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Am J Physiol Heart Circ Physiol 280: H1286-H1292, 2001;
0363-6135/01 $5.00
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Vol. 280, Issue 3, H1286-H1292, March 2001

Abnormal neurovascular control during exercise is linked to heart failure severity

Carlos Eduardo Negrão1,2,3, Maria Urbana P. Brandão Rondon1, Taís Tinucci3, Maria Janieire N. Alves1, Fabiana Roveda1, Ana Maria W. Braga1, Soraya F. Reis1, Luciano Nastari4, Antonio Carlos P. Barretto1, Eduardo M. Krieger2, and Holly R. Middlekauff5

Unit of 1 Cardiovascular Rehabilitation and Exercise Physiology, 2 Hypertension, and 4 General Clinic of Cardiopathies, 3 School of Physical Education and Sports, InCor-Heart Institute, University of São Paulo Medical School, São Paulo, CEP 05403-000, Brazil; and 5 Department of Cardiology, University of California Medical School, Los Angeles, California 90095


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of this study was to determine if abnormalities of sympathetic neural and vascular control are present in mild and/or severe heart failure (HF) and to determine the underlying afferent mechanisms. Patients with severe HF, mild HF, and age-matched controls were studied. Muscle sympathetic nerve activity (MSNA) and forearm vascular resistance (FVR) in the nonexercising arm were measured during mild and moderate static handgrip. MSNA during moderate handgrip was higher at baseline and throughout exercise in severe HF vs. mild HF (peak MSNA 67 ± 3 vs. 54 ± 3 bursts/min, P < 0.0001) and higher in mild HF vs. controls (33 ± 3 bursts/min, P < 0.0001), but the change in MSNA was not different between the groups. The change in FVR was not significantly different between the three groups during static exercise. During isolation of muscle metaboreceptors, MSNA and blood pressure remained elevated in normal controls and mild HF but not in severe HF. During mild handgrip, the increase in MSNA was exaggerated in severe HF vs. controls and mild HF, in whom MSNA did not increase. In summary, the increase in MSNA during static exercise in severe HF appears to be attributable to exaggerated central command or muscle mechanoreceptor control, not muscle metaboreceptor control.

autonomic nervous system


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE HALLMARK OF CONGESTIVE heart failure is dyspnea on exertion and decreased exercise tolerance. These symptoms signal heart failure in its earliest stages and persist and progress as heart failure becomes more severe. Similarly, activation of the sympathetic nervous system is present in mild heart failure and increases with heart failure severity (3). Sympathetic activation may contribute to progression of heart failure and is directly related to prognosis in heart failure (2). The mechanisms underlying exercise intolerance and sympathetic activation in heart failure are unknown, but recent evidence suggests that the two may be linked (1, 9). Coats and colleagues (1, 9) have proposed the "muscle hypothesis" in which abnormalities of skeletal muscle, attributable to decreased muscle perfusion and deconditioning, activate muscle afferent nerve fibers, which may be sensitized, resulting in an exaggerated reflex increase in systemic efferent sympathetic nerve activity and peripheral vasoconstriction.

There is evidence in humans consistent with abnormal neurovascular control during exercise in heart failure (10, 12). In normal controls, increases in muscle sympathetic nerve activity (MSNA) and renal vasoconstriction during exercise are mediated by type IV afferent nerve fibers sensitive to ischemic metabolites generated during exercise, termed "muscle metaboreceptors." We (8) and others (12) have found that muscle metaboreceptor control is blunted during static handgrip exercise in heart failure. In contrast, during rhythmic handgrip, the muscle metaboreflex is normally not engaged, but Silber and colleagues (10) concluded that the muscle metaboreflex was activated during rhythmic handgrip exercise in heart failure. Muscle metaboreceptor control can be isolated from central command and muscle mechanoreceptor control in experimental studies.

The above studies (8, 10, 12) of sympathetic activation and vascular control were performed in heterogeneous populations of heart failure or patients with advanced heart failure. To link abnormalities of reflex control of MSNA and the vasculature during exercise with exercise intolerance in heart failure, which is present early in the course of heart failure, it is necessary to study and compare control of sympathetic nerve activity and the vasculature in mild heart failure patients as well.

