, rest
HF, mild free-flow exercise
HF, mild exercise ⫹ MRA
0.81⫾0.09
1.17⫾0.11†
0.63⫾0.05‡
0.47⫾0.07*
0.76⫾0.08*†
0.60⫾0.07‡
131.8⫾5.4
133.4⫾5.4
178.3⫾5.5‡
102.0⫾5.5*
109.4⫾4.8*
140.0⫾6.8*‡
4.52⫾0.32
6.06⫾0.45†
7.33⫾0.52‡
3.46⫾0.31*
4.32⫾0.33*†
4.60⫾0.47*
42.2⫾3.4
46.7⫾3.6†
48.7⫾3.8‡
27.0⫾2.5*
27.7⫾2.8*
24.9⫾2.4*‡
CO-LVSP
SV-LVSP
HR, beats/ HR-LVSP Incidence,
Incidence,
Incidence,
min
sequences/100 beats sequences/100 beats sequences/100 beats
108⫾5
131⫾3†
152⫾5‡
130⫾6*
159⫾7*†
184⫾7*‡
9.3⫾1.5
6.5⫾1.1†
6.2⫾0.9
6.1⫾0.8*
3.0⫾0.6*†
2.7⫾0.6*
6.3⫾0.9
4.6⫾0.4†
4.5⫾0.4
3.8⫾0.6*
3.0⫾0.5*
2.9⫾0.5*
1.6⫾0.2
1.8⫾0.4
2.1⫾0.5
2.8⫾0.4*
2.9⫾0.6*
3.0⫾0.2*
MATERIALS AND METHODS
Experiments were performed on eight adult, mongrel dogs (weight,
⬃20 –25 kg) of either sex, selected for their willingness to run on a
motor-driven treadmill. The protocols employed in the present study
conform with the National Institutes of Health guidelines and were
reviewed and approved by the Wayne State University Animal Investigation Committee.
Surgical preparation and procedures. All animals were accustomed to human handling and trained to run freely on a motor-driven
treadmill before they were surgically instrumented in two different
procedures (sternotomy and left flank abdominal surgery). The first
surgical session with its pre- and postpharmachological treatments
have been previously described in detail by Sala-Mercado et al. (33a).
Briefly, under sterile conditions, a midline sternotomy was performed.
A telemetered blood pressure transducer (model PAD-70, Data Sciences International) was placed subcutaneously on the left side of the
chest. Its catheter was tunneled into the thoracic cavity and located
inside the left ventricle for measuring left ventricular pressure (LVP).
A 20- or 24-mm blood flow transducer (Transonic Systems) was
placed around the ascending aorta to measure CO, and three stainless
steel ventricular pacing electrodes (O-Flexon, Ethicon) were sutured
to the right ventricular free wall. For studies unrelated to the present
investigation, vascular occluders were placed on the superior and
inferior venous cava and two pairs of sonomicrometry crystals were
placed on the left ventricular endocardium. The pericardium was
reapproximated loosely, and the chest was closed in layers. After at
least 10 days (recovery period), a second surgical intervention was
performed through a left abdominal retroperitoneal approach (33a). A
10-mm blood flow probe (Transonic Systems) was placed on the
terminal aorta to measure blood flow to the hindlimbs (HLBF). A
hydraulic vascular occluder (DocXS Biomedical Products) was placed
on the terminal aorta just distal to the flow probe. All arteries
branching from the aorta between the iliac arteries and the HLBF
probe were ligated and severed, and a catheter was placed through a
lumbar artery proximal to the HLBF probe and occluder to measure
mean arterial pressure (MAP). All cables, wires, occluder tubings, and
the aortic catheter were tunneled subcutaneously and exteriorized
between the scapulae.
