Download Carlos E. Negrão Maria Urbana PB Rondon, Antonio CP

Andrea Di Vanna, Ana Maria F. W. Braga, Mateus C. Laterza, Linda M. Ueno,
Maria Urbana P. B. Rondon, Antonio C. P. Barretto, Holly R. Middlekauff and
Carlos E. Negrão
Am J Physiol Heart Circ Physiol 293:846-852, 2007. First published Apr 13, 2007;
doi:10.1152/ajpheart.00156.2007
You might find this additional information useful...
This article cites 29 articles, 15 of which you can access free at:
http://ajpheart.physiology.org/cgi/content/full/293/1/H846#BIBL
Updated information and services including high-resolution figures, can be found at:
http://ajpheart.physiology.org/cgi/content/full/293/1/H846
Additional material and information about AJP - Heart and Circulatory Physiology can be found at:
http://www.the-aps.org/publications/ajpheart
This information is current as of August 6, 2007 .
Downloaded from ajpheart.physiology.org on August 6, 2007
AJP - Heart and Circulatory Physiology publishes original investigations on the physiology of the heart, blood vessels, and
lymphatics, including experimental and theoretical studies of cardiovascular function at all levels of organization ranging from the
intact animal to the cellular, subcellular, and molecular levels. It is published 12 times a year (monthly) by the American
Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2005 by the American Physiological Society.
ISSN: 0363-6135, ESSN: 1522-1539. Visit our website at http://www.the-aps.org/.
Am J Physiol Heart Circ Physiol 293: H846–H852, 2007.
First published April 13, 2007; doi:10.1152/ajpheart.00156.2007.
Blunted muscle vasodilatation during chemoreceptor stimulation in patients
with heart failure
Andrea Di Vanna,1 Ana Maria F. W. Braga,1 Mateus C. Laterza,1 Linda M. Ueno,1
Maria Urbana P. B. Rondon,1 Antonio C. P. Barretto,1 Holly R. Middlekauff,3 and Carlos E. Negrão1,2
1
Heart Institute (InCor), University of São Paulo Medical School, and 2School of Physical Education and Sport, University of
São Paulo, São Paulo, Brazil; and 3Department of Cardiology, University of California Los Angeles, Los Angeles, California
Submitted 7 February 2007; accepted in final form 11 April 2007
chemoreflex sensitivity; sympathetic nerve activity; forearm blood
flow
CHEMORECEPTORS ARE IMPORTANT modulators of hemodynamics
and ventilation. Central chemoreceptors, located in the brain
stem, respond primarily to hypercapnia, while peripheral chemoreceptors, located on the carotid bodies, respond primarily
to hypoxia. In healthy individuals, chemoreceptor activation
increases ventilation, sympathetic nerve activity, blood pressure, and heart rate (10). In humans with chronic heart failure,
the chemoreflex control can be profoundly altered. Central
chemoreceptor stimulation in patients with heart failure has
been shown to produce exaggerated increases in ventilation
Address for reprint requests and other correspondence: C. E. Negrão, Instituto
do Coração (InCor), Unidade de Reabilitação Cardiovascular e Fisiologia do
Exercı́cio, Av. Dr. Enéas de Carvalho Aguiar, 44 Cerqueira César, São Paulo SP,
CEP 05403-000 Brazil (e-mail: [email protected]).
H846
and muscle sympathetic nerve activity (MSNA) (11). Peripheral chemoreceptor activation may also cause exaggerated
increases in ventilation and sympathetic activity in heart failure, although this is controversial. Heterogeneity of the heart
failure study populations, including severity and etiology of
heart failure, may explain the variation in findings during
peripheral chemoreceptor stimulation (3, 4, 16). In a rabbit
model of heart failure, peripheral chemoreflex control of renal
sympathetic nerve activity was found to be exaggerated (20,
23). However, the hemodynamic implications of the augmented sympathetic nerve activity during peripheral and central chemoreceptor stimulation in heart failure have not been
studied.
In healthy individuals, local metabolic changes, including
reduction in oxygen partial pressure levels elicited by skeletal
muscle contraction, modulate the postsynaptic ␣-adrenergic
receptor vasoconstrictor responses (1). These physiological
responses, described as functional sympatholysis, attenuate
sympathetic vasoconstriction to facilitate vascular blood flow
and, in consequence, improve oxygen delivery to skeletal
muscles during exercise. On the other hand, a recent study
provides evidence that the reflex sympathetic vasoconstrictor
responsiveness to systemic hypoxia is not completely abolished. Forearm vasodilatation responses during hypoxia were
significantly increased after local ␣-adrenergic receptor blockade (29).
In humans with heart failure, despite the early muscle
metabolic acidosis and lowered oxygen partial pressure, muscle vasodilatory responses to exercise are blunted (14). The
explanation for this vascular dysfunction is a complex issue
and seems to involve several mechanisms. However, results of
a recent study strongly suggest that the exaggerated muscle
sympathetic outflow during physiological maneuvers is a major
contributor to this attenuated vasodilatation. We found that
MSNA restrained the endothelial-mediated muscle vasodilatation during mental challenge in humans with heart failure.
