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Experimental Physiology 91.1 pp 73-77
DOI: 10.1113/expphysiol.2005.031179
© The Physiological Society 2006
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Altered reflex cardiovascular control during exercise in heart failure: animal studies

Donal S O'Leary1

1 Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201


   Abstract
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 Abstract
Introduction
 References
 
This brief review summarizes recent studies describing the potential role of the muscle metaboreflex in mediating the altered cardiovascular responses to dynamic exercise in heart failure and the interaction between the muscle metaboreflex and the arterial baroreflex in these responses. In normal dogs, activation of the muscle metaboreflex (via partial reductions in hindlimb blood flow) during submaximal exercise, elicits a powerful pressor response. This increase in arterial pressure is mediated by an increase in cardiac output with little, if any, peripheral vasoconstriction. The metaboreflex pressor response is buffered by the arterial baroreflex via baroreflex-mediated inhibition of metaboreflex-induced peripheral vasoconstriction. In contrast, after induction of heart failure, the mechanisms involved in the muscle metaboreflex are shifted to vasoconstriction with little, if any, increase in cardiac output. The loss of the cardiac output response of the metaboreflex in heart failure probably stems from inability to improve ventricular function. The shift towards vasoconstriction in this setting may be due to depressed ability of the arterial baroreflex to buffer metaboreflex-induced peripheral vasoconstriction. The relative underperfusion of active skeletal muscle in heart failure may tonically activate the metaboreflex and this probably contributes to the enhanced sympatho-excitation seen during exercise in heart failure.

(Received 1 September 2005; accepted after revision 13 September 2005; first published online 22 September 2005)
Corresponding author D. S. O'Leary: Department of Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. Email: doleary{at}med.wayne.edu


   Introduction
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 Abstract
 Introduction
References
 
A hallmark feature of heart failure is decreased exercise tolerance, depressed cardiac output (CO) and elevated sympathetic activity at rest which can increase to extreme levels during strenuous dynamic exercise causing excessive tachycardia and often intense peripheral vasoconstriction (Vatner et al. 1971; Higgins et al. 1972; Hammond et al. 2000, 2001; see Figure 1). The mechanisms mediating these altered cardiovascular responses to exercise in heart failure are not well understood. This brief review will focus on the potential role of activation of skeletal muscle afferents, specifically those afferents activated by a build up of metabolites within the active skeletal muscle when a mismatch exists between oxygen delivery and oxygen demand – termed the muscle metaboreflex. The potential interaction between the muscle metaboreflex and the arterial baroreflex in mediating the altered cardiovascular responses to exercise will also be explored.



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  		Figure 1.  Effect of heart failure on cardiac and arterial plasma noradrenaline (norepinephrine) responses to graded exercise
Excercise ranged from mild (3.2 kph, 0% gradient) to heavy (8 kph 15% gradient) workloads. Control data, grey bars; heart failure, black bars. Adapted from Hammond et al. 2001).

 
Mechanisms mediating cardiovascular responses to exercise

The cardiovascular responses to dynamic exercise are thought to be due to the action of and likely interaction between the feed-forward effects of central command, and the feedback effects of activation of skeletal muscle afferents (both mechano-sensitive and metabo-sensitive), as well as resetting of the arterial baroreflex to a higher operating point (Mitchell et al. 1983; Rowell, 1993; Rowell et al. 1996). Together, these reflexes probably mediate the large changes in autonomic output causing increases in heart rate, ventricular function and central blood volume mobilization which increases CO. In addition, there is vasoconstriction of the peripheral vasculature which redistributes the available CO towards the active skeletal muscle. Even the active muscle is functionally vasoconstricted inasmuch as the vasodilatation is restrained by the increase in sympathetic tone (O'Leary et al. 1997). This restraint of muscle vasodilatation may be mediated by the arterial baroreflex to prevent a precipitous fall in pressure which could occur if the blood vessels of a large mass of active muscle dilated to anywhere near the maximum capacity (Rowell, 1988; Rowell et al. 1996). This restraint of skeletal muscle vasodilatation may also elicit activation of the muscle metaboreflex, especially in situations where muscle blood flow is already compromised, such as in heart failure.