Experimental procedures. Experiments were performed after the
animals had recovered completely (i.e., alert, afebrile, active, and of
good appetite) from the second surgical session (7 days). Before every
experiment, each animal was transported to the laboratory and allowed to roam freely for 15–30 min and then was directed to the
treadmill. The CO and HLBF transducers were connected to the flow
meters (Transonic System). HR was computed by a cardiotachometer
triggered by the CO signal. The LVP signal was checked, and the
arterial catheter was connected to a pressure transducer (Transpac IV,
Abbott). All data were recorded on analog-to-digital recording systems for subsequent off-line analyses. For a given experimental
session, data were collected at rest and then at a randomly selected
workload (mild exercise, 3.2 km/h, 0% grade elevation; or moderate
exercise, 6.4 km/h, 10% grade elevation). Only one workload was
performed on any experimental day. All animals ran freely with only
positive verbal encouragement. Steady-state data were recorded at rest
while the animal was standing on the treadmill, during exercise with
unrestricted blood flow to the hindlimbs and after metaboreflex
activation elicited by reductions in HLBF achieved by partial inflation
of the terminal aortic occluder as previously described (37). Each dog
completed several experiments at both workloads. After the completion of the control experiments, modest congestive HF was induced
via rapid ventricular pacing as previously described by us and others
(25, 32). Briefly, the heart was paced at 240 –250 beats/min for ⬃ 30
days, and the experiments were repeated while in modest HF conditions [defined as resting tachycardia, reduced CO, SV, and maximum
Table 2. Hemodynamic values at rest, during moderate exercise and MRA at moderate exercise, in N and in the same
animals after induction of HF
Condition, Setting
HLBF, l/min
LVSP, mmHg
CO, l/min
SV, ml
HR, beats/min
HR-LVSP
Incidence,
sequences/
100 beats
N, rest
N, moderate free-flow exercise
N, moderate exercise ⫹ MRA
HF, rest
HF, moderate free-flow exercise
HF, moderate exercise ⫹ MRA
0.81⫾0.09
2.55⫾0.15†
1.87⫾0.14‡
0.47⫾0.07*
1.92⫾0.19*†
1.55⫾0.19‡
131.8⫾5.4
147.9⫾5.9†
186.3⫾6.9‡
102.0⫾5.5*
132.6⫾7.3*†
160.5⫾12.0*‡
4.52⫾0.32
8.84⫾0.55†
10.16⫾0.63‡
3.46⫾0.31*
6.80⫾0.59*†
7.14⫾0.78*
42.2⫾3.4
48.3⫾3.8†
52.4⫾4.1‡
27.0⫾2.5*
35.2⫾3.1*†
34.2⫾3.5*
108⫾5
186⫾7†
197⫾7‡
130⫾6*
194⫾3*†
208⫾4*‡
9.3⫾1.5
6.0⫾0.8†
4.9⫾0.7
6.1⫾0.8*
1.8⫾0.2*†
2.4⫾0.3*
CO-LVSP
Incidence,
sequences/
100 beats
SV-LVSP
Incidence,
sequences/
100 beats
6.3⫾0.9
3.6⫾0.4†
3.3⫾0.3
3.8⫾0.6*
2.2⫾0.4*
2.2⫾0.2*
1.6⫾0.2
2.2⫾0.3
2.3⫾0.2
2.8⫾0.4*
2.9⫾0.1*
3.4⫾0.7*
Values are means ⫾ SE; number of animals are the same as in Table 1. *P ⬍ 0.05, HF vs. N; †P ⬍ 0.05, free-flow exercise vs. rest; ‡P ⬍ 0.05, free-flow
exercise ⫹ MRA vs. free-flow exercise.
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Values are means ⫾ SE. MRA, metaboreflex activation; HF, heart failure; HLBF, hindlimb blood flow; LVSP, left ventricular systolic pressure; CO, cardiac
output; SV, stroke volume; HR-LVSP incidence, number of spontaneous baroreflex HR sequences; CO-LVSP incidence, number of spontaneous CO-LVSP
relationships; SV-LVSP incidence, number of spontaneous SV-LVSP relationships. For HLBF, n ⫽ 7 animals; for all other values, n ⫽ 8 normal animals (N)
and n ⫽ 7 HF animals. *P ⬍ 0.05, HF vs. N; †P ⬍ 0.05, free-flow exercise vs. rest; ‡P ⬍ 0.05, free-flow exercise ⫹ MRA vs. free-flow exercise.
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BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
RESULTS
Fig. 1. Average values of heart rate (HR)-left ventricular systolic pressure
(LVSP) (A), cardiac output (CO)-LVSP (B), and stroke volume (SV)-LVSP
(C) at rest and during mild and moderate (Mod) exercise with and without
muscle metaboreflex activation (MRA) in normal (N) and heart failure (HF)
condition. *P ⬍ 0.05, significant difference between N and HF; †P ⬍ 0.05,
free-flow exercise vs. rest; ‡P ⬍ 0.05 exercise ⫹ MRA vs. free-flow exercise.
and minimum first derivative of left ventricular pressure, as described
in our previous studies (11, 16, 32)].
