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POINT-COUNTERPOINT
David Geffen School of Medicine at UCLA
Department of Medicine (Cardiology)
Los Angeles, California
e-mail: hmiddlekauff{at}mednet.ucla.edu
Penn State Heart & Vascular Institute
Department of Medicine (Cardiology)
Hershey, Pennsylvania
PURPOSE AND SCOPE OF THE POINT:COUNTERPOINT DEBATES
This series of debates was initiated for the Journal of Applied Physiology because we believe an important means of searching for truth is through debate where contradictory viewpoints are put forward. This dialectic process whereby a thesis is advanced, then opposed by an antithesis, with a synthesis subsequently arrived at, is a powerful and often entertaining method for gaining knowledge and for understanding the source of a controversy. Before reading these Point:Counterpoint manuscripts or preparing a brief commentary on the content, the reader should understand that authors on each side of the debate are expected to advance a polarized viewpoint and to select the most convincing data to support their position. This approach differs markedly from the review article where the reader expects the author to present balanced coverage of the topic. Each of the authors has been strictly limited in the lengths of both the manuscript (1,200 words) and the rebuttal (400). The number of references to publications is also limited to 30, and citation of unpublished findings is prohibited.
POINT: INCREASED MECHANORECEPTOR STIMULATION EXPLAINS THE EXAGGERATED EXERCISE PRESSOR REFLEX SEEN IN HEART FAILURE
The concept that exercise limitation in patients with chronic heart failure (HF) is due to elevated filling pressures or inadequate cardiac output has been largely abandoned and replaced by a new paradigm. "The Muscle Hypothesis of HF," originated by Drs. Coats and Piepoli (1, 11), hypothesizes that abnormalities of skeletal muscle, including the sensory nerve fibers that mediate reflex changes in the circulation during exercise underlie the exercise limitations in HF. The question debated today is which sensory fibers are responsible for the reflex abnormalities during exercise?
Located within skeletal muscle, the sensory nerves mediating the reflex changes during exercise, termed the "exercise pressor reflex" (EPR), consist of type III mechanoreceptor fibers that are principally sensitive to mechanical stimuli and type IV metaboreceptor fibers that are principally sensitive to ischemic metabolites generated during exercise (3). In healthy humans, it is generally agreed that the muscle metaboreceptors, in conjunction with a contribution from the central nervous system ("central command"), mediate the increase in EPR. The notion that muscle mechanoreceptor sensitivity is augmented in HF was launched following the report that the muscle metaboreceptor contribution to EPR is blunted in HF (18). In humans, the muscle metaboreceptor contribution to reflex responses during exercise is isolated by "postexercise circulatory arrest" (PECA), in which a blood pressure (BP) cuff proximal to the exercising muscle is inflated to suprasystolic levels at the termination of exercise. This traps ischemic metabolites within muscle and selectively engages metaboreceptors without stimulating mechanoreceptors or central command. During 2 min of moderate handgrip exercise in NYHA Class II-IV HF patients, muscle sympathetic nerve activity (MSNA) increased, but then during PECA, which isolated the muscle metaboreceptors, plummeted to baseline levels (Ref. 18; Fig. 1). Thus the metaboreflex is blunted in HF and replaced by another system, such as muscle mechanoreflex or central command. If the muscle mechanoreflex were the mediator of the EPR in patients with HF, we would anticipate an immediate increase in MSNA at the onset of exercise, which would return to baseline during PECA. Low-level rhythmic exercise preferentially stimulates muscle mechanoreceptors over metaboreceptors. During low-level rhythmic handgrip (5), MSNA increased within the first minute of exercise in HF patients, but only in the third minute of exercise in healthy humans, consistent with heightened muscle mechanoreceptor sensitivity in HF. To further isolate the muscle mechanoreceptors from central command, passive exercise was employed and MSNA was recorded (5). MSNA increased significantly during passive exercise in HF patients, but not in healthy humans. This sensitization of muscle mechanoreceptor control in HF has been reported to be proportional to HF severity (8). Furthermore, muscle mechanoreceptor control of renal vascular resistance during exercise is also augmented in humans with HF (6, 7).
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How do we reconcile these conflicting results of heightened muscle metaboreceptor versus mechanoreceptor sensitivity in HF? Let's consider the possible explanations.