Intra-arterial brachial acetylcholine caused no change in forearm blood flow in heart failure patients (19). In contrast, acetylcholine associated with ␣-adrenergic blockade with phentolamine
significantly improved muscle vasodilatory responses during
mental stress in heart failure patients (19). These findings naturally support the notion that augmented sympathetic outflow may
be implicated in other hemodynamic alterations during physiological maneuvers in humans with heart failure. In the present
study, we report the muscle blood flow responses during hypoxia
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.
0363-6135/07 $8.00 Copyright © 2007 the American Physiological Society
http://www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
Di Vanna A, Braga AM, Laterza MC, Ueno LM, Rondon MU,
Barretto AC, Middlekauff HR, Negrão CE. Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart
failure. Am J Physiol Heart Circ Physiol 293: H846–H852, 2007. First
published April 13, 2007; doi:10.1152/ajpheart.00156.2007.—Chemoreflex control of sympathetic nerve activity is exaggerated in heart
failure (HF) patients. However, the vascular implications of the
augmented sympathetic activity during chemoreceptor activation in
patients with HF are unknown. We tested the hypothesis that the
muscle blood flow responses during peripheral and central chemoreflex stimulation would be blunted in patients with HF. Sixteen patients
with HF (49 ⫾ 3 years old, Functional Class II-III, New York Heart
Association) and 11 age-paired normal controls were studied. The
peripheral chemoreflex control was evaluated by inhalation of 10% O2
and 90% N2 for 3 min. The central chemoreflex control was evaluated
by inhalation of 7% CO2 and 93% O2 for 3 min. Muscle sympathetic
nerve activity (MSNA) was directly evaluated by microneurography. Forearm blood flow was evaluated by venous occlusion
plethysmography. Baseline MSNA were significantly greater in HF
patients (33 ⫾ 3 vs. 20 ⫾ 2 bursts/min, P ⫽ 0.001). Forearm
vascular conductance (FVC) was not different between the groups.
During hypoxia, the increase in MSNA was significantly greater in
HF patients than in normal controls (9.0 ⫾ 1.6 vs. 0.8 ⫾ 2.0
bursts/min, P ⫽ 0.001). The increase in FVC was significantly
lower in HF patients (0.00 ⫾ 0.10 vs. 0.76 ⫾ 0.25 units, P ⫽
0.001). During hypercapnia, MSNA responses were significantly
greater in HF patients than in normal controls (13.9 ⫾ 3.2 vs. 2.1 ⫾
1.9 bursts/min, P ⫽ 0.001). FVC responses were significantly
lower in HF patients (⫺0.29 ⫾ 0.10 vs. 0.37 ⫾ 0.18 units, P ⫽
0.001). In conclusion, muscle vasodilatation during peripheral and
central chemoreceptor stimulation is blunted in HF patients. This
vascular response seems to be explained, at least in part, by the
exaggerated MSNA responses during hypoxia and hypercapnia.
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
and hypercapnia and its relationship with the sympathetic nerve
activity in patients with chronic heart failure. The purpose of these
studies was to investigate the central and peripheral chemoreceptor control of MSNA and forearm blood flow in a group of
advanced heart failure patients with nonischemic cardiomyopathy.
Specifically, we tested the hypothesis that central and peripheral
chemoreflex control of MSNA would be exaggerated in this
population of advanced heart failure patients and would be accompanied by blunted forearm vasodilatation.
METHODS
Population
Procedures and Measures
MSNA. MSNA was directly measured through a multiunit recording
of the postganglionic efferent nerve from the nervous muscle fascicle, on
the posterior side of the peroneal nerve, immediately inferior to the fibular
head (18). This technique has been validated and employed in laboratory
studies in humans. The recordings were obtained from the peroneal
nerve, impaled by a recording microelectrode, which was grounded by a
reference microelectrode, placed 1–2 cm from it. The electrodes were
connected to a preamplifier, and the nerve signal was fed through a
passband filter and, after that, led to an amplitude discriminator to be
stored in an oscilloscope. For recording and analysis, the filtered
neurogram was fed through a resistance-capacitance integrator to
obtain the mean voltage of neural activity. The MSNA was evaluated
through the capture of its signal in a computer through an AT/CODAS
program, at a 1,000-Hz frequency. The nerve signal was evaluated by
counting bursts per minute.
Forearm blood flow. Forearm blood flow was measured by the
noninvasive technique of venous occlusion plethysmography (13).
