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Late preconditioning

Postconditioning

Figure 3. Time-intervals at which the "conditioning" stimulus should be applied in order to confer protection against the deleterious effects of ischemia/reperfusion therefore observed when the conditioning is initiated more than 24 hours before ischemia-reperfusion (figure 3). This protection window lasts for about 2 to 4 days [75]. In contrast to the first window, the second window seems to require de novo protein synthesis.

The two windows of preconditioning share signal transduction pathways necessary for execution of their protective properties [60], although early preconditioning is generally more effective than late protection. Analogous to the first window, also the second window of protection has been demonstrated to be inducible in patients experiencing pre-infarct angina. Like in early preconditioning, the delayed protective phase is observed in other organs than the heart, such as skeletal muscle [76]. Moreover, a preconditioning stimulus is able to precondition other regions within the same organ [77] or even organs remote from the site of that stimulus, a phenomenon entitled "remote preconditioning." [60, 78]

For postconditioning, timing of application of the stimulus is critical. Typically, application of the postconditioning stimulus should be applied within 1 to 10min after onset of reperfusion [67, 79] (Figure 3). This requisite is determined by the rapid sequence of events leading to reperfusion injury, such as formation of rapid oxygen species, calcium overload and mitochondrial swelling, all developing within minutes upon reperfusion.

4.2. Effects of Protection

The standard measure of protection is infarct size: the volume of infarcted, damaged tissue relative to the volume of tissue at risk. A reduction in infarct size is clinically important, because it is an important determinant of mortality [80]. Another clinically relevant measure of protection is the reduced incidence of arrhythmias such as ventricular tachycardia or fibrillation [69, 81-84] The anti-arrhythmogenic activity of the various conditioning procedures is likely associated with reduction in calcium accumulation upon reperfusion [85].

4.3. Mechanism of Preconditioning and Postconditioning

Myocardial protection can be induced by numerous general stressors, such as ischemia/reperfusion, heat shock, endotoxins, ventricular pacing (dyssynchrony), exercise and many pharmacological agents (e.g. adenosine, opioids, fluranes; for reviews see [86, 87]). Many of these stimuli have been shown to elicit both preconditioning -early and late- and postconditioning [63]. These stimuli give rise to a complex cascade of events that for the sake of clarity has been divided into 4 phases (Figure 4). The first phase identifies the triggers (metabolites and ligands) which are generated during the preconditioning challenge. The second phase includes the complex signal transduction pathways (including activation of kinases and transcription factors). The third phase involves the effectors, which are responsible for the observed protection, while the fourth phase identifies which functions are protected.

Each stimulus may activate various triggers and signaling pathways and some pathways are shared by various stimuli. Although one final common pathway probably does not exist, the number of final effectors appears to be limited. During recent years a prominent role for mitochondrial integrity has been evolving, with important roles for the mitochondrial permeability transition pore (mPTP) and the mitochondrial KATP channels in preconditioning and postconditioning. Also NO and HSPs are prominent effectors [60].

4.4. Stimuli for Conditioning

Already in 1986, it was shown that brief periods of reversible ischemia limited the infarct size caused by a subsequent prolonged period of ischemia [88]. Similar protection can be achieved by heat stress and by mechanical stimulation, both using the intrinsic protection mechanisms of the tissue. For skeletal muscle similar protection stimuli and mechanisms appears to exist [89, 90].

In the heart various kinds of mechanical overload can lead to protection. Increasing preload, by volume infusion in vivo or increase of the level of the atrial reservoir, causes preconditioning [91, 92]. Also dyssynchronous contraction induces preconditioning and postconditioning [70, 93]. While the discovery of pure dyssynchrony as stimulus for condition is quite recent, it is known for many years that rapid ventricular pacing induces preconditioning [94, 95]. This protection was explained by pacing induced ischemia as a result of increased workload. Since atrial pacing has similar hemodynamic effects and does not induce protection, this explanation needs to be revisited [96]. Studies from Koning et al. [97] and from our laboratory [93] showed that protection can be achieved by ventricular pacing at physiologic rates. We performed these studies in isolated perfused working rabbit hearts, where preload and afterload were kept constant and ischemia was avoided, leaving dyssynchrony of contraction as the sole explanation for the observed protection [93].

Time-line

Trigger

Signal Transduction

Effector

End -Effect

Early Preconditioning and Postconditioning

Bradykinin Opiods ROS Adenosine

MAPK PKC MEK/Erk-1

Akt/PI3

eNOS

mPTP

gap junctions

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