doi:10.1152/ajpheart.00156.

2007
293:846-852, 2007. First published Apr 13, 2007; Am J Physiol Heart Circ Physiol
Carlos E. Negro
Maria Urbana P. B. Rondon, Antonio C. P. Barretto, Holly R. Middlekauff and
Andrea Di Vanna, Ana Maria F. W. Braga, Mateus C. Laterza, Linda M. Ueno,
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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. Negrao
1,2
1
Heart Institute (InCor), University of Sao Paulo Medical School, and
2
School of Physical Education and Sport, University of
Sao Paulo, Sao Paulo, Brazil; and
3
Department of Cardiology, University of California Los Angeles, Los Angeles, California
Submitted 7 February 2007; accepted in nal form 11 April 2007
Di Vanna A, Braga AM, Laterza MC, Ueno LM, Rondon MU,
Barretto AC, Middlekauff HR, Negrao CE. Blunted muscle vaso-
dilatation during chemoreceptor stimulation in patients with heart
failure. Am J Physiol Heart Circ Physiol 293: H846H852, 2007. First
published April 13, 2007; doi:10.1152/ajpheart.00156.2007.Che-
moreex 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 ow responses during peripheral and central chemore-
ex 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 chemoreex control was evaluated by inhalation of 10% O2
and 90% N
2
for 3 min. The central chemoreex control was evaluated
by inhalation of 7% CO
2
and 93% O
2
for 3 min. Muscle sympathetic
nerve activity (MSNA) was directly evaluated by microneurogra-
phy. Forearm blood ow was evaluated by venous occlusion
plethysmography. Baseline MSNA were signicantly 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 signicantly 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 signicantly
lower in HF patients (0.00 0.10 vs. 0.76 0.25 units, P
0.001). During hypercapnia, MSNA responses were signicantly
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 signicantly
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.
chemoreex sensitivity; sympathetic nerve activity; forearm blood
ow
CHEMORECEPTORS ARE IMPORTANT modulators of hemodynamics
and ventilation. Central chemoreceptors, located in the brain
stem, respond primarily to hypercapnia, while peripheral che-
moreceptors, located on the carotid bodies, respond primarily
to hypoxia. In healthy individuals, chemoreceptor activation
increases ventilation, sympathetic nerve activity, blood pres-
sure, and heart rate (10). In humans with chronic heart failure,
the chemoreex control can be profoundly altered. Central
chemoreceptor stimulation in patients with heart failure has
been shown to produce exaggerated increases in ventilation
and muscle sympathetic nerve activity (MSNA) (11). Periph-
eral chemoreceptor activation may also cause exaggerated
increases in ventilation and sympathetic activity in heart fail-
ure, although this is controversial. Heterogeneity of the heart
failure study populations, including severity and etiology of
heart failure, may explain the variation in ndings during
peripheral chemoreceptor stimulation (3, 4, 16). In a rabbit
model of heart failure, peripheral chemoreex control of renal
sympathetic nerve activity was found to be exaggerated (20,
23). However, the hemodynamic implications of the aug-
mented sympathetic nerve activity during peripheral and cen-
tral 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 ow
and, in consequence, improve oxygen delivery to skeletal
muscles during exercise. On the other hand, a recent study
provides evidence that the reex sympathetic vasoconstrictor
responsiveness to systemic hypoxia is not completely abol-
ished. Forearm vasodilatation responses during hypoxia were
signicantly increased after local -adrenergic receptor block-
ade (29).
In humans with heart failure, despite the early muscle
metabolic acidosis and lowered oxygen partial pressure, mus-
cle 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 outow during physiological maneuvers is a major
contributor to this attenuated vasodilatation. We found that
MSNA restrained the endothelial-mediated muscle vasodilata-
tion during mental challenge in humans with heart failure.
Intra-arterial brachial acetylcholine caused no change in fore-
arm blood ow in heart failure patients (19). In contrast, acetyl-
choline associated with -adrenergic blockade with phentolamine
signicantly improved muscle vasodilatory responses during
mental stress in heart failure patients (19). These ndings natu-
rally support the notion that augmented sympathetic outow may
be implicated in other hemodynamic alterations during physio-
logical maneuvers in humans with heart failure. In the present
study, we report the muscle blood ow responses during hypoxia
Address for reprint requests and other correspondence: C. E. Negrao, Instituto
do Coracao (InCor), Unidade de Reabilitacao Cardiovascular e Fisiologia do
Exerc cio, Av. Dr. Eneas de Carvalho Aguiar, 44 Cerqueira Cesar, Sao Paulo SP,
CEP 05403-000 Brazil (e-mail: cndnegrao@incor.usp.br).
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.
Am J Physiol Heart Circ Physiol 293: H846H852, 2007.
First published April 13, 2007; doi:10.1152/ajpheart.00156.2007.
0363-6135/07 $8.00 Copyright 2007 the American Physiological Society http://www.ajpheart.org H846