The resting nondominant arm was elevated above the right atrium to
ensure adequate venous drainage. A mercury-filled Silastic tube attached to a low-pressure transducer was placed around the forearm, 5
cm distant from the humero-radial joint, and connected to a plethysmography device (Hokanson 201 AG). Sphygmomanometer cuffs
were placed around the wrist and the upper arm. One minute before
the measurements were taken, the wrist cuff was inflated at a level
above the systolic blood pressure level. At 15-s intervals, the upper
cuff was inflated above venous pressure for 7– 8 s. The increase in the
tension in the Silastic tube reflects the increase in the forearm volume
and, consequently, the vasodilation. The wave signal of the muscle
flow was captured in a computer through an AT/CODAS program, at
a 1,000-Hz frequency. Forearm vascular conductance was calculated
by dividing forearm blood flow (ml 䡠 min⫺1 䡠 100 ml⫺1) by mean
arterial pressure (mmHg), expressed in units.
Evaluation of peripheral and central chemoreceptors. Peripheral
chemoreflex control was evaluated through the inhaling of a hypoxic
gas mixture (10% O2 and 90% N2), for a 3-min period, as described
by others (21, 22). In the stimulation of peripheral chemoreceptors
during hypoxia, the influence of central chemoreceptors was miniAJP-Heart Circ Physiol • VOL
mized by the maintenance of isocapnia, with titrated carbon dioxide.
Central chemoreflex control was evaluated through the inhaling of a
hypercapnic gas mixture (7% CO2 and 93% O2) for a 3-min period. In
the stimulation of central chemoreceptors by hypercapnia, the influence of peripheral chemoreceptors was minimized by hyperoxia. The
sequence of interventions to evaluate peripheral and central chemoreceptors was randomized.
Functional capacity. Maximal exercise capacity was determined by
means of a maximal progressive exercise test on an electromagnetically braked cycle ergometer (Medifit 400L, Medical Fitness Equipment, Maarn, Netherlands), with work rate increments of 7.5–15
W/min at 60 rpm until exhaustion. Oxygen uptake (V̇O2) and carbon
dioxide production were determined by means of gas exchange on a
breath-by-breath basis in a computerized system (CAD/Net 2001,
Medical Graphics, St. Paul, MN). Peak V̇O2 was defined as the
maximum attained V̇O2 at the end of the exercise period in which the
subject could no longer maintain the cycle ergometer velocity at 60 rpm.
Other measurements. Blood pressure was continuously and noninvasively measured, on a per-minute basis. A cuff of adequate size was
placed around the left leg, which was kept at the level of the left
ventricle. This cuff was connected to an arterial pressure monitor
(Dixtal 2010, Manaus, Brazil), which measured systolic, diastolic, and
mean blood pressure at every minute. The heart rate was measured
through the electrocardiographic recording. The oxygen saturation
was monitored through a pulse oximeter (DX 2405, OXYPLETH,
Super Bright, Manaus, Brazil), and the carbon dioxide was monitored
with a capnograph (Dixtal, DX 1265 ETCO2 CAPNOGARD, Manaus, Brazil). The minute ventilation was monitored by pneumotacograph (Hans Rudolph, Kansas City, MO) and a differential pressure
transducer linked to a signal integrator.
Experimental Protocol
Protocol 1. The purpose of this protocol was to study the impact of
peripheral chemoreflex in MSNA, heart rate, mean blood pressure,
forearm blood flow, forearm vascular conductance, and pulmonary
ventilation in patients with heart failure. After at least 2 h of a light
meal without caffeine, each individual had his or her leg positioned
for microneurography, and a microelectrode was placed in the peroneal nerve. Electrodes were then placed to monitor electrocardiogram,
cuffs were placed to monitor forearm blood flow, and mouth piece and
nasal clip were placed to allow inhaling of gases. MSNA, heart rate,
mean blood pressure, forearm blood flow, forearm vascular conductance, and pulmonary ventilation were recorded for 3 min, followed by
3 min of recording during inhalation of a gas mixture of 10% oxygen.
Blood pressure, MSNA, and heart rate were continuously measured.
Regarding forearm blood flow, measures were taken at 15-s intervals.
Protocol 2. The purpose of this protocol was to study the impact of
central chemoreflex in MSNA, heart rate, mean blood pressure,
forearm blood flow, forearm vascular conductance, and pulmonary
ventilation in patients with heart failure. MSNA, heart rate, mean
blood pressure, forearm blood flow, forearm vascular conductance,
and pulmonary ventilation were recorded for 3 min, followed by 3 min
of recording during inhalation of hypercapnic gas mixture. Mean
blood pressure, MSNA, and heart rate were continuously monitored.
Regarding forearm blood flow, measures were taken at 15-s intervals.
Statistical Analysis
The data are presented as means ⫾ SE. The similarity in physical
characteristics between the groups was tested by use of an unpaired
T-test. The responses of heart rate, mean blood pressure, forearm
blood flow, forearm vascular conductance, pulmonary ventilation, O2
saturation, end-tidal CO2, and MSNA were analyzed by two-way
ANOVA with repeated measures. When significance was observed,
post hoc Scheffé’s comparison was used to test the difference between
conditions. Probability values of P ⬍ 0.05 were considered statistically significant.