In normal conscious dogs during submaximal exercise, the arterial (carotid) baroreflex and muscle metaboreflex are both capable of eliciting large increases in arterial blood pressure; however, they do so via very different mechanisms. Figure 2 compares the efferent mechanisms mediating pressor responses to unloading of the carotid baroreceptors (bilateral carotid occlusion) with that in response to modest activation of the muscle metaboreflex via partial reduction in blood flow to the hindlimbs (data summarizes the results from recent studies from our laboratory; Hammond et al. 2000; Augustyniak et al. 2001; Collins et al. 2001; Kim et al. 2004). Activation of either reflex during both mild and moderate treadmill exercise (3.2 kph and 6.4 kph, 10% gradient, respectively) elicited ~30–40-mmHg pressor response. The response to carotid occlusion was mediated almost solely via peripheral vasoconstriction (reduction in total vascular conductance). In contrast, a similar rise in arterial pressure by the muscle metaboreflex occurred almost solely via an increase in CO. Similar results to carotid unloading have recently been observed in humans (Ogoh et al. 2003). These data indicate that the carotid baroreflex exerts greater control over sympathetic activity to the peripheral vasculature, whereas the muscle metaboreflex exerts greater control over sympathetic tone to the heart.



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  		Figure 2.  Comparison of the mechanisms mediating pressor responses from the arterial (carotid) baroreflex and muscle metaboreflex
MAP, mean arterial pressure; CO, cardiac output; TVC, total vascular conductance. (Data from Hammond et al. 2000; Augustyniak et al. 2001; Collins et al. 2001; Kim et al. 2004).

 
This idea of differential reflex control of regional sympathetic outputs is further supported by our recent observations on the mechanisms of the muscle metaboreflex after arterial baroreceptor denervation (Kim et al. 2005b). Previously, Sheriff et al. (1990) had shown in conscious dogs that the metaboreflex pressor responses were ~2-fold greater after arterial baroreceptor denervation indicating that the baroreflex normally buffers the metaboreflex. We extended these observations by quantifying the mechanisms mediating this baroreflex attenuation of the muscle metaboreflex. After baroreceptor denervation, all of the increase in the strength of the muscle metaboreflex was due to peripheral vasoconstriction (Kim et al. 2005b); that is, in the control experiments all of the pressor response was due to increases in CO as previously observed, whereas after arterial baroreceptor denervation, the enhanced pressor response stemmed from substantial peripheral vasoconstriction occurring as well as increased CO. Thus, the baroreflex buffers the metaboreflex by limiting metaboreflex-induced peripheral vasoconstriction. The target vascular bed(s) constricted by the metaboreflex after baroreceptor denervation is not known. However, the ability of a given vascular bed to elicit substantial increases in arterial pressure via vasoconstriction is directly related to the fraction of the CO received by that bed (O'Leary, 1991). As workload increases, a progressively greater portion of CO is directed to the active skeletal muscle and a progressively smaller fraction is directed to inactive vascular beds (e.g. renal and splanchnic). Thus, the capacity of vasoconstriction in inactive vascular beds to raise arterial pressure becomes progressively smaller and that of vasoconstriction in active muscle becomes progressively greater as workload increases. Indeed Fig. 3 shows that for the pressor response to carotid occlusion, although substantial renal vasoconstriction occurs, the contribution of vasoconstriction in the kidney becomes negligible at higher workloads whereas vasoconstriction within active skeletal muscle becomes increasingly important and at high workloads this becomes the primary mechanism mediating the pressor response (Collins et al. 2001). These data indicate that active skeletal muscle may become a primary target vascular bed for metaboreflex-induced peripheral vasoconstriction when this reflex is left unbuffered by the arterial baroreflex. If this is the case, then one of the major functions of the baroreflex during exercise may be to prevent metaboreflex-mediated vasoconstriction of the active skeletal muscle. This could potentially set up a positive-feedback situation which could limit muscle perfusion and exercise capacity.



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  		Figure 3.  Contribution of vasoconstriction in the hindlimbs (skeletal muscle) and the kidney towards the pressor response to bilateral carotid occlusion at rest and across a broad range of workloads
Note as workload increases and the baseline level of hindlimb blood flow increases, the role of vasoconstriction in the kidney becomes trivial in terms of contributing to the pressor response, whereas that in active skeletal muscle becomes the primary mechanism. (Adapted from Collins et al. 2001)