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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 chemorecep-
tor control of MSNA and forearm blood ow in a group of
advanced heart failure patients with nonischemic cardiomyopathy.
Specically, we tested the hypothesis that central and peripheral
chemoreex control of MSNA would be exaggerated in this
population of advanced heart failure patients and would be ac-
companied by blunted forearm vasodilatation.
METHODS
Population
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 3570 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) pace-
maker, 5) absolute contraindication to discontinue use of vasodilator
diuretic drugs, and/or cardiovascular medications in the 24 h preced-
ing 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 Scientic and Ethical Commission of the Heart
Institute (InCor), and by the Ethics in Research Commission of the
Clinical Hospital of the Medicine University of Sao Paulo.
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 bular
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 12 cm from it. The electrodes were
connected to a preamplier, and the nerve signal was fed through a
passband lter and, after that, led to an amplitude discriminator to be
stored in an oscilloscope. For recording and analysis, the ltered
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 ow. Forearm blood ow 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-lled Silastic tube at-
tached to a low-pressure transducer was placed around the forearm, 5
cm distant from the humero-radial joint, and connected to a plethys-
mography 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 inated at a level
above the systolic blood pressure level. At 15-s intervals, the upper
cuff was inated above venous pressure for 78 s. The increase in the
tension in the Silastic tube reects the increase in the forearm volume
and, consequently, the vasodilation. The wave signal of the muscle
ow 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 ow (ml min
1
100 ml
1
) by mean
arterial pressure (mmHg), expressed in units.
Evaluation of peripheral and central chemoreceptors. Peripheral
chemoreex control was evaluated through the inhaling of a hypoxic
gas mixture (10% O
2
and 90% N
2
), for a 3-min period, as described
by others (21, 22). In the stimulation of peripheral chemoreceptors
during hypoxia, the inuence of central chemoreceptors was mini-
mized by the maintenance of isocapnia, with titrated carbon dioxide.
Central chemoreex control was evaluated through the inhaling of a
hypercapnic gas mixture (7% CO
2
and 93% O
2
) for a 3-min period. In
the stimulation of central chemoreceptors by hypercapnia, the inu-
ence of peripheral chemoreceptors was minimized by hyperoxia. The
sequence of interventions to evaluate peripheral and central chemo-
receptors was randomized.
Functional capacity. Maximal exercise capacity was determined by
means of a maximal progressive exercise test on an electromagneti-
cally braked cycle ergometer (Medit 400L, Medical Fitness Equip-
ment, Maarn, Netherlands), with work rate increments of 7.515
W/min at 60 rpm until exhaustion. Oxygen uptake (V