293 • JULY 2007 •
www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
After free and informed consent, 16 patients with advanced heart
failure, Functional Class II-III, New York Heart Association, with
ejection fraction ⬍40%, and age range of 35–70 yr old were studied.
Exclusion criteria were as follows: 1) myocardial infarction within 3
mo, 2) unstable angina, 3) in use of antiarrhythmic drugs, 4) pacemaker, 5) absolute contraindication to discontinue use of vasodilator
diuretic drugs, and/or cardiovascular medications in the 24 h preceding the study, 6) peripheral neuropathy, 7) diabetes mellitus,
8) obesity (or body mass index ⬎27), and 9) dislipidemia. Eleven
age-paired normal-control individuals were also studied. The study
was approved by the Scientific and Ethical Commission of the Heart
Institute (InCor), and by the Ethics in Research Commission of the
Clinical Hospital of the Medicine University of São Paulo.
H847
H848
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
RESULTS
Table 2. Baseline measures
Basal Measurements
NC
HF
P
33⫾3
0.001
66⫾3
98⫾2
1.85⫾0.10
1.92⫾0.11
0.95
0.12
0.42
0.31
10.3⫾0.8
38⫾1
97.0⫾0.3
0.04
0.42
0.18
Physical characteristics in normal control individuals and
heart failure patients are shown in Table 1. Age, weight, height,
and body mass index were not different between normal
control individuals and heart failure patients. Peak V̇O2 was
significantly lower in heart failure patients compared with
normal control individuals.
Baseline measures of MSNA, heart rate, mean blood pressure, forearm blood flow, forearm vascular conductance,
minute ventilation, end-tidal CO2, and O2 saturation are shown
in Table 2. Baseline measures of heart rate, mean blood
pressure, forearm blood flow, forearm vascular conductance,
end-tidal CO2, and O2 saturation were not significantly different between groups. MSNA and minute ventilation were significantly higher in patients with heart failure.
Neural measure
20⫾2
Hemodynamic measures
HR, beats/min
66⫾3
MBP mmHg
93⫾2
FBF, ml 䡠 min⫺1 䡠 100 ml⫺1
2.03⫾0.23
FVC, units
2.16⫾0.22
Respiratory measures
Minute ventilation, l/min
7.5⫾1.0
End-tidal CO2, mmHg
39⫾1
O2 saturation, %
97.6⫾0.3
Hypoxia
patients with heart failure (interaction, P ⫽ 0.0002). Similarly, forearm vascular conductance responses were significantly lower in heart failure patients compared with normal
control individuals (interaction, P ⫽ 0.001; Fig. 2, B and D).
Values are means ⫾ SE. MSNA, muscle sympathetic nervous activity; HR,
heart rate; MBP, mean blood pressure; FBF, forearm blood flow; FVC, forearm
vascular conductance.
Hypercapnia
The responses of heart rate, mean blood pressure, minute
ventilation, end-tidal CO2, and O2 saturation during hypercapnia
are shown in Table 3. Mean blood pressure and minute ventilation
to hypercapnia increased similarly and significantly in normal
control individuals and heart failure patients. Heart rate increased
significantly in heart failure patients. In normal controls, heart rate
Table 3. Hemodynamic and respiratory responses to hypoxia
and hypercapnia in normal control individuals and heart
failure patients
Baseline
HR, beats/min
MBP, mmHg
Table 1. Physical characteristics
V̇E, l/min
Gender (M/F)
Age, yr
Weight, kg
Height, m
BMI, kg/m2
Peak V̇O2, ml 䡠 kg⫺1 䡠 min⫺1
LVEF
HF etiology
Idiopathic dilated
Cardiomyopathy
Medications
␤-blocker
ACEI
Digitalic
Diuretic
Antiarrhythmic
Calcium blockers
NC
HF
P
5/6
46⫾3
68⫾3
1.67⫾0.03
24⫾1
28⫾2
11/5
49⫾3
68⫾3
1.63⫾0.02
25⫾1
19⫾2
0.30⫾0.01
0.21
0.42
0.89
0.27
0.38
0.003
16
16
16
15
16
5
4
Values are means ⫾ SE. NC, normal control; HF, heart failure; M, male;
F, female; BMI, body mass index; peak V̇O2, peak oxygen uptake; LVEF, left
ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitors.
