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Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angelos, California 90095
Submitted 5 April 2004 ; accepted in final form 29 June 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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heart failure; exercise; muscle mechanoreceptors; sympathetic nerve activity
In humans, two major systems control the autonomic responses to exercise: 1) central command, a central neural system closely linked to perceived effort during exercise; and 2) sensory nerve fibers located in the skeletal muscle itself, including the muscle mechanoreceptors, sensitive to stretch during contraction, and the muscle metaboreceptors, sensitive to ischemic metabolites generated during exercise (12, 30). In healthy humans, the muscle metaboreceptors are paramount in generating reflex increases in sympathetic nerve activity during static exercise. Central command plays a supporting role, underlying increases in muscle sympathetic nerve activity (MSNA) only during extreme, or near-maximal, effort (38). Two reports support the notion that the muscle mechanoreceptors also underlie the increase in MSNA during exercise, especially rhythmic exercise, in healthy humans (4, 11). These data and data in animals (2, 11–14, 31) suggest that the group III mechanosensory neurons are sensitized by metabolic by-products, such as lactic acid and/or prostaglandins, and contribute to the overall sympathetic activation during exercise. The precise identity of the metabolic by-products has not yet been studied in healthy humans.
In patients with heart failure, muscle metaboreceptor control of reflex increases in MSNA has been shown to be markedly blunted (34). In its place, the muscle mechanoreceptors have emerged as the most likely mediators of reflex control of the circulation during exercise in heart failure (15, 19, 33), although the evidence is far from conclusive. To date, studies of mechanoreceptor control of MSNA have only been performed in a rat model and a human model of heart failure but never before in actual humans with heart failure. Furthermore, the mechanisms of this potentially enhanced mechanoreceptor-mediated control of the circulation during exercise in heart failure remain unknown. Whether the muscle mechanoreceptors in patients with heart failure are sensitized by metabolic by-products generated during rhythmic exercise, and if so, which one(s) remains unknown. The purpose of the present study was to determine 1) whether muscle mechanoreceptor control of MSNA is enhanced in heart failure, and 2) whether lactic acid, which has been shown to sensitize group III mechanoreceptors in animals, sensitizes muscle mechanoreceptors during low-level rhythmic exercise in normal humans and in humans with heart failure.
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METHODS |
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After written informed consent on University of California, Los Angelos (UCLA), Internal Review Board-approved informed consent forms was obtained, 24 normal volunteers and 20 patients with advanced heart failure participated in these studies. Patient and control characteristics are shown in Table 1. Patients with advanced heart failure were recruited consecutively from the UCLA-Ahmansen Cardiomyopathy Center. All patients with heart failure met the following inclusion criteria: clinically stable; without change in cardiac medications for 3 mo before the study; not involved in a formal exercise program; and no significant liver or renal disease, autonomic neuropathy, myopathy, untreated thyroid disease, or peripheral vascular disease. All patients were New York Heart Association class II-III, had left ventricular ejection fraction 
35% with chronic (>12-mo duration) heart failure, and were under consideration for heart transplantation. Medications were not discontinued for study purposes, although furosemide was withheld the morning of the experimental protocol. All control subjects were healthy nonsmokers and not taking any medications, including over-the-counter medications.
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MSNA was recorded from the peroneal nerve by using the technique of microneurography (7). Briefly, multiunit postganglionic muscle sympathetic nerve recordings were made using a tungsten microelectrode. Signals were amplified by a factor of 50,000–100,000 and band-pass filtered (700–2,000 Hz). 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. All recordings of MSNA met previously established and described criteria (17, 36). Muscle sympathetic bursts were identified by visual inspection by a single investigator (H. R. Middlekauff) blinded to the intervention and expressed as burst frequency (bursts/min) and total activity (arbitrary units/min). Total activity per minute was determined by the sum of the heights of individual bursts per minute. The interobserver and intraobserver variability in identifying bursts is <10% and <5%, respectively (17, 18).
Rhythmic Handgrip Exercise
A short course of low-level rhythmic exercise was used to engage principally the muscle mechanoreceptors without simultaneously activating the metaboreceptors. Maximum voluntary capacity (MVC) was determined by having the subject briefly squeeze a handgrip dynamometer (Stoelting) at maximal levels. The greater of two maximal contractions was selected as the MVC. Rhythmic handgrip was performed at 20% of the subject's MVC at a rate of 30 contractions/min for 3 min. A metronome was used to optimize uniformity of contraction rate.