Data analysis. Each animal served as its own control. During the
experiments, beat-to-beat CO, HLBF, HR, MAP, and LVP were
collected continuously. Data were recorded for 3 to 5 steady-state min
to include several respiratory cycles. In the companion article by
Sala-Mercado et al. (33a), we have described in detail how we
assessed the HR-LVSP and CO-LVSP. Briefly, since left ventricular
systolic pressure (LVSP) is virtually identical to the aortic arch
systolic blood pressure, we used LVSP as the input to the arterial
baroreflex. We searched for three or more consecutive beats (sequences) in which the LVSP and HR or CO of the following beat
changed in the opposite directions. Subsequently, a linear regression
was applied to each individual sequence, and only those in which
r2 was ⬎0.85 were accepted and a slope was calculated. By averaging
all slopes, we obtained the mean slope of the HR-LVSP and COLVSP relationships within a given test period. By computing the
overlap between HR sequences and CO sequences, we examined the
AJP-Heart Circ Physiol • VOL
Table 1 shows the average values of HLBF, LVSP, CO, SV,
HR, and normalized number of spontaneous baroreflex HR,
CO, and SV-LVSP sequences (HR-, CO-, SV-LVSP incidences) at rest and during mild workload before (free flow) and
after muscle metaboreflex activation in normal and HF conditions. Table 2 shows the same measurements during moderate
exercise. The cardiovascular responses to exercise and muscle
metaboreflex activation before and after induction of HF were
essentially the same as we have reported in previous studies (1,
10, 32). Briefly, metaboreflex activation caused substantial
increases in HR, CO, and LVSP at both workloads. After the
induction of HF, CO and LVSP were significantly depressed
Fig. 2. The relationship between HR-LVSP and CO-LVSP in N and HF
conditions. Group average data during each setting in N condition (F) and
group average data during each setting in HF condition (E) are shown. The
lines represent the regression line.
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translation or coupling of baroreflex HR responses into CO responses.
We consider complete overlap when HR and CO sequences completely overlapped, and partial overlap when the sequences overlapped by at least two beats (thus partial overlap includes those which
completely overlapped). The proportion of complete and partial overlap to the total number of HR and CO sequences was calculated,
respectively. We also calculated the spontaneous changes in SV and
the percentage of CO sequences that completely or partially overlapped with SV sequences. Since not all baroreflex HR responses
caused compensatory changes in CO due to reciprocal changes in SV,
we further analyzed each baroreflex sequence and calculated within
each sequence the absolute amount of reciprocal change in SV per
change in HR (expressed as ml/beat) and the percentage of the HR
sequences associated with the reciprocal changes in SV at each setting
in normal and HF conditions.
Statistical analysis. With the use of the averaged responses for
each animal, statistical analyses were performed on the data with
Systat software (Systat 11.0). An ␣-level of P ⬍ 0.05 was set to
determine statistical significance. Two-way analysis of variance
for repeated measures was used for comparing hemodynamic data
obtained at rest [resting data before moderate exercise; those data
at rest before mild exercise were used in the accompanying article
(33a)], during each workload before and after muscle metaboreflex
activation, in normal and HF conditions. If a significant interaction
term was found, a test for simple effects post hoc analysis (CMatrix) was performed to determine significant group mean differences. In figures and text, data are expressed as means ⫾ SE and
reflect data from eight animals in normal state, with n ⫽ 7 animals
in HF.
BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
setting. Mild and moderate exercise decreased both HR-LVSP
and CO-LVSP as in normal animals. In HF, muscle metaboreflex activation caused a further slight yet significant decrease in
HR-LVSP, whereas it did not alter CO-LVSP at both workloads. SV-LVSP was low and did not vary across settings or
in HF.
Figure 2 shows that there were close linear relationships
between HR-LVSP and CO-LVSP, both before and after induction of HF; however, the slope of the linear regression line
in HF was markedly diminished compared with that in the
normal state, indicating that even at the same HR-LVSP, the
CO-LVSP was smaller in HF.
Figure 3 shows the percentage of partial and complete
overlap of HR sequences with CO sequences (Fig. 3, A and B),
of CO sequences with HR sequences (Fig. 3, C and D), and of
CO sequences with SV sequences (Fig. 3, E and F) at each
setting before and after induction of HF. The same conclusions
Fig. 3. The proportion of the overlap among
HR, CO, and SV sequences. HR-CO partial
overlap (A), proportion of the HR sequences
overlapped at least 2 beats with CO sequences; HR-CO complete overlap (B), proportion of the HR sequences completely
overlapped with CO sequences; CO-HR partial overlap (C), proportion of the CO sequences overlapped at least 2 beats with HR
sequences; CO-HR complete overlap (D),
proportion of CO sequences completely
overlapped with CO sequences; CO-SV partial overlap (E), proportion of the CO sequences overlapped at least 2 beats with SV
sequences; CO-SV complete overlap (F),
proportion of CO sequences completely
overlapped with SV sequences. *P ⬍ 0.05
between N and HF; †P ⬍ 0.05 vs. rest; ‡P ⬍
0.05 vs. mild exercise; §P ⬍ 0.05 vs. moderate exercise.