AJP-Heart Circ Physiol • VOL
End-tidal CO2,
mmHg
1⬘
Hypoxia
NC
66⫾3
4⫾1†
HF
66⫾3
5⫾2†
NC
93⫾2
3⫾2
HF
98⫾2
0⫾2
NC 7.5⫾1.0
1.8⫾0.6†
HF 10.3⫾0.8
1.3⫾0.4†
NC
39⫾1
⫺2.0⫾0.8
2⬘
3⬘
9⫾1†
10⫾1†
5⫾2†
2⫾2†
3.7⫾0.7†
4.5⫾0.7†
⫺1.5⫾0.9
12⫾2†
11⫾2†
5⫾1
1⫾2
4.7⫾1.0†
6.0⫾1.0†
⫺1.3⫾1.1
HF
38⫾1
0.1⫾0.6
⫺0.3⫾0.6
0.3⫾0.7
O2 saturation, % NC 97.6⫾0.3 ⫺1.8⫾0.8
⫺9.4⫾1.0† ⫺13.1⫾0.7†
HF 97.0⫾0.3 ⫺1.5⫾0.5 ⫺10.1⫾0.8† ⫺13.0⫾0.9†
Hypercapnia
HR, beats/min
NC
66⫾3
1⫾1
2⫾2
3⫾2
HF
66⫾3
4⫾1
7⫾2†
9⫾2†*
MBP, mmHg
NC
93⫾2
6⫾1†
8⫾2†
9⫾3†
HF
98⫾2
3⫾2†
7⫾2†
7⫾3†
NC 7.5⫾1.0
5.0⫾1.9
8.7⫾1.8†
15.2⫾3.7†
V̇E, l/min
HF 10.3⫾0.8
2.1⫾0.8
7.1⫾2.0†
9.4⫾2.2†
End-tidal CO2,
NC
39⫾1
14⫾3†
14⫾2†
17⫾2†
mmHg
HF
38⫾1
14⫾1†
14⫾1†
15⫾1†
O2 saturation, % NC 97.6⫾0.3
1.2⫾0.2†
1.7⫾0.3†
1.9⫾0.2†
HF 97.0⫾0.3
1.2⫾0.2†
2.1⫾0.4†
2.0⫾0.4†
Values are mean ⫾ SE. V̇E, minute ventilation. *Significant difference
between groups, P ⬍ 0.05. †Significant difference vs. baseline, P ⬍ 0.05.
293 • JULY 2007 •
www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
The responses of heart rate, mean blood pressure, minute
ventilation, end-tidal CO2, and O2 saturation during hypoxia are
shown in Table 3. Heart rate, mean blood pressure, and minute
ventilation during hypoxia increased similarly and significantly in
normal control individuals and heart failure patients. End-tidal
CO2 during hypoxia did not significantly change in normal control
individuals and heart failure patients. As expected, O2 saturation
was significantly and similarly reduced during hypoxia in both
normal controls and heart failure patients. MSNA increased significantly in heart failure patients, but not in normal controls
(Fig. 1, A and B). Thus the comparisons between groups showed
that the responses in MSNA were significantly greater in patients
with heart failure than in normal control individuals (interaction,
P ⫽ 0.001). Forearm blood flow during hypoxia increased progressively and significantly in normal control individuals
(Fig. 2, A and C). In contrast, forearm blood flow did not
significantly change in response to hypoxia in heart failure
patients (Fig. 2, A and C). The comparisons between groups
showed that the responses in forearm blood flow were
significantly greater in normal control individuals than in
MSNA, bursts/min
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
H849
Fig. 1. Muscle sympathetic nerve activity
(MSNA) responses during hypoxia (A and B)
and hypercapnia (C and D) in heart failure
patients and normal controls. Note that the
MSNA responses are augmented in heart failure patients. PETCO2, end-tidal PCO2. *Significant difference between groups, P ⬍ 0.05.
hypercapnia in heart failure patients. Thus the comparisons between groups showed that the responses of forearm blood flow to
hypercapnia were significantly lower in heart failure patients
(interaction, P ⫽ 0.001). Similarly, forearm vascular conductance
responses during hypercapnia were significantly lower in heart
failure patients compared with normal control individuals (interaction, Fig. 3, B and D, P ⫽ 0.001).
DISCUSSION
The new finding of the present study is that, in contrast to
individuals with normal ventricular function, patients with
chronic left ventricular dysfunction have no increase in forearm blood flow during hypoxia and hypercapnia. This unexpected response seems to be linked to the exaggerated sympathetic outflow. MSNA significantly increased during hypoxia
Fig. 2. Forearm blood flow (FBF; A and C)
and forearm vascular conductance (FVC; B and
D) responses during hypoxia in heart failure
patients and normal controls. Note that FBF
and FVC responses are blunted in heart failure
patients. *Significant difference between groups,
P ⬍ 0.05.
