Exercise with angina and cramp?

Exercise training reverses the pathological symptoms of heart failure including the cardiac fibrosis and poor left ventricular ejection fraction. Yet, isn't this incongruous? Having heart failure is hardly conducive to doing a lot of physical activity let alone training. When you have heart failure you also have ‘exercise intolerance’ as manifested by dyspnoea, excessive ventilation, sympathetic activity and hypertension, the latter putting you at risk of stroke and lethal arrhythmias. The incongruity continues.

Notwithstanding these limitations, an intriguing question is raised: how does physical exercise assist the failing heart in its role of maintaining adequate blood perfusion throughout the body? Is there cross talk between contracting skeletal and cardiac muscles? And if so, what form does this take. A paper published by Wang et al. (2010a) in a recent issue of The Journal of Physiology has started to probe some of these questions and has contributed to our understanding of the changes that occur in the signals generated by contracting skeletal muscle in the condition of chronic heart failure.

Wang and colleagues have made a comprehensive study of the activity of two distinct types of afferent fibres innervating skeletal muscle that respond to mechanical stretch (group III) and locally released metabolites (group IV) in rats with chronic heart failure, induced a priori by ligation of the left anterior descending coronary artery. Chronic heart failure had a differential effect on these afferents with group III becoming sensitised and group IV desensitised.

The importance of group III and IV afferent fibres is well established. Physiological activation of these fibres by exercising (contracting) muscle through stretch and changes in the composition of the extracellular milieu respectively both contribute to the well described ‘exercise pressor reflex’ consisting of tachycardia, a rise in arterial pressure and tachypnoea. The relevance of this is to maintain cardiovascular and respiratory homeostasis during exercise, with the magnitude of the responses geared to the intensity of exercise. In heart failure, there is considerable evidence indicating that the exercise pressor response is exaggerated in animals with chronic heart failure (Smith et al. 2006; Wang et al. 2010b), perhaps leading to the exercise intolerance mentioned above as discussed by Wang et al. (2010a). However, Floras (2009) has recently emphasised the temporally related importance of the activated sympathetic nervous system during heart failure: it assists initially to preserve cardiac function but later compounds the progression of heart pathology. Functionally, sensitisation of the group III fibres may, therefore, bolster cardiac output during the early stages of heart failure to assist the failing heart.

The reason for the differential changes in group III and IV afferent sensitivity was also investigated by Wang et al. (2010a). They provided evidence of changes in receptor expression in dorsal root ganglion cells. They found increased purinergic (P2X receptor) involvement in the sensitization of group III afferents associated with increased P2X3 receptor expression in corresponding dorsal root ganglion neurones. In contrast, dorsal root ganglion neurones associated with group IV fibres exhibited a down regulation of transient receptor potential vanilloid type 1 (VR1). The significance of the VR1 mediated desensitization of group IV afferents remains unclear. However, by analogy, in conditions of cardiovascular disease where sympathetic overdrive is prominent, pain threshold is elevated and hypoalgesia expressed. Could heart failure itself cause an elevation of the threshold of group IV fibres in skeletal muscle? After all, these fibres were reported to be responsive to noxious pinching (Wang et al. 2010a). As it seems unlikely that there is a direct interaction between postganglionic sympathetic fibre activity (which is raised in heart failure) and modulation of primary afferent sensitivity (Elam et al. 1999) an additional mechanism must exist.

It is now known that exercise training suppresses the exaggerated exercise pressor response in heart failure rats (Wang et al. 2010b) supporting the notion of cross-talk between contracting skeletal and cardiac muscles as posed earlier. Heart failure increases pro-inflammatory cytokines that stimulate the sympathetic nervous system and angiotensin II activity leading to oxidative stress (Guggilam et al. 2008). Equally, the sympathetic nervous system modulates the immune system in cardiovascular disease (Levick et al. 2010). Could the activated immune cells and the associated release of inflammatory signalling molecules that occur in chronic heart failure affect group III and IV sensory afferents? The immune system is known to modulate the sensitivity of dorsal root ganglion cells including those mediating nociception (Djouhri et al. 2001). Also, inflammation increases expression of P2X3 receptors on dorsal root ganglion neurones (Ambalavanar et al. 2005). It now becomes pertinent to assess whether exercise training can restore expression levels of both P2X3 receptors and VR1 in cardiac sensory neurones. The question of whether increased P2X3 receptor expression and reduced VR1 expression is a cause or consequence of the inflammatory condition in heart failure must also be worked out if these are to be effective druggable therapeutic targets. It is noted that reduced numbers of VR1 in cardiac ganglion neurons appears to exacerbate inflammation and deterioration of cardiac function post-myocardial infarction (Huang et al. 2009), so who leads the ‘dance’ remains unclear.

In conclusion, Wang et al. (2010a) have provided data that may explain the exaggerated exercise pressor response and exercise intolerance in chronic heart failure. Their study has rallied a lot of new questions about exercise in individuals with heart failure. Evidence is unequivocal that exercise training alleviates the pathology, yet the incongruity remains as to how best to overcome the limitations of intolerance, especially dyspnoea. Based on the discussion above, one wonders whether anti-inflammatory treatment would improve exercise tolerance in individuals with chronic heart failure.