Abstract
Myocardial ischaemia–reperfusion injury can be significantly reduced by an episode(s) of ischaemia–reperfusion applied prior to or during myocardial ischaemia (MI) to peripheral tissue located at a distance from the heart; this phenomenon is called remote ischaemic conditioning (RIc). Here, we compared the efficacy of RIc in protecting the heart when the RIc stimulus is applied prior to, during and at different time points after MI. A rat model of myocardial ischaemia–reperfusion injury involved 30 min of left coronary artery occlusion followed by 120 min of reperfusion. Remote ischaemic conditioning was induced by 15 min occlusion of femoral arteries and conferred a similar degree of cardioprotection when applied 25 min prior to MI, 10 or 25 min after the onset of MI, or starting 10 min after the onset of reperfusion. These RIc stimuli reduced infarct size by 54, 56, 56 and 48% (all P < 0.001), respectively. Remote ischaemic conditioning applied 30 min into the reperfusion period was ineffective. Activation of sensory nerves by application of capsaicin was effective in establishing cardioprotection only when elicited prior to MI. Vagotomy or denervation of the peripheral ischaemic tissue both completely abolished cardioprotection induced by RIc applied prior to MI. Cardioprotection conferred by delayed remote postconditioning was not affected by either vagotomy or peripheral denervation. These results indicate that RIc confers potent cardioprotection even if applied with a significant delay after the onset of myocardial reperfusion. Cardioprotection by remote preconditioning is critically dependent on afferent innervation of the remote organ and intact parasympathetic activity, while delayed remote postconditioning appears to rely on a different signalling pathway(s).
Highlights
Ischaemic heart disease is a major cause of morbidity and mortality in the western world (Lloyd-Jones et al 2009)
Remote ischaemic preconditioning induced by 15 min occlusion of both femoral arteries, followed by 10 min of reperfusion applied prior to myocardial ischaemia conferred significant cardioprotection, as evident from a marked reduction in infarct size (19 ± 1%, P < 0.001; Fig. 1B and C)
The peripheral remote ischaemic conditioning (RIc) stimulus is efficient in protecting the heart when applied before myocardial ischaemia, during ischaemia and as late as 10 min after restoration of the blood flow through the compromised myocardium
Summary
Ischaemic heart disease is a major cause of morbidity and mortality in the western world (Lloyd-Jones et al 2009). Kin et al (2004), using a rat model of myocardial ischaemia– reperfusion, confirmed that IPost is only effective in protecting myocardium when applied not later than 1 min after the onset of reperfusion These results from in vivo experiments and numerous data obtained in studies conducted in isolated cardiomyocytes and whole heart preparations using a variety of techniques have led to a general consensus that any treatments of myocardial reperfusion injury can only be effective if applied either prior to or at the immediate onset of reperfusion (reviewed by Gomez et al 2009; Ovize et al 2010). Roubille et al (2011) have recently demonstrated in a mouse model that IPost confers significant cardioprotection when applied as late as 30 min after reperfusion onset These data directly challenged the prevailing concept that lethal myocardial injury occurs in the first minutes of reperfusion. Ischaemic myocardium can be protected by brief episodes of ischaemia–reperfusion applied either before or during ischaemia to peripheral tissue (Gho et al 1996; Kerendi et al 2005), and promising results of recent trials in patients with acute myocardial infarction (Bøtker et al 2010) may facilitate the introduction of RIc procedure(s) into clinical practice
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