AJP-Heart Circ Physiol • VOL
293 • JULY 2007 •
www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
increased slightly. The comparisons between groups showed that
heart rate response was significantly greater in the heart failure
patients at the 3rd min of hypercapnia. End-tidal CO2 increased
similar and significantly in normal control individuals and heart
failure patients. O2 saturation increased significant and similarly
during hypercapnia in normal control individuals and heart failure
patients. MSNA increased progressive and significantly in heart
failure patients, but not in normal controls (Fig. 1, C and D). The
comparisons between groups showed that the responses in MSNA
were significantly greater in patients with heart failure than in
normal controls (interaction, P ⫽ 0.001). Forearm blood flow
increased progressive and significantly in responses to hypercapnia in normal control individuals (Fig. 3, A and C). In contrast,
forearm blood flow did not significantly change during hypercapnia in heart failure patients (Fig. 3, A and C). In fact, forearm
blood flow slightly decreased throughout the 2nd and 3rd min of
H850
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
Fig. 3. FBF (A and C) and FVC (B and D)
responses during hypercapnia in heart failure
patients and normal controls. Note that FBF
and FVC responses are blunted in heart failure patients. *Significant difference between
groups, P ⬍ 0.05.
AJP-Heart Circ Physiol • VOL
novirus expressing NO synthase reduces baseline renal sympathetic nerve activity and the response to hypoxia from the
carotid body chemoreceptors in heart failure rabbits.
In the normal controls, hypoxia caused only a slight increase
in MSNA. This response seems to be below those reported by
others. Somers and colleagues, in two different reports, found
an ⬃20% increase in MSNA during hypoxia in healthy humans
(21, 22). There is no clear explanation for our lower response
in humans in our study. However, a recent study reported that
chemoreflex control of MSNA is directly related to spontaneous respiratory rate (12). Slower respiratory rate was associated with lower levels of MSNA and potentiation of the
chemoreflex response to hypoxia and hypercapnia. This seems
to be the case in our study, since the respiratory rate in normal
controls was between the first tertile and the second tertile described by Narkiewicz and colleagues (13 ⫾ 1 breaths/min) (12).
We found no alteration in minute ventilation responses to
acute hypercapnia in patients with heart failure. These findings
are not consistent with the previous reports in which minute
ventilation responses during central chemoreceptor stimulation
were augmented in heart failure patients (11). One possible
explanation is that our patients were leaner than those in
Narkiewicz’s study (11). Obesity plus left ventricular dysfunction may exert additive effects on central chemoreflex control.
Etiology, duration, severity, and treatment of heart failure may
also be involved in these inconsistent results. All of our patients
had idiopathic dilated cardiomyopathy and were under carvedilol
treatment. They studied idiopathic dilated cardiomyopathy and
valvular heart disease alcohol-related cardiomyopathy. In addition, in their study, only two patients were under ␤-blocker
treatment. In a recent study, carvedilol improved ventilatory
responses during exercise in patients with heart failure (7).
Limitations
We recognize many limitations in our study. It has been
proposed that chemoreflex dysfunction and exaggerated sympathetic activity are linked to central sleep apnea in patients
with heart failure (25). Although none of our patients had been
293 • JULY 2007 •
www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
and hypercapnia in heart failure patients, but not in normal
controls in whom MSNA increased only slightly. We have
previously reported other conditions during which exaggerated
sympathetic outflow in heart failure overwhelms vasodilatory
stimuli. For example, during mental stress in heart failure
patients (19), we found that blockade of postsynaptic ␣-adrenergic receptors with phentolamine increased forearm blood.
Additionally, phentolamine associated with acetylcholine significantly improved forearm blood flow responses during mental challenge in the heart failure patients. Thus it is reasonable
to suggest that, during hypoxia and hypercapnia in humans
with chronic heart failure, the exaggerated sympathetic outflow
overrides the skeletal muscle vasodilatory forces. However, we
cannot rule out the possibility that the blunted muscle vasodilatation to hypoxia and hypercapnia in heart failure patients is
due to intrinsic endothelial dysfunction. Hirooka and colleagues (6) found that, when they administered acetylcholine into
the brachial arterial at rest and during reactive hyperemia in heart
failure patients, forearm blood flow did not increase, consistent
with endothelial dysfunction in heart failure. Our study confirms
previous findings that demonstrated augmented central and peripheral chemoreflex control of sympathetic nerve activity in a
group of advanced heart failure patients with nonischemic cardiomyopathy (11, 26). These responses are consistent with the idea
that the peripheral and central chemoreflex-mediated sympathoexcitation overrides the inspiratory inhibition of sympathetic
nerve activity in chronic heart failure patients.