Posthandgrip Circulatory Arrest
To assess whether the muscle metaboreceptors had been inadvertently engaged, posthandgrip circulatory arrest was performed (3). Five seconds before the conclusion of exercise, a blood pressure cuff was rapidly inflated to suprasystolic blood pressure levels (220 mmHg) using an automatic inflation device (University of Iowa). Exercise was then terminated so that muscle mechanoreceptors and central command were no longer engaged. This maneuver is a well-accepted means to trap ischemic metabolites in the exercising muscle bed thereby isolating the muscle metaboreflex contribution to activation of MSNA. The cuff was deflated after 2 min.
Pharmacological Inhibition of Lactic Acid Production
A 20-gauge venous catheter was inserted into an antecubital vein for dichloroacetate (DCA) infusion. Intravenous DCA (35 mg/kg), which reduces the production of lactic acid by increasing the activity of pyruvate dehydrogenase, was infused intravenously into an antecubital vein over 30 min before initiation of exercise. This dose and method of delivery has been shown to significantly blunt changes in lactate and pH as well as MSNA levels during static forearm exercise in healthy humans (8).
Passive Arm Exercise
To isolate muscle mechanoreceptors from central command, passive exercise was used. The subject's nondominant wrist was flexed and extended by the investigator (H. R. Middlekauff) at 30 times/min for 3 min. A metronome was used to optimize uniformity of contraction rate.
Miscellaneous
Blood pressure was monitored noninvasively with an automatic blood pressure cuff (Press-Mate 8800, Colin Medical Instrument; San Antonio, TX). The monitor was cycled continuously during the exercise protocol, resulting in measurement of systolic, diastolic, and mean blood pressure every 20–30 s. Heart rate (HR) was monitored continuously through lead II of the ECG. Lactate and pH values were measured in venous blood obtained through the catheter in the antecubital vein. Lactate levels were measure in the UCLA Clinical laboratory using automated chemistry analyzer LX-20 (Beckman-Colter; Brea, CA). Blood was collected in prechilled, standard collection tubes prepared with NaCl. Venous pH values were determined in the UCLA Clinical Laboratory using a semiautomated analyzer Radiometer-700 (Copenhagen, Denmark). Blood was collected in prechilled, standard collection tubes prepared with heparin. All samples were analyzed immediately. The coefficient of variation for these assays is 5%.
Experimental Protocols
Blinded DCA study. A timeline of the protocol is shown in Fig. 1. Subjects participated in the research on 2 nonconsecutive days. On each day, following an unblinded saline infusion administered in the same volume and rate as the study material (either DCA or blinded-saline), the exercise protocol (as described above in Rhythmic Handgrip Exercise) was performed. After a 45-min rest period for recovery, study material was administered in a double-blind, randomized fashion, and the exercise protocol was repeated. On the second day, the protocol was repeated, but the study material was saline if it had been DCA on the first day and vice versa. With this design, unblinded saline served as a control for the DCA effect. The double-blind saline served as a control for an order or time effect. The half-life of DCA prohibited a design in which both saline and drug were only administered in a double-blind manner on the same day, because a subject receiving DCA during the first exercise session may have a spillover effect during the second session.
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Statistical Analysis
Data are presented as means ± SE. Repeated-measures ANOVA was used for comparison of between and within-group means and to compute the P values. Paired t-test, which is a special case of repeated-measures ANOVA when only two time points are used, was also used in some of the analyses. P values <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Thirteen normal control subjects and 12 patients with heart failure participated in these DCA studies.
Saline-Blinded Saline Day
Baseline measurements are shown on Table 2. Baseline MSNA was significantly greater in patients with heart failure compared with controls. Baseline HR was greater in patients with heart failure, and mean arterial pressure (MAP) was not different. MVC was lower in patients with heart failure.
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At rest, venous pH and lactate were similar in normal controls and patients with heart failure (7.39 ± 0.01 vs. 7.41 ± 0.001, P = not significant; 9.8 ± 1.4 vs. 11.1 ± 0.9 mg/dl, P = not significant, respectively). During the blinded and unblinded saline runs, the decrease in pH during exercise was not greater in patients with heart failure compared with that in normal controls during this low-level exercise (Table 4). Peak lactate during exercise was greater in patients with heart failure compared with that of normal controls in one of the three saline runs (Table 4). After the DCA infusion, resting pH was unchanged, but resting lactate fell in normal controls (9.8 ± 1 vs. 5.7 ± 0.3 mg/dl, P = 0.001) and in patients with heart failure (11.0 ± 2 vs. 6.7 ± 1.8 mg/dl, P < 0.0001). In both normal controls and patients with heart failure, DCA significantly blunted the peak pH and peak lactate levels compared with saline infusion (Table 4). This was not an order effect, because changes in pH and lactate were similar following unblinded and blinded saline.