The purpose of these studies, using well-established experimental paradigms to isolate the muscle metaboreceptors from central command/muscle mechanoreceptors, was to test the hypotheses that 1) muscle sympathetic activation during static exercise is exaggerated in mild heart failure and even more so in severe heart failure; 2) muscle metaboreceptor control of MSNA is exaggerated in mild heart failure but blunted in severe heart failure; 3) central command/muscle mechanoreceptor control of MSNA is exaggerated in mild and severe heart failure; and 4) during static exercise, the increase in blood flow to nonexercising forearm is attenuated in mild heart failure and even more so in severe heart failure.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Study Population

After written informed consent was obtained, 24 severe heart failure patients (14 men and 10 women; mean age, 44.4 ± 2.1 yr), 21 mild heart failure patients (18 men and 3 women; mean age, 47.8 ± 2.1 yr), and 17 age-matched, normal control subjects (12 men and 5 women; mean age, 40.6 ± 1.5 yr) participated in this study. The diagnosis of severe or mild heart failure was based on clinical symptoms and signs. In patients with severe heart failure (New York Heart Association functional class III or IV), the mean ejection fraction measured by echocardiography was 29.4 ± 0.6%. The etiology of heart failure was idiopathic dilated cardiomyopathy in 19 patients and Chagas dilated cardiomyopathy in 5 patients. In patients with mild heart failure (New York Heart Association functional class I or II), the mean ejection fraction was 35.6 ± 1.2%. The etiology of heart failure was idiopathic dilated cardiomyopathy in 19 patients, coronary artery disease in 1 patient, and Chagas cardiomyopathy in 1 patient. Peak oxygen uptake determined by cardiopulmonary exercise (CPX) testing was 16 ± 0.9 ml O2 · kg-1 · min-1 in the mild heart failure patients; severe heart failure patients were too ill to undergo CPX testing. Exclusion criteria were unstable angina, recent (<3 mo) acute myocardial infarction, valvular heart disease, significant chronic pulmonary illness, uncontrolled hypertension, renal insufficiency, and peripheral neuropathy. Normal control subjects were healthy, as confirmed by medical history and physical examinations, complete blood count, blood urea nitrogen, and serum creatinine, and were not taking any medications. The study protocol was approved by the Human Subject Protection Committees of the Heart Institute and Clinical Hospital, School of Medicine, University of São Paulo. Medications, including vasodilators, diuretics, digoxin, and converting-enzyme inhibitors, were discontinued 8-24 h before the study without untoward event. No patients were taking beta -adrenergic blockers. Patients and controls abstained from caffeine for 24 h before the study. These studies were conducted in the postabsorptive state.

Measurements and Procedures

MSNA. MSNA was directly measured from the peroneal nerve using the technique of microneurography (13). Multiunit postganglionic muscle sympathetic nerve recordings were made using a tungsten microelectrode (tip diameter 5-15 µm). The signals were amplified by a factor of 50,000-100,000 and band-pass filtered (700-2,000 Hz). For recordings and analysis, nerve activity was rectified and integrated (time constant, 0.1 s) to obtain a mean voltage display of sympathetic nerve activity that was recorded on paper. Nerve activity was analyzed by the same investigator (C. E. Negrão) who was blinded to the study protocol.

Forearm blood flow. Forearm blood flow was measured by venous occlusion plethysmography. The arm was elevated above the heart level. A mercury-filled Silastic tube attached to a low-pressure transducer was placed around the forearm and connected to a plethysmography (Hokanson). Sphygmomanometer cuffs were placed around the wrist and upper arm. At 15-s intervals, the upper cuff was inflated above venous pressure for 7-8 s. Forearm blood flow (ml · min-1 · 100 ml of tissue) during each minute of exercise was determined on the basis of four separate readings. Forearm vascular resistance (FVR; units) was calculated by dividing mean arterial pressure (oscillometrically measured) by forearm blood flow.

Miscellaneous measurements. Blood pressure was monitored noninvasively from an automatic blood pressure cuff that was inflated every 20-30 s. Blood pressure (mmHg) during each minute of exercise was determined on the basis of two to three separate readings. Heart rate was monitored continuously through lead II of the electrocardiogram. Heart rate (beats/min) during each minute of exercise was determined from the onset to the end of each minute.