 
Effects of heart failure

In contrast to the responses observed in normal subjects, in dogs after induction of congestive heart failure, the efferent mechanisms of the muscle metaboreflex are completely shifted from normally increases in CO with little, if any, peripheral vasoconstriction to little, if any, increases in CO and marked peripheral vasoconstriction (Hammond et al. 2000; O'Leary et al. 2004; Ansorge et al. 2005). How this occurs is not well understood. The loss of the CO response likely reflects the impaired ability to increase ventricular function. In normal dogs during submaximal workloads, the increase in CO stems from marked increases in ventricular performance (O'Leary & Augustyniak, 1998) combined with substantial central blood volume mobilization (Sheriff et al. 1998). In heart failure, whereas significant central blood volume mobilization still occurs (Hammond et al. 2000), the ability to improve ventricular function is markedly reduced (O'Leary et al. 2004) and little if any increase in CO occurs with activation of the muscle metaboreflex. Although a significant tachycardia still occurs, stroke volume falls and thus CO remains essentially unchanged (Hammond et al. 2000; O'Leary et al. 2004). Still, a pressor response occurs and since CO does not increase, all of this pressor response is due to peripheral vasoconstriction (Ansorge et al. 2005; Hammond et al. 2000; O'Leary et al. 2004). In heart failure, even the coronary circulation becomes vasoconstricted with metaboreflex activation (Ansorge et al. 2005). To what extent this coronary vasoconstriction further limits the ability to improve ventricular function in heart failure is not known although even in normal animals, previous studies have concluded that sympathetic activity limits ventricular perfusion and function during exercise (Huang & Feigl, 1988; Gwirtz et al. 1986; Gwirtz et al. 1992; Kim et al. 1996).

Whereas ventricular dysfunction as well as enhanced coronary vasoconstriction are likely reasons which limit the ability of the muscle metaboreflex to increase CO, how enhanced peripheral vasoconstriction occurs is not well understood. It is possible that the metaboreceptors are activated to a stronger degree in this setting (Smith et al. 2003; Shoemaker et al. 1998; Silber et al. 1998). Indeed, at higher workloads skeletal muscle blood flow is significantly attenuated and clearly low enough to elicit tonic activation of the metaboreflex (Hammond et al. 2000; Hammond et al. 2001). Another potential mechanism is reduced buffering by the arterial baroreflex. Baroreflex function is depressed at rest in heart failure (Chen et al. 1991; Chen et al. 1992; Grima et al. 1994; Olivier & Stephenson, 1993; Thames et al. 1993; Zucker & Wang, 1991) and we recently demonstrated that this suppressed baroreflex function persists across a broad range of exercise workloads (Kim et al. 2004). Very recently, we demonstrated that arterial baroreceptor denervation did not markedly affect the efferent mechanisms of the muscle metaboreflex in dogs with heart failure (Kim et al. 2005a); the pressor response was somewhat greater but the pattern remained as in the baro-intact, heart failure state – little change in CO and enhanced peripheral vasoconstriction. Thus, the extent of baroreflex buffering of the muscle metaboreflex appears reduced in heart failure which may explain how the metaboreflex is then capable of eliciting marked peripheral vasoconstriction. Again, the target vascular bed(s) are not known but given the size of the responses and distribution of the available CO, it is unlikely such a large decrease in systemic vascular conductance could occur without some vasoconstriction within the active skeletal muscle (Kim et al. 2005a). If this is the case, then this may exacerbate an already precarious situation further limiting muscle perfusion during exercise in heart failure.


   References
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Ansorge EJ, Augustyniak RA, Perinot ML, Hammond RL, Kim JK, Sala-Mercado JA, Rodriguez J, Rossi NF & O'Leary DS (2005). Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure. Am J Physiol Heart Circ Physiol 288, H1381–H1388.[Abstract/Free Full Text]

Augustyniak RA, Collins HL, Ansorge EJ, Rossi NF & O'Leary DS (2001). Severe exercise alters the strength and mechanisms of the muscle metaboreflex. Am J Physiol Heart Circ Physiol 280, H1645–H1652.[Abstract/Free Full Text]

Chen J-C, Wang W, Bartholet T & Zucker IH (1991). Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure. Circulation 83, 260–267.[Abstract/Free Full Text]

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Collins HL, Augustyniak RA, Ansorge EJ & O'Leary DS (2001). Carotid baroreflex pressor responses at rest and during exercise: cardiac output vs. regional vasoconstriction. Am J Physiol Heart Circ Physiol 280, H642–H648.[Abstract/Free Full Text]

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   Acknowledgements
 
The author's work is supported by a grant from the National Heart, Lung and Blood Institute HL-55473.




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