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and the animals were tachycardic. Metaboreflex activation in
HF still caused a tachycardia; however, the fall in SV markedly
limited any reflex increase in CO. Exercise decreased the
incidence of HR-LVSP sequences with no further change with
metaboreflex activation both before and after the induction of
HF. The incidence of HR-LVSP and CO-LVSP sequences was
significantly less in all settings in HF. The SV-LVSP incidence
was quite low and did not vary significantly with exercise and
metaboreflex activation, although it was significantly increased
in all settings in HF.
Figure 1 shows the HR-LVSP (Fig. 1A), CO-LVSP (Fig.
1B), and SV-LVSP (Fig. 1C) in each setting. In normal animals, both HR-LVSP and CO-LVSP significantly decreased
with mild and moderate exercise. Although muscle metaboreflex activation at both workloads caused a further decrease in
HR-LVSP, it had no obvious effect on CO-LVSP. In HF, both
HR-LVSP and CO-LVSP were significantly attenuated at each
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BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
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Fig. 4. A: percentage of HR sequences associated with reciprocal changes in
SV. B: average absolute amount of change in SV per beat (in the HR baroreflex
sequences) at each setting in N and HF conditions. *P ⬍ 0.05 between N and
HF; †P ⬍ 0.05 vs. rest; ‡P ⬍ 0.05 vs. mild exercise; §P ⬍ 0.05 vs. moderate
exercise.
DISCUSSION
To our knowledge, this is the first study to investigate to
what extent the spontaneous baroreflex-induced changes in HR
translate into functional changes in CO during dynamic exercise. Furthermore, we investigated the effects of muscle
metaboreflex activation on this coupling and how these relationships are affected after the induction of congestive HF.
Cardiac baroreflex responses during dynamic exercise and
metaboreflex activation in normal subjects. Our results confirm
previous studies showing that dynamic exercise attenuates
spontaneous baroreflex control of HR (3, 14, 23, 31) and
furthermore show that dynamic exercise progressively decreases both HR-LVSP and CO-LVSP as exercise intensity
increases. In addition to the attenuation in the gain of cardiac
baroreflex responses, we found that dynamic exercise reduces
the coupling of the HR responses into CO responses. This
reduction in the ability of HR responses to elicit effective
changes in CO was due to simultaneous reciprocal changes in
SV; that is, as HR increased, often SV fell (and the magnitude
of the fall in SV per beat increased), such that CO remained
relatively unchanged. The progressive decrease in baroreflex
control of HR together with the fewer number of HR responses
actually causing effective changes in CO suggests that the
contribution of baroreflex-mediated CO responses to blood
pressure regulation progressively declines as exercise intensity
increases.
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are reached using either partial or complete overlap. In agreement with the companion article by Sala-Mercado et al. (33a),
in normal animals, at rest, ⬃50% of HR sequences overlapped
with CO sequences, whereas most of CO sequences overlapped
with HR sequences. The CO sequences (either partial or
complete) overlapped with SV sequences were around 10% at
rest. When compared with rest, HR-CO overlap and CO-HR
overlap slightly decreased during mild exercise but significantly decreased with moderate exercise intensity, whereas
CO-SV overlap slightly increased at mild exercise and significantly increased at moderate exercise. Furthermore, muscle
metaboreflex activation during mild and moderate exercise
showed no significant change in HR-CO overlap with respect
to the values during exercise before hindlimb ischemia. Muscle
metaboreflex activation at mild exercise significantly decreased
the CO-HR overlap seen during free-flow exercise, but during
moderate exercise muscle, metaboreflex activation had no
effect on the CO-HR overlap. Moreover, CO-SV overlap rose
significantly during muscle metaboreflex activation at both
mild and moderate exercise compared with free-flow exercise.
In HF, the HR-CO overlap and CO-HR overlap were significantly decreased and the CO-SV overlap was significantly
increased at all settings. HR-CO overlap slightly decreased
during mild exercise and significantly decreased at moderate
exercise. CO-HR overlap significantly decreased during both
mild and moderate exercise. CO-SV overlap progressively
increased as exercise intensity increased. Muscle metaboreflex
activation during both workloads significantly decreased
HR-CO overlap and also tended to decrease CO-HR overlap.