Handgrip exercise. After the maximal voluntary contraction (MVC) was determined, handgrip exercise was performed with the dominant arm using a handgrip dynamometer. Subjects were instructed to breathe normally during exercise to avoid inadvertent performance of a Valsalva maneuver.

Experimental Protocols

Protocol 1: Moderate static handgrip exercise (30% MVC) and posthandgrip circulatory arrest. The purpose of this protocol was to determine whether MSNA is exaggerated during handgrip in mild heart failure, and even more so in severe heart failure, and to determine the role of the muscle metaboreceptors in mediating these responses. Furthermore, the influence of this sympathetic excitation on contralateral forearm vasodilatation was determined. In the first part of this protocol, during moderate static handgrip exercise (30% MVC), central command/muscle mechanoreceptors and muscle metaboreceptors were all engaged. All of the studies were performed in a quiet, temperature-controlled (21°C) room at approximately the same time of day. The arm was positioned for venous occlusion plethysmography. The leg was positioned for microneurography, and an adequate nerve recording site was obtained. The subject then rested for 15 min. Baseline MSNA, forearm blood flow, mean blood pressure, and heart rate were recorded for 3 min. Handgrip exercise was then performed for 3 min at 30% MVC. MSNA, forearm blood flow, mean blood pressure, and heart rate were recorded continuously during handgrip exercise and a 3-min recovery period.

In the second part of this protocol, during posthandgrip circulatory arrest, muscle metaboreceptors were isolated from central command and the muscle mechanoreceptors. Just before release of 30% MVC handgrip exercise, the circulation to the exercising forearm was arrested by inflating the upper arm occlusion cuff (240 mmHg). Posthandgrip circulatory arrest was continued for 2 min. Physiological parameters were recorded at baseline and during posthandgrip circulatory arrest.

Protocol 2: Mild static handgrip exercise (10% MVC). The purpose of this study was to determine if central command/muscle mechanoreceptor control of MSNA is exaggerated in mild and severe heart failure. During this mild static handgrip exercise (10% MVC) protocol, central command/muscle mechanoreceptors were principally engaged, with minimal, if any, input from the muscle metaboreceptors. Baseline MSNA, forearm blood flow, mean blood pressure, and heart rate were recorded for 3 min. Handgrip exercise was then performed for 3 min at 10% MVC. MSNA, blood pressure, forearm blood flow, and heart rate were recorded continuously during handgrip exercise and a 3-min recovery period.

Statistical Analysis

Data of MSNA, forearm blood flow, mean blood pressure, FVR, and heart rate are presented as means ± SE. Data for all three groups studied during isometric exercise were subjected to two-way ANOVA with repeated measures. When a significance was found, Scheffé's post hoc comparison test was performed. Data for each group during the regional circulatory arrest were subjected to paired t-tests for intragroup comparisons and to two-way ANOVA with repeated measures for between-group comparisons. P < 0.05 was considered statistically significant.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Baseline Physiological Parameters (24 Severe Heart Failure, 21 Mild Heart Failure, and 17 Normal Controls)

Because baseline physiological parameters were not different in the moderate and mild exercise protocols, only baseline parameters before mild exercise are reported. Baseline heart rate was higher in severe heart failure patients compared with mild heart failure patients and normal controls. Baseline MSNA was greater in heart failure patients compared with normal controls and greater in severe heart failure compared with mild heart failure patients. Baseline forearm blood flow was lower, and FVR was higher, in severe heart failure patients compared with both mild heart failure patients and normal controls. Respiratory rate was greater in both heart failure groups compared with normal controls. MVC was significantly less for severe heart failure compared with mild heart failure patients and normal controls, which were not different from each other (Table 1).

                              
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  		Table 1.   Baseline absolute values of MBP, MSNA, FBF, FVR, HR, and RR in normal controls and mild and severe heart failure patients

Protocol 1: Moderate (30% MVC) Static Handgrip Exercise (24 Severe Heart Failure, 21 Mild Heart Failure, and 17 Normal Controls)

The purpose of this protocol was to test the hypotheses that MSNA is exaggerated during static exercise in mild and severe heart failure and that during static exercise the decrease in FVR in the nonexercising forearm is attenuated in mild and severe heart failure (Table 2).

