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period caused by full reperfusion and hibernation refers to hypo-contractile but
viable myocardium under limited blood flow [ 53 ].
Periods of prolonged ischemia followed by revascularization elicit the mostsevere level of IRI. Cardiomyocytes become irreversibly damaged and substantial
cell death can lead to tissue remodeling, progressive cardiac dysfunction and chronic
ischemic cardiomyopathy.
3 Cardioprotection Against Ischemia/Reperfusion Injury
Due to this major clinical problem, investments in therapeutic approaches to treat
IRI have been considered of importance in the research field [ 54 ]. On this matter,
Murry et al. [ 55 ] showed infarct size reduction after submitting anesthetized dogs to
4 periods of 5 min coronary artery occlusion interspaced by 5 min-periods of reper-
fusion before the onset of a 40 min sustained coronary occlusion. This phenomenon,
known as ischemic preconditioning, is a method whereby repeated brief ischemia
episodes confer cardioprotection against a subsequent longer ischemic insult (as
represented in Fig. 10.2A). It has been speculated that the preconditioning stimuli
triggers a signaling cascade of intracellular events and thus create a memory effect
that attenuates IRI. Among the putative mediators of this cardioprotection signal are
bradykinin, norepinephrine, adenosine, inhibitory guanine nucleotide binding pro-
teins, free radicals, opioids, protein kinase C (PKC), sarcolemmal and mitochon-
drial KAT P channels [ 56 ]. Ischemic preconditioning is a biphasic phenomenon with
two distinct windows of cardioprotection – the first one occurs within few minutes
after the ischemic insult and persists for only 1–2 h, while the second one starts after
12–24 h of IRI and lasts for 48–72 h [ 57 ].
The initial observation of ischemic preconditioning has encouraged innumerousscientists to investigate other possible cardioprotective strategies [ 4 , 54 ]. The major
strategies developed so far are briefly presented below:
- Ischemic post-conditioning: in contrast to unimpeded reperfusion, slowly bring-
ing the heart out of ischemia salvages myocardial cells (Fig. 10.2B). This inter-
mittent reperfusion interspaced with brief periods of myocardial ischemia after a
prolonged ischemic insult has been reported to attenuate IRI by reducing the
infarct size [ 58 , 59 ].- Remote ischemic preconditioning: it was first described in 1993 [ 60 ] that brief
episodes of ischemia in circumflex branch reduced the infarct size induced by 1 h
of sustained left anterior descending coronary artery occlusion and 4.5 h of
reflow. In other words, brief episodes of ischemia in one vascular bed protect
remote myocardium from subsequent sustained coronary artery occlusion of
another vascular bed. Unfortunately, the difficulty of accessing the heart’s arter-
ies may hinder the use of such strategy in most clinical interventions. On the
other hand, cardioprotection has also been achieved by applying brief periods of
ischemia to tissues or organs other than the heart, which could be easier for clini-
cal application [ 61 ].10 Cardiac Ischemia/Reperfusion Injury: The Bene cial Effects of Exercise