O
2
) 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 V

O
2
was dened as the
maximum attained V

O
2
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 nonin-
vasively 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 ETCO
2
CAPNOGARD, Man-
aus, Brazil). The minute ventilation was monitored by pneumotaco-
graph (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 chemoreex in MSNA, heart rate, mean blood pressure,
forearm blood ow, 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 pero-
neal nerve. Electrodes were then placed to monitor electrocardiogram,
cuffs were placed to monitor forearm blood ow, and mouth piece and
nasal clip were placed to allow inhaling of gases. MSNA, heart rate,
mean blood pressure, forearm blood ow, forearm vascular conduc-
tance, 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 ow, measures were taken at 15-s intervals.
Protocol 2. The purpose of this protocol was to study the impact of
central chemoreex in MSNA, heart rate, mean blood pressure,
forearm blood ow, forearm vascular conductance, and pulmonary
ventilation in patients with heart failure. MSNA, heart rate, mean
blood pressure, forearm blood ow, 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 ow, 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 ow, forearm vascular conductance, pulmonary ventilation, O
2
saturation, end-tidal CO
2
, and MSNA were analyzed by two-way
ANOVA with repeated measures. When signicance was observed,
post hoc Scheffes comparison was used to test the difference between
conditions. Probability values of P 0.05 were considered statisti-
cally signicant.
H847 VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
AJP-Heart Circ Physiol VOL 293 JULY 2007 www.ajpheart.org

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RESULTS
Basal Measurements
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 V

O
2
was
signicantly lower in heart failure patients compared with
normal control individuals.
Baseline measures of MSNA, heart rate, mean blood pres-
sure, forearm blood ow, forearm vascular conductance,
minute ventilation, end-tidal CO
2
, and O
2
saturation are shown
in Table 2. Baseline measures of heart rate, mean blood
pressure, forearm blood ow, forearm vascular conductance,
end-tidal CO
2
, and O
2
saturation were not signicantly differ-
ent between groups. MSNA and minute ventilation were sig-
nicantly higher in patients with heart failure.
Hypoxia
The responses of heart rate, mean blood pressure, minute
ventilation, end-tidal CO
2
, and O
2
saturation during hypoxia are
shown in Table 3. Heart rate, mean blood pressure, and minute
ventilation during hypoxia increased similarly and signicantly in
normal control individuals and heart failure patients. End-tidal
CO
2
during hypoxia did not signicantly change in normal control
individuals and heart failure patients. As expected, O
2
saturation
was signicantly and similarly reduced during hypoxia in both
normal controls and heart failure patients. MSNA increased sig-
nicantly 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 signicantly greater in patients
with heart failure than in normal control individuals (interaction,
P 0.001). Forearm blood ow during hypoxia increased pro-
gressively and signicantly in normal control individuals
(Fig. 2, A and C). In contrast, forearm blood ow did not
signicantly 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 ow were
signicantly greater in normal control individuals than in
patients with heart failure (interaction, P 0.0002). Simi-
larly, forearm vascular conductance responses were signif-
icantly lower in heart failure patients compared with normal
control individuals (interaction, P 0.001; Fig. 2, B and D).
Hypercapnia
The responses of heart rate, mean blood pressure, minute
ventilation, end-tidal CO
2
, and O
2
saturation during hypercapnia
are shown in Table 3. Mean blood pressure and minute ventilation
to hypercapnia increased similarly and signicantly in normal
control individuals and heart failure patients. Heart rate increased
signicantly in heart failure patients. In normal controls, heart rate
Table 1. Physical characteristics
NC HF P
Gender (M/F) 5/6 11/5 0.21
Age, yr 463 493 0.42
Weight, kg 683 683 0.89
Height, m 1.670.03 1.630.02 0.27
BMI, kg/m
2
241 251 0.38
Peak V

O2, ml kg
1
min
1
282 192 0.003
LVEF 0.300.01
HF etiology
Idiopathic dilated 16
Cardiomyopathy
Medications
-blocker 16
ACEI 16
Digitalic 15
Diuretic 16
Antiarrhythmic 5
Calcium blockers 4
Values are means SE. NC, normal control; HF, heart failure; M, male;
F, female; BMI, body mass index; peak V