There are at least two lines of thinking to explain the
exacerbated neural sympathetic response during peripheral and
central chemoreceptor stimulation in heart failure. Nitric oxide
(NO) synthase activity is reduced in the carotid body chemoreceptors, which results in lowered NO production and, in
consequence, disinhibition of carotid body chemoreceptor activity (17, 24). Central angiotensin II is augmented, whereas
central NO production is decreased in heart failure. Previous
investigations provide evidences for the important role of the
angiotensin II and NO in modulating both inhibitory and
excitatory reflexes (9, 27, 28). Also, more recently, Li et al. (8),
in an elegant study, demonstrated that application of an ade-
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
Perspectives
The abnormal forearm blood flow during hypoxia and hypercapnia and its association with the exaggerated MSNA
discharge demonstrate that sympathetic nerve activity plays a
role in the vasoconstrictor status during peripheral and central
chemoreceptor stimulation in humans with heart failure. Moreover, sympathetic nerve activity should be the major target to
improve muscle blood flow in heart failure patients. So far,
there are two strategies that have been shown to reduce
sympathoexcitation in heart failure: 1) the pharmacological
therapy with angiotensin II blockade, ␤-blockers, and, more
recently, statins (2, 5, 15); and 2) the nonpharmacological
therapy based on regular exercise that dramatically reduces
central-mediated sympathetic activation in patients with heart
failure, which seems to explain, at least in part, the increase in
muscle blood flow and functional capacity in these patients
(18). In conclusion, muscle vasodilatation during central and
peripheral chemoreceptor stimulation is blunted in heart failure
patients. This response is associated with the exaggerated
sympathetic outflow during this stimulation.
GRANTS
This study was supported by Fundação de Amparo à Pesquisa do Estado de
São Paulo, São Paulo (FAPESP no. 2000/04915-3 and no. 2005/59740-7), and
in part by Fundação Zerbini, São Paulo. C. E. Negrão (CNPq no. 304304/
2004-2) and M. U. P. B. Rondon (CNPq no. 305159/2005-4) were supported
by Conselho Nacional de Pesquisa (CNPq). A. Di Vanna was supported by
Programa Institucional de Bolsas de Iniciação Cientı́fica (PIBIC/CNPq, 2004 –
2005). L. M. Ueno was supported by FAPESP (no. 03/10881-2), and M. C.
Laterza was supported by Coordenação de Aperfeiçoamento de Pessoal de
Nı́vel Superior.
REFERENCES
1. Andersen KM, Faber JE. Differential sensitivity of arteriolar alpha
1- and alpha 2-adrenoceptor constriction to metabolic inhibition during rat
skeletal muscle contraction. Circ Res 69: 178 –184, 1991.
2. Azevedo LF, Brum PC, Mattos KC, Junqueira CM, Rondon MU,
Barretto AC, Negrao CE. Effects of losartan combined with exercise
training in spontaneously hypertensive rats. Braz J Med Biol Res 36:
1595–1603, 2003.
3. Chua TP, Clark AL, Amadi AA, Coats AJS. Relation between chemorsensitivity and the ventilatory response to exercise in chronic heart
failure. J Am Coll Cardiol 27: 650 – 657, 1996.
AJP-Heart Circ Physiol • VOL
4. Chua TP, Ponikowski P, Webb-Peploe K, Harrington D, Anker S,
Piepoli M, Coats AJS. Clinical characteristics of patients with an augmented peripheral chemoreflex in chronic heart failure. Eur Heart J 18:
480 – 487, 1997.
5. De Mattos LD, Gardenghi G, Rondon MU, Soufen HN, Tirone AP,
Barretto AC, Brum PC, Middelekauff HR, Negrao CE. Impact of 6
months of therapy with caverdilol in muscle sympathetic nerve activity in
heart failure patients. J Card Fail 10: 496 –502, 2004.
6. Hirooka Y, Imaizumi T, Tagawa T, Shiramoto M, Endo T, Ando S,
Takeshita A. Effects of L-arginine on impaired acetylcholine-induced and
ischemic vasodilation of the forearm in patients with heart failure. Circulation 90: 658 – 668, 1994.
7. Javaheri S. A mechanism of central sleep apnea in patients with heart
failure patients. N Engl J Med 341: 949 –954, 1999.
8. Li YL, Li YF, Liu D, Cornish KG, Patel KP, Zucker IH, Channon
KM, Schultz HD. Gene transfer of neuronal nitric oxide synthase to
carotid body reverses enhanced chemoreceptor function in heart failure
rabbits. Circulation 97: 260 –267, 2005.
9. Liu JL, Zucker IH. Regulation of sympathetic nerve activity in heart
failure-a role for nitric oxide and angiotensin II. Circ Res 84: 417– 423, 1999.
10. Marshall JM. Peripheral chemorecptors and cardiovascular regulation.
Physiol Rev 74: 543–594, 1994.
11. Narkiewicz K, Pesek CA, Van de Borne PJH, Kato M, Somers VK.
Enhanced sympathetic and ventilatory responses to central chemoreflex
activation in heart failure. Circulation 100: 262–267, 1999.
12. Narkiewicz K, Van de Borne PJH, Montano N, Hering D, Kara T,
Somers VK. Sympathetic neural outflow and chemoreflex sensitivity are
related to spontaneous breathing rate in normal men. Hypertension 47:
51–55, 2006.
13. Negrao CE, Hamilton MA, Foranow CG, Hage A, Moriguchi JD,
Middlekauff HR. Impaired endothelium-mediated vasodilation is not the
principal cause of vasoconstriction in hear failure. Am J Physiol Heart
Circ Physiol 278: H168 –H174, 2000.