In contrast, CO-SV overlap significantly increased during muscle metaboreflex activation at both mild and moderate exercise
intensities in HF. Both before and after the induction of HF,
HR sequences overlapped with SV sequences were ⬍10% in
all the settings, and we observed neither significant changes
between settings nor a significant difference between normal
and HF states.
Figure 4 shows the percentage of the HR sequences associated with reciprocal changes in SV at each setting before and
after induction of HF (Fig. 4A), in addition to the change in SV
(absolute amount) per beat within the baroreflex sequences
(Fig. 4B). In normal animals, from rest to mild exercise, no
significant changes occurred. Muscle metaboreflex activation
tended to increase both values. Muscle metaboreflex activation
significantly increased the percentage of HR sequences that
showed reciprocal changes in SV compared with the resting
situation. In contrast, moderate exercise significantly increased
the percentage of overlap (HR with reciprocal changes in SV)
and the quantity that SV changed. Muscle metaboreflex activation at this workload had no further effect. In accordance
with the companion article by Sala-Mercado et al. (33a), the
percentage of the HR-LVSP sequences in which reciprocal
changes in SV occurred was substantially increased at rest in
HF. In addition, the changes in HR were accompanied by
larger changes in SV, not only at rest but at each setting.
Although, when in HF, neither mild nor moderate exercise
before and after muscle metaboreflex activation altered the
percentage of overlap, larger reciprocal changes in SV per beat
occurred with each workload before and after muscle
metaboreflex activation.
BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
AJP-Heart Circ Physiol • VOL
CO occur. These results suggest that the depressed dynamic
baroreflex control of CO in HF is induced by both a decreased
baroreflex chronotropic response (i.e., diminished HR baroreflex gain) and an impaired inotropic state of the heart (i.e.,
reduced SV). In addition, in HF, a higher percentage of CO
responses were associated with spontaneous baroreflex-like
changes in SV. The increased contribution of SV changes to
CO responses seen in HF might reflect a higher afterload
sensitivity of the left ventricle in HF subjects (32). Accordingly, baroreflex-mediated blood pressure regulation relies less
on CO control and is more dependent on peripheral vascular
regulation in HF (17, 24).
Limitations of the study. Our approach employed to evaluate
arterial baroreflex control of HR and CO (based on spontaneous fluctuations in blood pressure, HR and CO) has several
advantages and disadvantages that we have previously described in detail (14, 16, 31). Briefly, the reduction in spontaneous baroreflex HR sensitivity seen with exercise and with
muscle metaboreflex activation may be due to a shift of the
operating point to a lower sensitivity portion of the entire
stimulus response relationship (9, 27). In addition, the autonomic mechanisms mediating these rapid baroreflex changes in
HR and CO are likely confined to the parasympathetic component of baroreflex (22, 23).
The spontaneous baroreflex technique does, however, enable
a qualitative and quantitative estimate of the integrated baroreceptor-cardiac response relationships during the spontaneous
blood pressure fluctuations that characterize both the resting
and exercise conditions, without the necessity of any pharmacological or mechanical interventions. This aspect is particularly relevant in HF conditions, in which, for example, sympathostimulatory reflexes by stretch of cardiac chambers after
phenylephrine-induced increase of afterload or a direct ␤-adrenergic stimulation at the sinus node level by high doses of the
drug superimposed to the already heightened blood pressure of
exercise may affect baroreflex responses.
Conclusions. We found that dynamic exercise decreases
both HR-LVSP and CO-LVSP and the translation of the HR
responses into CO responses. Muscle metaboreflex activation
further decreases HR-LVSP, whereas it has no significant
effect on CO-LVSP and the translation of HR responses into
CO responses in normal animals. After the induction of congestive HF, HR-LVSP, CO-LVSP, and the translation of HR
responses into CO responses decreased significantly at rest,
during dynamic exercise with and without muscle metaboreflex
activation, further supporting the concept that in HF baroreflex-mediated blood pressure regulation relies less on CO
control and is more dependent on peripheral vascular regulation.
ACKNOWLEDGMENTS
We thank Erin Krengel, Sue Harris, Jaime Rodriguez, and Dominic Fano
for expert technical assistance and care of the animals and also Dr. Jong-Kyung
Kim for assistance with the surgeries.