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Passive Exercise Study
Eight patients with heart failure and 11 normal controls participated in this study. In normal control subjects during passive exercise, MSNA (Fig. 4), HR (baseline vs. 1, 2, and 3 min: 68 ± 3 vs. 68 ± 3, 69 ± 3, and 69 ± 3 beats/min, respectively), and MAP (baseline vs. 1, 2, and 3 min: 91 ± 4 vs. 90 ± 3, 91 ± 3, and 89 ± 3 mmHg, respectively) remained unchanged from baseline. In contrast, in patients with heart failure, MSNA increased above baseline levels (Fig. 4) and remained increased throughout passive exercise. HR (baseline vs. 1, 2, and 3 min: 72 ± 6 vs. 71 ± 6, 74 ± 6, and 74 ± 6 beats/min) and MAP (baseline vs. 1, 2, and 3 min: 78 ± 2 vs. 76 ± 2, and 77 ± 2, and 77 ± 3 mmHg, respectively) were unchanged during passive exercise in patients with heart failure.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Rhythmic treadmill exercise has been used in animal models to stimulate muscle mechanoreceptors. Pickar and colleagues (22) recorded group III muscle mechanosensitive afferent nerve activity in decerebrate cats during low-intensity dynamic treadmill exercise and found that muscle mechanoreceptors were very sensitive to changes in muscle tension. Adreani and colleagues (1) studied decerebrate cats and found that low-level rhythmic exercise increased group III and IV nerve firing. This increase in muscle afferent nerve activity was further increased by arterial occlusion (ischemia) in the exercising muscle (2). These investigators concluded that dynamic exercise stimulated polymodal group III and IV nerve fibers and that a compound that accumulated in the working muscle sensitized the nerve fibers.
In healthy humans, Batman and colleagues (4) measured the MSNA responses during prolonged, low-level (25% MCV) rhythmic handgrip exercise. They reported progressive increases in MSNA during 30 min of low-level rhythmic exercise. This increase in MSNA was not attributable to muscle metaboreceptors because MSNA returned to baseline levels during posthandgrip circulatory arrest. Interestingly, despite a repetitive, constant (not escalating) exercise stimulus, MSNA progressively increased after a short latency. These investigators concluded that group III mechanically sensitive nerve fibers were sensitized by metabolic by-products of contraction.
Herr and colleagues (11) used repetitive 25-s contractions separated by 5-s rest periods of the quadriceps muscles at 25% MVC in healthy humans to stimulate muscle mechanoreceptors and reported a progressive increase in MSNA. Then, by using signal averaging techniques to examine the onset latency, these investigators reported a latency of 4–6 s after the onset of contraction that only reached steady state by the third contraction, consistent once again with the concept that mechanosensitive afferent nerve fibers were sensitized by metabolic by-products. In summary, data in healthy humans are consistent with the concept that rhythmic exercise engages principally the group III muscle mechanoreceptors, resulting in sympathetic activation, and that the muscle mechanoreceptors are sensitized by metabolic by-products. However, the following question remains: By which metabolic by-product(s)?
Despite a large body of data investigating the role for lactic acid and hydrogen ions in mediating sympathetic activation during exercise in humans, it remains controversial whether acidosis plays a role, and, if so, whether it is a central one (16, 32, 35, 37, 40). Victor and colleagues (37), using 31P nuclear magnetic spectroscopy, reported a simultaneous fall in pH and increase in MSNA in humans during static exercise, consistent with a dominant role. Sinoway and colleagues (32), on the other hand, also used 31P nuclear magnetic spectroscopy and found a dissociation between muscle pH and MSNA. MacLean and colleagues (16) used the microdialysis technique to measure interstitial levels of ischemic metabolites during 5 min of leg exercise in healthy humans while simultaneously measuring MSNA. They found a decrease in pH and increases in lactate and MSNA during exercise. Interestingly, during recovery, pH and MSNA levels rapidly returned to baseline, but lactate continued to decline further, suggesting that in healthy humans, pH, lactate, and MSNA levels are dissociated.
