Exercise for Cardiovascular Disease Prevention and Treatment From Molecular to Clinical, Part 1

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of cell death: the first one in the acute initial phase of reperfusion injury and the

second one in a more chronic period (days) post-reperfusion. While the mechanisms

responsible for the acute phase of reperfusion cell death were described previously

(excess ROS, Ca2+ overload and MPTP activation), the mechanisms in post-

reperfusion cell death include reminiscent irreversibly injured myocytes (once cell

death can take several hours to completion), regions of myocardial no-reflow and

progressive inflammatory reaction [ 46 ].

Due to limited capacity of cardiac myocytes for proliferation, even low levels of

cell death can result in myocardial functional impairment. Identification and quan-

tification of the different types of cell death may help to understand consequent

myocardial structural composition and the resultant functional behavior.

2.1 Levels of Post-reperfusion Myocardial Dysfunction

In the previous section a spectrum of cell derangements elicited by ischemia and

reperfusion was described. The level of myocardial function impairment that will

ensue depends on duration of ischemia, extent of committed area and pattern of

reperfusion.

Early and prompt restitution of coronary flow after an ischemic episode may

result in reperfusion arrhythmia. It occurs immediately with the onset of reperfusion

and is explained by large intracellular calcium oscillations. Short periods of isch-

emia followed by sudden reperfusion allow for cytosolic calcium overload and

excess recycling upon restitution of ATP level. Repetitive extreme calcium oscilla-

tions result in transient ionic inward current and delayed after depolarizations [ 47 ].

This phenomenon is most likely to occur in the experimental setting where abrupt

reversion of coronary occlusion takes place. To date, only preliminary antiarrhyth-

mic action of selective inhibitors of NCX have been published [ 48 ].

A second level of myocardial dysfunction despite fully restored coronary flow is

stunning. In the stunned heart revascularization is complete and successfully

achieved in the absence of permanent damage, notwithstanding myocardial contrac-

tile function remains depressed. Full mechanical recovery can take hours, days or

even weeks to be accomplished [ 49 , 50 ]. The reduced mechanical efficiency is

explained by an intracellular functional remodeling resulting in decreased respon-

siveness of the contractile filaments to Ca2+. It is an adaptive response triggered by

Ca2+ overload and ROS damages to the contractile apparatus [ 51 , 52 ]. It has been

proposed that full myocardial recovery is accomplished after the damaged contrac-

tile proteins have been resynthesized [ 52 ].

Repetitive ischemia and stunning episodes can lead to a condition called hiberna-

tion, also characterized by myocardial hypo-contractility. In this condition,

depressed contractile function due to limited blood perfusion prevails. It is a vascu-

lar dysfunction in the absence of cell damage enabling cardiomyocytes to resume

contractile activity when revascularization takes place. Nevertheless, with pro-

longed chronic hibernation cardiomyocyte may atrophy and dye. Although the two

conditions, stunning and hibernation, can coexist, the first one is a hypo-contractile

J.P. Borges and K. da Silva Verdoorn