Preconditioning And Postconditioning

Conditioning of ischemic tissue refers to the characteristic that tissues may adapt to episodes of low oxygen supply or high oxygen demand and to the damage caused by subsequent reperfusion or reoxygenation. This phenomenon is amply recognized in vivo and in isolated organs, like heart and skeletal muscle, and is therefore considered an endogenous feature of the tissue. It can be elicited by brief periods of hypoxia or ischemia, mechanical stress (increased workload, asynchronous activation), but also by extrinsic stimuli, such as drugs (e.g. fluranes, opioids) and environmental stress (like heat). Preconditioning protocols typically apply protective stimuli before the onset of the ischemic period, whereas in postcon-ditioning stimuli are applied almost instantly upon reperfusion or reoxygenation. Myocardial preconditioning has been reviewed in depth recently [60]. Clearly, protection of tissue against damage is a subject of great scientific relevance. Nevertheless, its clinical application is limited, primarily because most ischemic events occur unexpectedly.

To the surprise of many, a few years ago the group of Vinten-Johansson showed that postconditioning of the myocardium, induced by brief coronary re-occlusion in the early reperfusion period, offers the same protection as preconditioning [61]. Post-conditioning obviously has a much wider clinical applicability than preconditioning. Indeed, recently the first patient study was published, showing that rapid reocclusions during PCI procedures reduces infarct size in patients by approximately 30% [62]. At least two recent reviews appeared on this topic [63, 64]. It appears that preconditioning and postconditioning share many triggers and molecular and cellular processes involved in their protective action. Therefore, the extensive research on preconditioning may find its greatest translational value in supplying knowledge for the rapidly evolving approach of postconditioning.

In studies, comparing the protective potential of early preconditioning and postconditioning, the degree of protection is either similar [61] or slightly higher in preconditioning [65-67]. Combination of pre- and postconditioning appears to have no additive effect, supporting the notion that they use the same cellular and biochemical mechanisms [68, 69].

While these studies employed classical ischemic preconditioning and postcondi-tioning protocols, we recently showed similar protection for preconditioning and postconditioning by dyssynchronous contraction [70].

The observation that postconditioning affords protection against ischemia-reperfusion injury equal to preconditioning, lends further support to the idea that these conditioning strategies primarily affect reperfusion and not ischemia injury. As illustrated in Figure 2, it was originally thought that preconditioning diminishes ischemic injury and as consequence also reperfusion injury (right panel) [71]. Postconditioning however cannot be expected to influence irreversible damage, which is developed during the period of ischemia. Thus, postconditioning presumably reduces reperfusion damage only (left panel).

4.1. Timing of Protection and Timing of Triggering

With respect to preconditioning two windows of protection are recognized exemplifying its time-dependency: the first (early) and second window of protection (Figure 3). The two windows are defined based on the delay of the protective effects with respect to the onset of the stimulus. The "early" protection starts approximately 10min after the stimulus and has a relatively short duration, i.e. about 2 hours after coronary occlusion [72]. The "second" window of protection is afforded by the same initial stimuli as early preconditioning, This delayed or "late" myocardial protection becomes apparent about 24 hours after conditioning [73, 74] and is

reperfusion reperfusion procedure procedure

Figure 2. Two concepts about the role of preconditioning and postconditioning on reduction of infarct size. Infarct size within a given area at risk progresses over time along an approximately S-shaped curve [71]. Reperfusion stops the gradual increase in infarct size due to damage caused by energy depletion (ischemic injury, I.I.), but induces a sudden reperfusion injury (R.I.). Postconditioning reduces R.I. (left panel; in this figure depicted as if postconditioning completely prevents R.I.), resulting in reduced total final injury (compare level horizontal line w/o conditioning with dashed line). Originally, preconditioning was considered to reduce I.I., thereby also reducing R.I. (right panel). However, recent evidence suggests that preconditioning might also primarily reduce R.I. (left panel)

reperfusion reperfusion procedure procedure

Figure 2. Two concepts about the role of preconditioning and postconditioning on reduction of infarct size. Infarct size within a given area at risk progresses over time along an approximately S-shaped curve [71]. Reperfusion stops the gradual increase in infarct size due to damage caused by energy depletion (ischemic injury, I.I.), but induces a sudden reperfusion injury (R.I.). Postconditioning reduces R.I. (left panel; in this figure depicted as if postconditioning completely prevents R.I.), resulting in reduced total final injury (compare level horizontal line w/o conditioning with dashed line). Originally, preconditioning was considered to reduce I.I., thereby also reducing R.I. (right panel). However, recent evidence suggests that preconditioning might also primarily reduce R.I. (left panel)

Early preconditioning

24-72 hrs

Early preconditioning

24-72 hrs

0-2 hrs

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