The studies of muscle mechanoreflex control of MSNA in heart failure are few (15, 19, 33). In the rat infarct model of heart failure, Smith and colleagues (33) used passive muscle stretch using a rack and pinion system to preferentially stimulate the muscle mechanoreceptors. They found that passive muscle stretch in the heart failure model evoked elevations in MAP and HR significantly above those of sham and control rats, consistent with heightened muscle mechanoreceptor sensitivity. Mechanisms of this heightened sensitivity remain unstudied and unknown. To date, no studies have examined the compounds that may potentially sensitize muscle mechanoreceptors in heart failure in humans or in animals. In patients with heart failure, the focus of studies of exercise dysfunction has been muscle metaboreceptor control, especially of respiration (21, 27–29). Scott and colleagues (27) used sodium bicarbonate infusion during intense (50% MVC) rhythmic handgrip exercise to reduce the H+ concentration and found that a reduction in H+ concentration markedly diminished the metaboreceptor-mediated increases in ventilation. MSNA was not measured during these protocols. Thus our study is the first to study muscle mechanoreceptor control of MSNA in humans with heart failure.
Two lines of evidence in these studies support the notion that muscle mechanoreceptors are persistently sensitized in heart failure, independent of any further sensitization by metabolic by-products. First, by using passive exercise to isolate the muscle mechanoreceptors from central command and muscle metaboreceptors, we found a significant increase in MSNA in heart failure, but not in healthy humans, consistent with enhanced muscle mechanoreceptor sensitivity in heart failure. Second, during low-level rhythmic handgrip exercise in patients with heart failure, MSNA increased during the first minute of exercise. In contrast, in normal controls, MSNA did not increase until the third minute of exercise. This early increase in MSNA in patients with heart failure is consistent with chronically sensitized muscle mechanoreceptors. Just as may occur in chronic pain syndromes in which afferent nerve fibers are persistently sensitized by repetitive exposure to inflammatory compounds (5), muscle afferent nerve fibers in patients with heart failure may have undergone persistent changes after repetitive exposure to ischemic metabolites.
MSNA increased during rhythmic handgrip exercise in both patients with heart failure and normal controls, consistent with sensitization of muscle mechanoreceptors by metabolic by-products generated during exercise. Our study is the first to use a pharmacological intervention in humans to determine whether attenuation of lactic acid production would interfere with sensitization of muscle mechanoreceptor control of sympathetic excitation. We found that sympathetic activation during exercise was not attenuated in healthy humans or in patients with heart failure, despite attenuation in pH and lactate generation. These findings are consistent with the concept that lactic acid is not a critical component in muscle mechanoreceptor sensitization in humans. It may be that another compound, such as a prostaglandin, adenosine, potassium, or some other yet unidentified compound, is critical. Or it may be that there is redundancy in the sensitization process and that inhibition of only one compound is inadequate to prevent muscle mechanoreceptor sensitization.
Limitations
We recognize several limitations in this study. First, we drew venous samples at peak exercise for pH and lactate measurements ("peak pH" and "peak lactate"), but because we did not make serial measurements, we do not know if in fact these values changed further during recovery. In fact, using the microdialysis technique, MacLean and colleagues (16) found a further decline of lactate, but not pH, during recovery. Second, although DCA did significantly attenuate the changes in pH and lactate during exercise in both normal controls and patients with heart failure, perhaps the attenuation was not sufficient to block the mechanoreceptor sensitization. This seems unlikely because the degree of attenuation of pH and lactate in our study is similar to that during sodium bicarbonate infusion in the study of heart failure by Scott et al. (28), in which they reported a significant attenuation of the respiratory response to exercise, and similar to that in the study of Ettinger et al. (8) in normal humans, in which they reported a significant reduction in MSNA responses during static handgrip exercise. Furthermore, venous effluent pH and lactate levels are only estimates of the acid/base changes in the extracellular space of the muscle where the afferent nerve endings reside. Only the microdialysis technique has been successfully used in healthy humans to measure interstitial levels of ischemic by-products during 5 min of leg exercise, but this technique is not suitable for use in shorter exercise protocols in smaller muscle beds, such as was used in these protocols (16).
Although DCA did not attenuate the HR and blood pressure responses during exercise, the increases in HR and blood pressure were quite small and thus may have impeded our ability to detect an attenuating effect.
In conclusion, muscle mechanoreceptors are paramount to the increase in MSNA during low-level rhythmic exercise in healthy humans, and this muscle mechanoreceptor control is augmented further in patients with heart failure. Neither lactate generation nor the fall in pH that accompanies rhythmic exercise plays a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with heart failure have heightened basal sensitivity to mechanical stimuli, resulting in exaggerated early increases in MSNA. Further studies to determine the mechanisms of this persistent muscle mechanoreceptor sensitization in heart failure and to identify the metabolic by-product(s) that sensitize muscle mechanoreceptors further during rhythmic exercise are warranted in both normal humans and patients with heart failure.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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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.
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REFERENCES |
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