O2, peak oxygen uptake; LVEF, left

ventricular ejection fraction; ACEI, angiotensin-converting enzyme inhibitors.
Table 2. Baseline measures
NC HF P
Neural measure
MSNA, bursts/min 202 333 0.001
Hemodynamic measures
HR, beats/min 663 663 0.95
MBP mmHg 932 982 0.12
FBF, ml min
1
100 ml
1
2.030.23 1.850.10 0.42
FVC, units 2.160.22 1.920.11 0.31
Respiratory measures
Minute ventilation, l/min 7.51.0 10.30.8 0.04
End-tidal CO2, mmHg 391 381 0.42
O2 saturation, % 97.60.3 97.00.3 0.18
Values are means SE. MSNA, muscle sympathetic nervous activity; HR,
heart rate; MBP, mean blood pressure; FBF, forearm blood ow; FVC, forearm
vascular conductance.
Table 3. Hemodynamic and respiratory responses to hypoxia
and hypercapnia in normal control individuals and heart
failure patients
Baseline 1 2 3
Hypoxia
HR, beats/min NC 663 41 91 122
HF 663 52 101 112
MBP, mmHg NC 932 32 52 51
HF 982 02 22 12
V

E, l/min NC 7.51.0 1.80.6 3.70.7 4.71.0

HF 10.30.8 1.30.4 4.50.7 6.01.0
End-tidal CO2,
mmHg
NC 391 2.00.8 1.50.9 1.31.1
HF 381 0.10.6 0.30.6 0.30.7
O2 saturation, % NC 97.60.3 1.80.8 9.41.0 13.10.7
HF 97.00.3 1.50.5 10.10.8 13.00.9
Hypercapnia
HR, beats/min NC 663 11 22 32
HF 663 41 72 92*
MBP, mmHg NC 932 61 82 93
HF 982 32 72 73
V

E, l/min NC 7.51.0 5.01.9 8.71.8 15.23.7

HF 10.30.8 2.10.8 7.12.0 9.42.2
End-tidal CO2,
mmHg
NC 391 143 142 172
HF 381 141 141 151
O2 saturation, % NC 97.60.3 1.20.2 1.70.3 1.90.2
HF 97.00.3 1.20.2 2.10.4 2.00.4
Values are mean SE. V

E, minute ventilation. *Signicant difference

between groups, P 0.05. Signicant difference vs. baseline, P 0.05.
H848 VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
AJP-Heart Circ Physiol VOL 293 JULY 2007 www.ajpheart.org

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increased slightly. The comparisons between groups showed that
heart rate response was signicantly greater in the heart failure
patients at the 3rd min of hypercapnia. End-tidal CO
2
increased
similar and signicantly in normal control individuals and heart
failure patients. O
2
saturation increased signicant and similarly
during hypercapnia in normal control individuals and heart failure
patients. MSNA increased progressive and signicantly 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 signicantly greater in patients with heart failure than in
normal controls (interaction, P 0.001). Forearm blood ow
increased progressive and signicantly in responses to hypercap-
nia in normal control individuals (Fig. 3, A and C). In contrast,
forearm blood ow did not signicantly change during hypercap-
nia in heart failure patients (Fig. 3, A and C). In fact, forearm
blood ow slightly decreased throughout the 2nd and 3rd min of
hypercapnia in heart failure patients. Thus the comparisons be-
tween groups showed that the responses of forearm blood ow to
hypercapnia were signicantly lower in heart failure patients
(interaction, P 0.001). Similarly, forearm vascular conductance
responses during hypercapnia were signicantly lower in heart
failure patients compared with normal control individuals (inter-
action, Fig. 3, B and D, P 0.001).
DISCUSSION
The new nding of the present study is that, in contrast to
individuals with normal ventricular function, patients with
chronic left ventricular dysfunction have no increase in fore-
arm blood ow during hypoxia and hypercapnia. This unex-
pected response seems to be linked to the exaggerated sympa-
thetic outow. MSNA signicantly increased during hypoxia
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 fail-
ure patients. PETCO
2
, end-tidal PCO2. *Signi-
cant difference between groups, P 0.05.
Fig. 2. Forearm blood ow (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. *Signicant difference between groups,
P 0.05.
H849 VASODILATATION AND CHEMOREFLEX CONTROL IN HEART FAILURE
AJP-Heart Circ Physiol VOL 293 JULY 2007 www.ajpheart.org