                              
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  		Table 2.   Absolute values of MBP, FBF, FVR, and RR at baseline and during isometric exercise at 10 and 30% of maximal voluntary contraction in normal controls and mild and severe heart failure patients

MSNA increased progressively and similarly during moderate isometric exercise in all three groups (group effect P < 0.0001, time effect P < 0.0001, interaction P = 0.55). MSNA was higher at baseline and remained significantly higher throughout exercise in severe heart failure compared with mild heart failure and normal controls (Fig. 1A). Similarly, MSNA remained significantly higher throughout exercise in mild heart failure patients compared with normal controls. However, the change in (Delta ) MSNA was not different between the three groups (group effect P = 0.56, time effect P = 0.002, interaction P = 0.40).


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  		Fig. 1.   Muscle sympathetic nerve responses during static handgrip exercise. A: moderate [30% maximal voluntary contraction (MVC)] static handgrip exercise. Muscle sympathetic nerve activity (MSNA) increased progressively and similarly during moderate isometric exercise in all three groups (group effect P < 0.0001, time effect P < 0.0001, interaction P = 0.55). The absolute increase in MSNA was not different between the three groups (group effect P = 0.56, time effect P = 0.002, interaction P = 0.40). B: mild (10% MVC) static handgrip exercise. MSNA increased significantly during exercise in severe heart failure (HF) but not in mild heart failure patients or controls (group effect P < 0.0001, time effect P < 0.0001, interaction P = 0.02). The increase in MSNA during mild exercise was exaggerated in severe heart failure. At minute 2 of exercise (10% MVC), the change in (Delta ) MSNA was significantly greater in severe heart failure patients compared with mild heart failure patients (*P = 0.02) and tended to be greater than normal controls (**P = 0.08).

FVR changed significantly during moderate isometric exercise in the three groups (group effect P = 0.0004, time effect P = 0.006, interaction P = 0.68; Fig. 2A). The Delta FVR during moderate isometric exercise was similar between normal controls and mild or severe heart failure patients (group effect P = 0.46, time effect P = 0.003, interaction P = 0.65).


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  		Fig. 2.   Forearm vascular resistance (FVR) in the nonexercising arm during static handgrip exercise. A: moderate (30% MVC) static handgrip exercise. The Delta FVR during moderate isometric exercise was similar between normal controls and severe and mild heart failure patients (group effect P = 0.46, time effect P < 0.003, interaction P = 0.65). B: mild (10% MVC) static handgrip exercise. The Delta FVR during mild exercise was not different between normal controls and mild or severe heart failure patients (group effect P = 0.18, time effect P = 0.15, interaction P = 0.33).

Posthandgrip (30% MVC) Circulatory Arrest (16 Severe Heart Failure, 18 Mild Heart Failure, and 10 Normal Controls)

The purpose of this study was to test the hypothesis that muscle metaboreceptor control of MSNA is exaggerated in mild heart failure but blunted in severe heart failure (Table 3 and Fig. 3).

                              
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  		Table 3.   Absolute values of MBP, FVR, and HR at baseline and during postexercise regional circulatory arrest in normal controls and mild and severe heart failure patients



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  		Fig. 3.   MSNA and blood pressure responses during posthandgrip circulatory arrest. A: during posthandgrip circulatory arrest, MSNA remained significantly increased compared with baseline in normal controls and mild heart failure patients. In severe heart failure patients during posthandgrip circulatory arrest, muscle sympathetic nerve activation was blunted and was not significantly different from baseline. B: during posthandgrip circulatory arrest, mean blood pressure remained significantly elevated in normal controls and mild heart failure patients but not in severe heart failure patients, in whom mean blood pressure returned toward baseline. *P < 0.05, intragroup vs. baseline.