14. Negrao CE, Rondon MU, Tinucci T, Alves MJ, Roveda F, Braga AM,
Reis SF, Nastari L, Barretto AC, Krieger EM, Middlekauff HR.
Abnormal neurovascular control during exercise is linked to heart failure
severity. Am J Physiol Heart Circ Physiol 280: H1286 –H1292, 2001.
15. Pliquett RU, Cornish KG, Peuler JD, Zucker IH. Simvastatin normalizes autonomic neural control in heart failure. Circulation 107: 2493–
2498, 2003.
16. Ponikowski P, Chua TP, Piepoli M, Ondusova D, Harrington Anker S,
Volterrani M, Columbo R, Mazzuero G, Giordano A, Coats AJS.
Augmented peripheral chemosensitivity as a potential input to barereflex
impariment and autonomic imballance in chronic heart failure. Circulation
96: 2586 –2594, 1997.
17. Prabhakar NR, Kumar GK, Chang CH, Agani FH, Haxhiu MA. Nitric
oxide in the sensory function of the carotid body. Brain Res 625: 16 –22, 1993.
18. Roveda F, Middlekauff HR, Rondon MUPB, Reis SF, Souza M,
Nastari L, Barretto ACP, Krieger EM, Negrão CE. The effects of
exercise training on sympathetic neural activation in advanced heart
failure: a randomized controlled trial. J Am Coll Cardiol 42: 854 – 860,
2003.
19. Santos AC, Alves MJ, Rondon MU, Barretto AC, Middleukauff HR,
Negrao CE. Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients. Am J Physiol Heart Circ
Physiol 289: H593–H599, 2005.
20. Schultz HD, Sun SY. Chemoreflex function in heart failure. Heart Fail
Rev 5: 45–56, 2000.
21. Somers VK, Mark AL, Zavala DC, Abboud FM. Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal
humans. J Appl Physiol 67: 2095–2100, 1989.
22. Somers VK, Mark AL, Zavala DC, Abboud FM. Contrasting effects of
hypoxia and hypercapnia on ventilation and sympathetic activity in
humans. J Appl Physiol 67: 2101–2106, 1989.
23. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced peripheral
chemoreflex function in conscious rabbits with pacing-induced heart
failure. J Appl Physiol 86: 1264 –1272, 1999.
24. Sun SY, Wang W, Zucker IH, Schultz HD. Enhanced activity of carotid
body chemoreceptors in rabbits with heart failure: role of nitric oxide.
J Appl Physiol 86: 1273–1282, 1999.
25. Turini GA, Brunner HR, Gribic M, Waeber B, Gravas H. Improvement of chronic congestive heart-failure by oral captopril. Lancet 1:
1213–1215, 1979.
293 • JULY 2007 •
www.ajpheart.org
Downloaded from ajpheart.physiology.org on August 6, 2007
diagnosed as having sleep apnea, we did not specifically test
for sleep apnea in our study. The ventilation during systemic
hypoxia was not controlled in the present study. It is possible
that the hypoxia-induced increase in ventilation may have
masked the peripheral chemoreflex control of MSNA by inhibitory feedback from pulmonary afferents. However, it is
unlikely that this inhibitory feedback would change the difference in MSNA responses during hypoxia and hypercapnia
between heart failure patients and normal controls. We studied
patients uniformly in the advanced stage of ventricular dysfunction. It is unknown whether these results can be extrapolated to patients with less severe heart failure. We measured
MSNA in the leg, while muscle blood flow was assessed in the
forearm. Although leg and arm MSNA are both governed by
similar control systems (arterial baroreceptors and chemoreceptors), and typically exhibit similar responses to stimuli, we
did not directly record arm sympathetic nerve activity. Some of
our patients were taking calcium channel blockers, which
might have prevented the increase in vascular conductance in
response to hypoxia and hypercapnia.
H851
H852
VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
26. Ueno H, Asanoi H, Yamada K, Oda Y, Takagawa T, Hirai T, Nozawa
T, Takashima S, Inoue H. Attenuated respiratory modulation of chemoreflex-mediated sympathoexcitation in patients with chronic heart failure. J Card Fail 10: 236 –246, 2004.
27. Wang W, Ma R. Cardiac sympathetic afferent reflexes in heart failure.
Heart Fail Rev 5: 57–71, 2000.
28. Wang W, Zhu GQ, Patel KP, Zucker IH. AT1 receptor mRNA antisense normalizes enhanced cardiac sympathetic afferent reflex in rats with
heart failure (Abstract). FASEB J 16: A830, 2002.
29. Weisbrod CJ, Minson CT, Joyner MJ, Halliwill JR. Effects of regional
phentolamine on hypoxic vasodilatation humans. J Physiol 537: 613– 621,
2001.
Downloaded from ajpheart.physiology.org on August 6, 2007
AJP-Heart Circ Physiol • VOL
293 • JULY 2007 •
www.ajpheart.org