1) The increased metaboreceptor sensitivity position largely depends on measurement of the ventilation, whereas the increased mechanoreceptor sensitivity position largely depends on neurovascular measurements; is it possible that augmented mechanoreceptor control of BP and MSNA coexists with augmented metaboreceptor control of ventilation? Possible, but unlikely. At present we know of no other neural circuitry in humans or animals that behaves in this fashion.
2) Variability in the exercise protocols used, specifically exercise type, site, duration, and degree. Unlikely, inasmuch as our adversaries have reported the satisfactory reproducibility and significant correlation of muscle metaboreceptor contribution to ventilation during the EPR during both handgrip exercise and cycling in HF patients (12, 13).
3) These human experiments rely on specific maneuvers to preferentially isolate one neural control system over another, but there may be overlap. For example, PECA isolates the metaboreceptor contribution to the EPR and some patients will complain of pain during PECA. However, subjects do not normally complain of pain during the EPR; thus, in some individuals, PECA may actually stimulate nociceptive neurons not engaged during the EPR. These changes seen by PECA may be mediated by muscle metaboreceptors and to an unknown extent by nociceptors. Each of the techniques have been used to isolate the muscle mechanoreceptor contribution to the EPR is imperfect: low-level rhythmic exercise also engages central command and perhaps even metaboreceptors, involuntary contraction can be painful and recruitment patterns are not physiological, and passive exercise may evoke an arousal response. Thus one explanation for discrepant results is that the techniques to isolate one muscle receptor type may inadvertently stimulate another.
Finally, 4) each small group of HF patients studied by different investigators, or even by the same investigators, is likely heterogeneous in many respects, including degree of cachexia and muscle atrophy, daily activity level, nutritional status, confounding diseases including diabetes and renal insufficiency, HF etiology, gender, HF duration, duration on treatment, and types of treatment. In summary, heterogeneous patient populations studied with imperfect techniques likely underlie the controversy explored in this debate.
Let us now look to animal models of HF, in which we can be more secure regarding the homogeneity of the study group and the selectivity of the afferents being engaged by the various maneuvers used. For example, metabolically sensitive group IV neurons can be selectively activated by capsaicin infusions into the arterial supply of the hindlimb muscle. In the infarct model of HF in rats, intra-arterial capsaicin led to a blunted BP response in HF rats compared with controls (4). Muscle mechanoreceptor stimulation with 
,
-methylene ATP enhanced the BP response to muscle stretch to a greater degree in HF rats compared with controls. Similar results were reported from an independent laboratory using a similar, but not identical, protocol (17). Moreover, in the infarct model of HF in rats, the EPR, including BP and heart rate, were significantly exaggerated in HF rats compared with controls during static muscle contraction. A dose-dependent increase in BP in response to intra-arterial capsaicin was observed in healthy rats, but was significantly blunted in HF rats (17). Furthermore, when muscle mechanoreceptors were blocked using gadolinium, this exaggerated EPR in HF rats during muscle contraction was eliminated. In summary, studies using the rat infarct model of HF provides convincing data that increased mechanoreceptor stimulation explains the exaggerated EPR seen in HF. These data strongly support our premise that metaboreceptor activity is reduced and mechanoreceptor activity is increased in HF.
Although we are indebted to Drs. Coates and Piepoli for their work examining the role muscle afferents play in mediating symptoms in HF, we think that they have erred in the details. We hope that we have now set the record straight.
REFERENCES
This article has been cited by other articles:
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  Z. Gao, S. Koba, L. Sinoway, and J. Li 20-HETE increases renal sympathetic nerve activity via activation of chemically and mechanically sensitive muscle afferents J. Physiol., May 15, 2008; 586(10): 2581 - 2591. [Abstract] [Full Text] [PDF]
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 A. Crisafulli, E. Salis, F. Tocco, F. Melis, R. Milia, G. Pittau, M. A. Caria, R. Solinas, L. Meloni, P. Pagliaro, et al. Impaired central hemodynamic response and exaggerated vasoconstriction during muscle metaboreflex activation in heart failure patients Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2988 - H2996. [Abstract] [Full Text] [PDF]
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 M. K. Stickland, J. D. Miller, C. A. Smith, and J. A. Dempsey Carotid Chemoreceptor Modulation of Regional Blood Flow Distribution During Exercise in Health and Chronic Heart Failure Circ. Res., May 11, 2007; 100(9): 1371 - 1378. [Abstract] [Full Text] [PDF]
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