GRANTS
M. Ichinose and T. Ichinose are recipients of research fellowships of the
Japan Society for the Promotion of Science for Young Scientists. This research
was supported by a National Heart, Lung, and Blood Institute Grant HL-55473
and by a Agenzia Spaziale Italiana, Disturbi del Controllo Motorio e Cardiorespiratorio project, Grant ASI I/006/06/0 (to F. Iellamo).
294 • MARCH 2008 •
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Previous studies demonstrated that the muscle metaboreflex
and the arterial baroreflex interact to regulate cardiovascular
responses during exercise (13, 18 –20, 34, 36). A recent study
from our laboratory showed that muscle metaboreflex activation in normal dogs during dynamic exercise resets the arterial
baroreflex to higher blood pressure and HR and reduces HRLVSP (31), which we also observed in the present study. The
mechanism(s) responsible for the decrease in HR-LVSP by
muscle metaboreflex activation during dynamic exercise are
surely complex, as discussed in our previous studies (16, 31).
A likely cause of the decrease in HR-LVSP is the alteration in
the balance of autonomic activity to the heart during muscle
metaboreflex activation, mainly a further enhancement in sympathetic activity (11, 22). In contrast, to the decrease in HRLVSP, muscle metaboreflex activation had no obvious effect
on CO-LVSP and on the translation of HR responses into CO
responses. One likely explanation is that the muscle metaboreflex activation-induced increase in SV via augmented ventricular performance (33) coupled with central blood mobilization
(35) would work to maintain CO-LVSP in the face of a
decreased baroreflex HR response. Therefore, despite the decreased baroreflex chronotropic response, cardiac baroreflexmediated blood pressure regulation would be maintained via an
inotropic response during metaboreflex activation.
Cardiac baroreflex responses during dynamic exercise and
metaboreflex activation in HF. HF is characterized by increased sympathetic activity, depressed vagal tone, and an
attenuated baroreflex control of HR (8, 12). In addition, this
increased sympathetic activity is further augmented during
dynamic exercise (11). In this context, an enhanced muscle
metaboreflex-induced sympathetic activation has been proposed as a key factor in the evolution and worsening of HF (4).
In HF, the ability of the metaboreflex to improve ventricular
function is virtually abolished (5, 32) and the pressor response
occurs via peripheral vasoconstriction. Iellamo et al. (16) have
recently reported that HR-LVSP is significantly depressed at
rest and during dynamic exercise before and after muscle
metaboreflex activation in subjects with HF. In addition, in the
companion article, Sala-Mercado et al. (33a) showed that HF
also decreased CO-LVSP and the ability of baroreflex changes
in HR to cause changes in CO.
In the present study we observed that HF significantly
decreased CO-LVSP and HR-LVSP not only at rest but also
during both mild and moderate exercise before and after
muscle metaboreflex activation. Furthermore, in HF, significantly fewer HR responses caused CO responses in each
setting. This markedly reduced ability of changes in HR to
elicit effective changes in CO was due to the significantly
larger reciprocal changes in SV that occurred during HR-LVSP
sequences (Fig. 4). Indeed, at the highest workload with
metaboreflex activation, over a twofold greater fall in SV
occurred with increases in HR, thereby markedly limiting the
ability of increases in HR to elicit increases in CO. Thus,
whereas in normal subjects it is likely that the increased
ventricular contractility induced by metaboreflex activation
acts to sustain CO-LVSP, the impaired ability to improve
ventricular function in HF likely contributed in an important
manner to the further decrease in CO-LVSP in this setting. In
addition, the marked decrease in the slope of the linear regression between HR-LVSP and CO-LVSP in HF indicates that
even at the same baroreflex HR sensitivity, smaller changes in
H1315
H1316
BAROREFLEX HR-CO OVERLAP: EXERCISE, N, AND HF CONDITIONS
REFERENCES
AJP-Heart Circ Physiol • VOL
294 • MARCH 2008 •
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1. Ansorge EJ, Augustyniak RA, Perinot RL, Hammond RL, Kim JK,
Sala-Mercado JA, Rodriguez J, Rossi NF, O’Leary DS. Altered muscle
metaboreflex control of coronary blood flow and ventricular function in
heart failure. Am J Physiol Heart Circ Physiol 288: H1381–H1388, 2005.
2. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A,
Mancia G. Evaluation of baroreceptor reflex by blood pressure monitoring in unanesthetized cats. Am J Physiol Heart Circ Physiol 254: H377–
H383, 1988.
