Muscle metaboreflex and exercise heart rate: insights from studies in subjects with and without heart failure

We read with interest the recent work of Fisher et al. (2010), who demonstrated, in healthy young men, that muscle metaboreflex-induced sympathetic excitation contributes to the heart rate response to ischaemic handgrip exercise in a graded manner. This effect, masked at lower intensity of exercise by parasympathetic reactivation at the cessation of handgrip, was unmasked by glycopyrrolate during post-handgrip ischaemia, which prolongs metaboreflex stimulation of muscle afferents independently of central command and muscle mechanoreflex influences, and abolished by β-blockade. The authors interpret their findings as indicating that heart rate returns to resting values during ischaemia after moderate exercise because of an overwhelming effect of parasympathetic reactivation, which counters metaboreflex increases in cardiac sympathetic activity. However, after more intense handgrip, cardiac sympathetic activity predominates and the impact of parasympathetic restoration is less obvious. Although this concept has been supported by animal work (O’Leary, 1993), it has not been investigated directly in humans as in the present study (Fisher et al. 2010). Fisher et al. (2010) speculate that in the absence of parasympathetic reactivation, increased cardiac sympathetic nerve activity should delay the post-exercise recovery of heart rate and propose heart failure, which is characterized by augmented cardiac sympathetic activation and diminished cardiac vagal heart rate modulation (Floras, 2009), as an important clinical condition where this independent predictor of mortality (Cole et al. 1999) may be particularly evident. Our own studies of post-handgrip ischaemia provide independent validation of the mechanism tested by Fisher which is of potential concern in heart failure. Our principal findings were: first, that in heart failure the muscle metaboreflex elicits a greater increase in muscle sympathetic nerve activity during ischaemic or intense non-ischaemic handgrip exercise than in age-matched healthy controls; second, that this excitatory reflex response occurs at a lower threshold in heart failure than in healthy subjects; and third, that the magnitude of this effect is a function of exercise capacity (Notarius et al. 2001). Importantly, unlike the young men studied by Fisher et al. (2010), in our series all subjects were of middle age. As we commented upon in the Discussion in our paper, in contrast to the lower intensities of dynamic handgrip (10% and 30% MVC), heart rate did not return to baseline in these heart failure patients after ischaemic (30% MVC) and intense non-ischaemic (50% MVC) handgrip exercise. A graded response to ischaemic and non-ischaemic handgrip also was observed in simultaneously acquired microneurographic recordings of sympathetic nerve traffic directed at calf skeletal muscle. Our findings are therefore consistent with Fisher's hypothesis that diminished vagal drive in heart failure may be insufficient to counter the cardiac sympathetic excitatory response to metaboreflex stimulation once exercise ceases. Together, these clinical and experimental studies (O’Leary, 1993; Notarius et al. 2001; Fisher et al. 2010) offer compelling evidence in favour of a role for the muscle metaboreflex in stimulating the accelerated heart rate response to ischaemic handgrip exercise and intense dynamic exercise, and suggest that this mechanism may be of particular clinical relevance in conditions such as heart failure (Floras, 2009) or hypertension (Esler, 2010) that exhibit cardiac sympathetic excitation and blunted parasympathetic tone.

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