During posthandgrip circulatory arrest, MSNA increased significantly compared with baseline in normal controls and mild heart failure patients (Fig. 3A). Similarly, during posthandgrip circulatory arrest, MSNA remained significantly elevated compared with recovery in normal controls and mild heart failure patients (Delta MSNA controls: 2.8 ± 1.0 bursts/min, P = 0.02; Delta MSNA mild heart failure 6.1 ± 1.2 bursts/min, P = 0.0001). The Delta MSNA was not exaggerated in mild heart failure patients compared with normal controls. In severe heart failure patients during posthandgrip circulatory arrest, muscle sympathetic nerve activation was blunted, returning toward baseline (Fig. 3A) and toward recovery levels in the absence of ischemic arrest (posthandgrip circulatory arrest vs. recovery: Delta MSNA 3.5 ± 2.0 vs. 1.8 ± 1.9 bursts/min, P = not significant). During posthandgrip circulatory arrest, mean blood pressure remained significantly elevated in normal control and mild heart failure patients but not in severe heart failure patients, in whom mean blood pressure returned toward baseline (Fig. 3B). Heart rate remained elevated in both heart failure groups, whereas it returned to baseline in normal controls (Table 3).

Protocol 2: Mild (10% MVC) Static Handgrip Exercise (24 Severe Heart Failure, 21 Mild Heart Failure, and 17 Normal Controls)

The purpose of this protocol was to test the hypotheses that central command/muscle mechanoreceptor control of MSNA is exaggerated in mild and severe heart failure and that during static exercise the increase in blood flow to nonexercising forearm is attenuated in mild and severe heart failure (Table 2).

The increase in MSNA during mild exercise was exaggerated in severe heart failure; MSNA increased significantly during exercise in severe heart failure patients but not in mild heart failure patients or controls (group effect P < 0.0001, time effect P < 0.0001, interaction P = 0.02; Figs. 1B and 4). Similarly, the Delta MSNA during mild exercise was greater in severe heart failure patients (group effect P = 0.45, time effect P < 0.01, interaction P = 0.01). During the second minute of exercise, the Delta MSNA was significantly greater in severe heart failure compared with mild heart failure patients (P = 0.02) and tended to be greater than normal controls (P = 0.08).


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  		Fig. 4.   Raw sympathetic nerve recordings from normal control and mild and severe heart failure patients during mild (10% MVC) handgrip exercise. Resting MSNA was greatest (51 bursts/min) in the patient with severe heart failure (SHF) and increased further (61 bursts/min) during mild (10% MVC) handgrip exercise. MSNA did not increase during mild exercise in the mild heart failure patient (MHF) or normal control (NC).

FVR changed significantly during mild isometric exercise in the three groups (group effect P = 0.0014, time effect P = 0.05, interaction P = 0.21; Fig. 2B). The Delta FVR during mild exercise was not different between normal controls and mild or severe heart failure patients (group effect P = 0.18, time effect P = 0.15, and interaction P = 0.33).


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The major new findings of this study are 1) the increase in MSNA during static exercise in severe heart failure is not exaggerated, although the absolute MSNA levels are significantly higher than normal controls or mild heart failure patients; 2) muscle metaboreflex control of MSNA is blunted in severe heart failure but intact in mild heart failure; 3) the increase in MSNA during exercise in severe heart failure appears to be attributable to exaggerated central command or mechanoreceptor control of MSNA; 4) heart rate remains elevated during posthandgrip ischemic arrest in both mild and severe heart failure patients, consistent with an early loss of cardiac parasympathetic tone in heart failure (4); and 5) the changes in FVR in the contralateral arm in heart failure patients are not significantly different from normal controls.

Central command control of MSNA may be expected to be augmented in heart failure, since central command is related to voluntary motor effort during exercise and heart failure patients expend greater effort than normal controls during exercise. In fact, when exercise is normalized to an individual's maximum exercise capacity, heart failure patients have higher Borg scores, indicative of greater effort (10). Similarly, muscle mechanoreceptor control of MSNA may be expected to be increased in heart failure. Augmented mechanoreceptor control of sympathetic nerve activity in heart failure was suggested by a study of normal subjects in whom an arm cuff inflated to impede venous outflow was used to simulate the muscle congestion of heart failure (7). In this model of heart failure, muscle mechanoreceptor control of sympathetic nerve activity was augmented during handgrip exercise. Finally, ischemic metabolites generated during exercise have been shown to sensitize muscle mechanoreceptors in animal studies (5, 11).