3. Burger HR, Chandler MP, Rodenbaugh DW, Dicarlo SE. Dynamic
exercise shifts the operating point and reduces the gain of the arterial
baroreflex in rats. Am J Physiol Regul Integr Comp Physiol 275: R2043–
R2048, 1998.
4. Coats AJ, Clark AL, Piepoli M, Volterrani M, Poole-Wilson PA.
Symptoms and quality of life in heart failure: the muscle hypothesis. Br
Heart J 72: S36 –S39, 1994.
5. Crisafulli A, Salis E, Tocco F, Melis F, Milia R, Pittau G, Caria MA,
Solinas R, Meloni L, Pagliaro P, Concu A. Impaired central hemodynamic response and exaggerated vasoconstriction during muscle
metaboreflex activation in heart failure patients. Am J Physiol Heart Circ
Physiol 292: H2988 –H2996, 2007.
6. Crisafulli A, Salis E, Pittau G, Lorrai L, Tocco F, Melis F, Pagliaro P,
Concu A. Modulation of cardiac contractility by muscle metaboreflex
following efforts of different intensities in humans. Am J Physiol Heart
Circ Physiol 291: H3035–H3042, 2006.
7. Dicarlo SE, Bishop VS. Onset of exercise shifts operating point of arterial
baroreflex to higher pressures. Am J Physiol Heart Circ Physiol 262:
H303–H307, 1992.
8. Eckberg DL. Baroreflex inhibition of the human sinus node: importance
of stimulus intensity, duration, and rate of pressure change. J Physiol 269:
561–577, 1977.
9. Eiken O, Convertino VA, Doerr DF, Dudley GA, Morariu G, Mekjavic IB. Characteristics of the carotid baroreflex in man during normal
and flow-restricted exercise. Acta Physiol Scand 144: 325–331, 1992.
10. Hammond RL, Augustyniak RA, Rossi NF, Churchill PC, Lapanowski K, O’Leary DS. Heart failure alters the strength and mechanisms
of the muscle metaboreflex. Am J Physiol Heart Circ Physiol 278:
H818 –H828, 2000.
11. Hammond RL, Augustyniak RA, Rossi NF, Lapanowski K, Dunbar
JC, O’Leary DS. Alteration of humoral and peripheral vascular responses
during graded exercise in heart failure. J Appl Physiol 90: 55– 61, 2001.
12. Higgins CB, Vatner SF, Eckberg D, Braunwald E. Alterations in the
baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 51:
715–724, 1972.
13. Ichinose M, Saito M, Kondo N, Nishiyasu T. Time-dependent modulation of arterial baroreflex control of muscle sympathetic nerve activity
during isometric exercise in humans. Am J Physiol Heart Circ Physiol
290: H1419 –H1426, 2006.
14. Iellamo F. Neural mechanisms of cardiovascular regulation during exercise. Auton Neurosci 90: 66 –75, 2001.
15. Iellamo F, Galante A, Legramante JM, Lippi ME, Condoluci C,
Albertini G, Volterrani M. Altered autonomic cardiac regulation in
individuals with Down syndrome. Am J Physiol Heart Circ Physiol 289:
H2387–H2391, 2005.
16. Iellamo F, Sala-Mercado JA, Ichinose M, Hammond RL, Pallante M,
Ichinose TK, Stephenson LW, O’Leary DS. Spontaneous baroreflex
control of heart rate during exercise and muscle metaboreflex activation in
heart failure. Am J Physiol Heart Circ Physiol 293: H1929 –H1936, 2007.
17. Kim JK, Augustyniak RA, Sala-Mercado JA, Hammond RL, Ansorge
EJ, O’Leary DS. Heart failure alters the strength and mechanisms of
arterial baroreflex pressor responses during dynamic exercise. Am J
Physiol Heart Circ Physiol 287: H1682–H1688, 2004.
18. Kim JK, Sala-Mercado JA, Rodriguez J, Scislo TJ, O’Leary DS. The
arterial baroreflex alters the strength and mechanisms of the muscle
metaboreflex pressor response during dynamic exercise. Am J Physiol
Heart Circ Physiol 288: H1374 –H1380, 2005.
19. McIlveen SA, Hayes SG, Kaufman MP. Both central command and
exercise pressor reflex reset carotid sinus baroreflex. Am J Physiol Heart
Circ Physiol 280: H1454 –H1463, 2001.
20. Nishiyasu T, Tan N, Morimoto K, Nishiyasu M, Yamaguchi Y,
Murakami N. Enhancement of parasympathetic cardiac activity during
activation of muscle metaboreflex in humans. J Appl Physiol 77: 2778 –
2783, 1994.