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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 outow in heart failure overwhelms vasodilatory
stimuli. For example, during mental stress in heart failure
patients (19), we found that blockade of postsynaptic -adren-
ergic receptors with phentolamine increased forearm blood.
Additionally, phentolamine associated with acetylcholine sig-
nicantly improved forearm blood ow responses during men-
tal 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 outow
overrides the skeletal muscle vasodilatory forces. However, we
cannot rule out the possibility that the blunted muscle vasodi-
latation to hypoxia and hypercapnia in heart failure patients is
due to intrinsic endothelial dysfunction. Hirooka and col-
leagues (6) found that, when they administered acetylcholine into
the brachial arterial at rest and during reactive hyperemia in heart
failure patients, forearm blood ow did not increase, consistent
with endothelial dysfunction in heart failure. Our study conrms
previous ndings that demonstrated augmented central and pe-
ripheral chemoreex control of sympathetic nerve activity in a
group of advanced heart failure patients with nonischemic cardio-
myopathy (11, 26). These responses are consistent with the idea
that the peripheral and central chemoreex-mediated sympatho-
excitation 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 chemo-
receptors, which results in lowered NO production and, in
consequence, disinhibition of carotid body chemoreceptor ac-
tivity (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 reexes (9, 27, 28). Also, more recently, Li et al. (8),
in an elegant study, demonstrated that application of an ade-
novirus expressing NO synthase reduces baseline renal sym-
pathetic 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
chemoreex control of MSNA is directly related to spontane-
ous respiratory rate (12). Slower respiratory rate was associ-
ated with lower levels of MSNA and potentiation of the
chemoreex response to hypoxia and hypercapnia. This seems
to be the case in our study, since the respiratory rate in normal
controls was between the rst tertile and the second tertile de-
scribed 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 ndings
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
Narkiewiczs study (11). Obesity plus left ventricular dysfunc-
tion may exert additive effects on central chemoreex 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 addi-
tion, 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 chemoreex dysfunction and exaggerated sym-
pathetic activity are linked to central sleep apnea in patients
with heart failure (25). Although none of our patients had been
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 fail-
ure patients. *Signicant difference between
groups, P 0.05.
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diagnosed as having sleep apnea, we did not specically 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 chemoreex control of MSNA by in-
hibitory feedback from pulmonary afferents. However, it is
unlikely that this inhibitory feedback would change the differ-
ence in MSNA responses during hypoxia and hypercapnia
between heart failure patients and normal controls. We studied
patients uniformly in the advanced stage of ventricular dys-
function. It is unknown whether these results can be extrapo-
lated to patients with less severe heart failure. We measured
MSNA in the leg, while muscle blood ow was assessed in the
forearm. Although leg and arm MSNA are both governed by
similar control systems (arterial baroreceptors and chemore-
ceptors), 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.
Perspectives
The abnormal forearm blood ow during hypoxia and hy-
percapnia 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. More-
over, sympathetic nerve activity should be the major target to
improve muscle blood ow 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 ow 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 outow during this stimulation.
GRANTS
This study was supported by Fundacao de Amparo a` Pesquisa do Estado de
Sao Paulo, Sao Paulo (FAPESP no. 2000/04915-3 and no. 2005/59740-7), and
in part by Fundacao Zerbini, Sao Paulo. C. E. Negrao (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 Iniciacao Cient ca (PIBIC/CNPq, 2004
2005). L. M. Ueno was supported by FAPESP (no. 03/10881-2), and M. C.
Laterza was supported by Coordenacao de Aperfeicoamento de Pessoal de
N vel Superior.
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