In the present study, we used mild (10% MVC) static handgrip exercise as a means to isolate both central command and muscle mechanoreceptors from muscle metaboreceptors. In normal subjects, MSNA does not increase during mild static handgrip exercise (6). In contrast, in the present study, in severe heart failure, muscle sympathetic nerve activation was significantly augmented during mild (10% MVC) static exercise. Augmented central command and/or muscle mechanoreceptor control during exercise in severe heart failure likely underlies this sympathoexcitation, consistent with alternate sympathetic control mechanisms in severe heart failure. It seems unlikely that this sympathoexcitation during mild static exercise in severe heart failure patients is attributable to activation of the muscle metaboreceptors, since we and others have found evidence for blunted muscle metaboreceptor control of MSNA in severe heart failure (see below and Refs. 8 and 12). Interestingly, the increase in heart rate during posthandgrip circulatory arrest was present in both mild and severe heart failure. The return of heart rate to basal levels in normal controls after exercise has been attributed to return of parasympathetic tone (4). The prolonged elevation in heart rate after static exercise, even in mild heart failure patients, is consistent with an abnormality of parasympathetic tone that is present early in the course of heart failure.

In heart failure, ischemic metabolites, produced in the setting of abnormal skeletal muscles, may sensitize and stimulate sensory nerve endings in muscle. In animal studies, afferent nerve fibers exposed to ischemic metabolites are sensitized to excitatory stimuli (5, 11). In the present study, however, we found no evidence that the muscle metaboreceptors are sensitized in mild or severe heart failure, leading to exaggerated sympathetic nerve responses during static exercise. In fact, in severe heart failure, we found that muscle metaboreceptor control of MSNA was blunted. Our findings confirm those reported by Sterns and colleagues (12) who found blunted muscle metaboreceptor control of MSNA in severe heart failure and extend them to mild heart failure patients, in whom the situation differs. That is, in mild heart failure, muscle metaboreceptor control of MSNA is intact and similar to normal controls. Abnormalities of control of sympathetic nerve activity during static exercise in heart failure are tied to the severity of heart failure.

The findings in this study are consistent with, and add nuances to, the muscle hypothesis (1, 9). The increase in MSNA during static exercise in severe heart failure patients is not attributable to muscle metaboreceptor afferents; activation of muscle mechanoreceptors and/or central command appear to underlie the sympathetic activation during static exercise in severe heart failure. In mild heart failure, the muscle metaboreceptor control of MSNA is intact and similar to that in normal controls.

Limitations

Medications in our heart failure patients were discontinued for only a short period before the experimental study. Although it would be ideal to study mild and severe heart failure patients in a drug-free state, this would not be safe. With the use of our current approach, we have had no untoward events during these experimental studies. The influence of these medications, including ANG-converting enzyme inhibitors and digoxin, on the integration of these exercise reflexes in heart failure is not known. Posthandgrip circulatory arrest after handgrip at 10% MVC was not performed, so we cannot definitely exclude the possibility that muscle metaboreceptors were activated during this protocol. This seems unlikely, however, since we found no evidence of muscle metaboreceptor activation during handgrip at 30% MVC.

In summary, in severe heart failure, baseline MSNA is markedly elevated and increases further during static exercise. This increase appears to be mediated by exaggerated central command and/or muscle mechanoreceptor control. Muscle metaboreceptor control of MSNA is intact in mild heart failure but is blunted in severe heart failure. Abnormalities of control of MSNA are linked to the severity of heart failure.


    ACKNOWLEDGEMENTS

This study was supported by National Heart, Lung, and Blood Institute Grant 1R29 HL-56796 (to H. R. Middlekauff).


    FOOTNOTES

Address for reprint requests and other correspondence: C. E. Negrão, InCor-Instituto do Coração, 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.

Received 14 January 2000; accepted in final form 25 October 2000.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

1.   Clark, AL, Poole-Wilson PA, and Coats AJ. Exercise limitation in chronic heart failure: central role of the periphery. J Am Coll Cardiol 28: 1092-1102, 1996[Abstract].

2.   Cohn, JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, and Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311: 819-823, 1984[Abstract].