21. Nobrega ACL, Williamson JW, Garcia JA, Mitchell JH. Mechanisms
for increasing stroke volume during static exercise with fixed heart rate in
humans. J Appl Physiol 83: 712–717, 1997.
22. O’Leary DS. Autonomic mechanisms of muscle metaboreflex control of
heart rate. J Appl Physiol 74: 1748 –1754, 1993.
23. Ogoh S, Fisher JP, Dawson EA, White MJ, Secher NH, Raven PB.
Autonomic nervous system influence on arterial baroreflex control of heart
rate during exercise in humans. J Physiol 566: 599 – 611, 2005.
24. Olivier NB, Stephenson RB. Characterization of baroreflex impairment
in conscious dogs with pacing-induced heart failure. Am J Physiol Regul
Integr Comp Physiol 265: R1132–R1140, 1993.
25. Patel HJ, Pilla JJ, Polidori DJ, Pusca SV, Plappert TA, Sutton MS,
Lankford EB, Acker MA. Ten weeks of rapid ventricular pacing creates
a long-term model of left ventricular dysfunction. J Thorac Cardiovasc
Surg 119: 834 – 841, 2000.
26. Potts JT, Shi XR, Raven PB. Carotid baroreflex responsiveness during
dynamic exercise in humans. Am J Physiol Heart Circ Physiol 265:
H1928 –H1938, 1993.
27. Raven PB, Fadel PJ, Ogoh S. Arterial baroreflex resetting during exercise: a current perspective. Exp Physiol 91: 37– 49, 2006.
28. Rowell LB, O’Leary DS, Kellogg DL Jr. Integration of Cardiovascular
Control Systems in Dynamic Exercise. New York: Oxford Press, 1996, p.
770 – 838.
29. Ryan S, Ward S, Heneghan C, McNicholas WT. Predictors of decreased
spontaneous baroreflex sensitivity in obstructive sleep apnea syndrome.
Chest 131: 1100 –1107, 2007.
30. Sagawa K. Baroreflex control of systemic arterial pressure and vascular
bed. In: Handbook of Physiology. The Cardiovascular System. Peripheral
Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc.,
1983, sect. 2, vol. III, pt. 2, chapt. 14, p. 453– 496.
31. Sala-Mercado JA, Ichinose M, Hammond RL, Ichinose TK, Pallante
M, Stephenson LW, O’Leary DS, Iellamo F. Muscle metaboreflex
attenuates spontaneous heart rate baroreflex sensitivity during dynamic
exercise. Am J Physiol Heart Circ Physiol 292: H2867–H2873, 2007.
32. Sala-Mercado JA, Hammond RL, Kim JK, McDonald PJ, Stephenson
LW, O’Leary DS. Heart failure attenuates muscle metaboreflex control of
ventricular contractility during dynamic exercise. Am J Physiol Heart Circ
Physiol 292: H2159 –H2166, 2007.
33. Sala-Mercado JA, Hammond RL, Kim JK, Rossi NF, Stephenson LW,
O’Leary DS. Muscle metaboreflex control of ventricular contractility
during dynamic exercise. Am J Physiol Heart Circ Physiol 290: H751–
H757, 2006.
33a.Sala-Mercado JA, Ichinose M, Hammond RL, Coustos M, Ichinose T,
Pallante M, Iellamo F, O’Leary DS. Spontaneous baroreflex control of
heart rate versus cardiac output: altered coupling in heart failure. Am J
Physiol Heart Circ Physiol (January 11, 2008); doi:10.1152/ajpheart.
01186.2007.
34. Scherrer U, Pryor SL, Bertocci LA, Victor RG. Arterial baroreflex
buffering of sympathetic activation during exercise-induced elevations in
arterial pressure. J Clin Invest 86: 1855–1861, 1990.
35. Sheriff DD, Augustyniak RA, O’Leary DS. Muscle chemoreflex-induced increases in right atrial pressure. Am J Physiol Heart Circ Physiol
275: H767–H775, 1998.
36. Sheriff DD, O’Leary DS, Scher AM, Rowell LB. Baroreflex attenuates
pressor response to graded muscle ischemia in exercising dogs. Am J
Physiol Heart Circ Physiol 258: H305–H310, 1990.
37. Wyss CR, Ardell JL, Scher AM, Rowell LB. Cardiovascular responses
to graded reductions in hindlimb perfusion in exercising dogs. Am J
Physiol Heart Circ Physiol 245: H481–H486, 1983.