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Am J Physiol Heart Circ Physiol 293: H846-H852, 2007. First published April 13, 2007; doi:10.1152/ajpheart.00156.2007
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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. Negrão1,2

1Heart 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


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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.

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 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 {alpha}-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 {alpha}-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 {alpha}-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 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
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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 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.

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·min–1·100 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 minimized 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 (VO2) 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 VO2 was defined as the maximum attained VO2 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.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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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 VO2 was significantly lower in heart failure patients compared with normal control individuals.


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  		Table 1. Physical characteristics

 
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.


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  		Table 2. Baseline measures

 
Hypoxia

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 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).


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  		Table 3. Hemodynamic and respiratory responses to hypoxia and hypercapnia in normal control individuals and heart failure patients

 

Figure 1
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  		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.

 

Figure 2
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  		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.

 
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 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 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).


Figure 3
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  		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.

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
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 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 {alpha}-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 adenovirus 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 beta-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 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.

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, beta-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
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
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 Científica (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 Nível Superior.


   FOOTNOTES
 

Address for reprint requests and other correspondence: C. E. Negrão, Instituto do Coração (InCor), Unidade de Reabilitação Cardiovascular e Fisiologia do Exercício, Av. Dr. Enéas de Carvalho Aguiar, 44 Cerqueira César, São Paulo SP, CEP 05403-000 Brazil (e-mail: cndnegrao{at}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.


   REFERENCES
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 RESULTS
 DISCUSSION
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