3.   Grassi, G, Seravelle G, Cattaneo BM, Lanfranch A, Vailati S, Giannattasio C, Del Bo A, Sala C, Bolla GB, Pozzi M, and Mancia G. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 92: 3206-3211, 1995[Abstract/Free Full Text].

4.   Imai, K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H, Takeda H, Inoue M, and Kamada T. Vagally mediated heart rate recivery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 24: 1529-1535, 1994[Abstract].

5.   Kaufman, MP, Rybicki KJ, Waldrop TG, and Ordway GA. Effect of ischemia on responses of group III and IV afferents to contraction. J Appl Physiol 57: 644-650, 1984[Abstract/Free Full Text].

6.   Mark, AL, Victor RG, Nerhed C, and Wallin BG. Microneurographic studies of the mechanisms of sympathetic nerve response to static exercise in humans. Circ Res 57: 461-469, 1985[Abstract/Free Full Text].

7.   McClain, J, Hardy C, Enders B, Smith M, and Sinoway LI. Limb congestion and sympathoexcitation during exercise: implications for congestive heart failure. J Clin Invest 92: 2352-2359, 1993.

8.   Middlekauff, HR, Nitzsche EU, Hoh CK, Hamilton MA, Fonarow GC, Hage A, and Moriguchi JD. Exaggerated renal vasoconstriction during exercise in heart failure patients. Circulation 101: 784-789, 2000[Abstract/Free Full Text].

9.   Piepoli, M, Clark AL, Volterrani M, Adamopoulos S, Sleight P, and Coats AJS Contribution of muscle afferents to the hemodynamic, autonomic, and ventilatory responses to exercise in patients with chronic heart failure. Circulation 93: 940-952, 1996[Abstract/Free Full Text].

10.   Silber, DH, Sutliff G, Yang QX, Smith MB, and Sinoway LI. Altered mechanisms of sympathetic activation during rhythmic forearm exercise in heart failure. J Appl Physiol 84: 1551-1559, 1998[Abstract/Free Full Text].

11.   Sinoway, LI, Hill JM, Pickar JG, and Kaufman MP. Effects of contraction and lactic acid on the discharge of group III muscle afferents in cats. J Neurophysiol 69: 1053-1059, 1993[Abstract/Free Full Text].

12.   Sterns, DA, Ettinger SM, Gray KS, Whisler SK, Mosher TJ, Smith MB, and Sinoway LI. Skeletal muscle metaboreceptor exercise responses are attenuated in heart failure. Circulation 84: 2034-2039, 1991[Abstract/Free Full Text].

13.   Valbo, AB, Hagbarth KE, Toreebjork HE, and Wallin BG. Somatosensory, proprioceptive and sympathetic activity in human peripheral nerves. Physiol Rev 59: 919-957, 1979[Free Full Text].

Am J Physiol Heart Circ Physiol 280(3):H1286-H1292
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart failure
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I. H. Zucker, H. D. Schultz, W. Wang, M. Guazzi, A. C. Scott, C. E. Negrao, M. U. P. B. Rondon, E. S. Prakash, A. L. Clark, A. Crisafulli, et al.
Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure
J Appl Physiol, January 1, 2007; 102(1): 498 - 501.
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H. R. Middlekauff and L. I. Sinoway
Point:Counterpoint: Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure
J Appl Physiol, January 1, 2007; 102(1): 492 - 494.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
S. Koba, Z. Gao, J. Xing, L. I. Sinoway, and J. Li
Sympathetic responses to exercise in myocardial infarction rats: a role of central command
Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2735 - H2742.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
A. C. Santos, M. J. N. N. Alves, M. U. P. B. Rondon, A. C. P. Barretto, H. R. Middlekauff, and C. E. Negrao
Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients
Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H593 - H599.
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L. I. Sinoway and J. Li
A perspective on the muscle reflex: implications for congestive heart failure
J Appl Physiol, July 1, 2005; 99(1): 5 - 22.
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 Am. J. Physiol. Heart Circ. Physiol.Home page
C. E. Negrao, I. C. Trombetta, L. T. Batalha, M. M. Ribeiro, M. U. P. B. Rondon, T. Tinucci, C. L. M. Forjaz, A. C. P. Barretto, A. Halpern, and S. M. F. Villares
Muscle metaboreflex control is diminished in normotensive obese women
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