Cardioprotection at a distance – remote conditioning takes the stage

Cardioprotection often means keeping the coronary arteries in good health. Increasingly and more logically, we are focussing on how best to protect the myocardium directly, and the most intriguing mode of protection is the subject of a recent paper in Experimental Physiology on remote conditioning by Basaly et al. (2012). Until a few years go, it would have stretched scientific belief that transient occlusion of the femoral arteries would protect the heart from ischaemic and reperfusion injury. Yet in 1993, Przyklenk et al. had shown how preconditioning of one area of the myocardium, by repeated coronary occlusions and reperfusion, could protect a distant myocardial zone, thereby setting the scene for remote preconditioning. Then in a flash of inspiration in 1996, Gho et al. found that brief occlusion of remote arteries in the abdomen protected against myocardial infarction. Regarding mechanisms, ganglion blockade abolished the protection. However, mainstream cardiologists paid little attention. Then we can fast-forward to Hausenloy & Yellon (2008), who elegantly extended the concept of remote organ protection beyond that of solely protecting the heart to providing ‘a general form of inter-organ protection against ischaemia–reperfusion injury’. Among the recent controversies in cardioprotection is whether reperfusion damage occurs rapidly and within minutes of reperfusion, but not thereafter, versus the novel point of view first proposed by Roubille et al. (2011) that application of postconditioning could be delayed. These workers, using a mouse model, were able to show in their article in Circulation that delayed postconditioning was effective in reducing infarct size up to 45 min after the onset of reperfusion. Thus, remote conditioning is a powerful tool, applicable both before and after the opening of the blocked coronary artery, as in an acute heart attack (acute myocardial infarction) by rapid percutaneous intervention. The article by Basaly et al. (2012), using a rat model, has tackled the mechanism of these important observations and confirmed that remote ischaemic conditioning applied to the femoral arteries was effective 10 min after the onset of reperfusion but, in this case, ineffective when applied 30 min afterwards. They confirmed that lethal reperfusion injury not only occurs very rapidly, within minutes after the onset of reperfusion, but that there could be a longer time delay for the therapeutic application of remote postconditioning. How do the messages travel from the remote site (in this case, the occluded–reperfused femoral arteries) to the heart? The two main mechanisms are travelling by the bloodstream or by the autonomic nervous system (Hausenloy & Yellon, 2008). The article by Basaly et al. (2012) stresses the role of the intact parasympathetic nervous system in remote ischaemic preconditioning. Another elegant article by Shimizu et al. (2009) found that diasylate of plasma from rabbits and humans with remote ischaemic preconditioning protected an isolated heart from necrosis. This protective effect was blocked by pretreatment with the opiate receptor blocker naloxone, the process thus requiring opioid receptor activation. The opioid receptors in turn respond to parasympathetic stimulation (Deo et al. 2009), so that mechanistically there seems to be a duet, with both parasympathic and vascular mechanisms playing mutually interactive roles. The involvement of the vagal/parasympathetic system in remote preconditioning, as shown by Basaly et al. (2012), is important and relevant. Certain drugs given to patients with acute infarction promote vagal activity; for example, morphine given for pain acts on opioid receptors. Other drugs, namely the β-receptor antagonists, promote vagal activity by blocking sympathetic activity. Added to that, remote preconditioning applied by repetitive intermittent limb occlusion by a blood pressure cuff should have an additive powerful protective effect. To prove the expectation that mortality in patients with threatened acute myocardial infarction could be reduced by remote preconditioning would require large, prospective, well-designed clinical studies, of which several are in the planning stage or the pipeline. Yet, in the meantime the harmless procedure of pumping up and down a blood pressure cuff can and should be applied in the ambulance with the knowledge that ultimate infarct size is modestly decreased and, there even better, are no serious adverse effects.

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