Page 27 - 82_01

3. ISCHEMIA AND REPERFUSION
Sudden interruption of blood supply through a
coronary artery can occur in patients as a result of the
rupture or erosion of an atherosclerotic plaque situated in
the wall of a coronary artery, with a superimposed
thrombosis of this artery. Sudden interruption of blood
supply through a coronary artery also can be reproduced
in laboratory animals in which mechanical occlusion of a
coronary artery can be induced. In both cases, coronary
occlusion results in myocardial infarction if coronary
perfusion is not restored within <40 min. Following a lag
phase of fully reversible damage, myocardial infarction
spreads depending on duration of coronary occlusion as a
wave front phenomenon from the most central core of the
affected coronary perfusion territory to its peripheral
borders. The main determinants of the final amount of
myocardium affected (size of the myocardial infarction)
are the coronary circulation (area at risk), duration of
coronary occlusion and presence of collateral blood flow.
The area at risk is the anatomic perfusion territory of the
coronary artery distal to the site of its occlusion, and this mitochondrial membranes reduces the ability of cells to
area determines myocardial infarct size, and infarct size
is a principal determinant of prognosis of patients. The
duration of coronary occlusion is determined both by the
initial occlusive event and the restoration of coronary
perfusion, and this restoration may be spontaneous or
through a therapeutic intervention. In healthy and young
experimental animals, the coronary circulation may be
not compromised by atheromathosis and the onset and
release of the mechanical coronary occlusion are clearly
defined. In patients, however, the situation is very
different and more complex, as coronary vasculature is
usually deseased, and complete coronary occlusion may
be preceded by intermittent changes in blood flow. In
addition to the area at risk and the duration of coronary
occlusion, residual blood flow through the coronary
collateral circulation may be a significant determinant of
infarct size. Studies in experimental animals have been
performed in species with and without an innate coronary
collateral circulation, and therefore the conditions differ.
In humans, that have an innate coronary collateral
circulation, the possibility of a recruitable collateral
circulation may improve the outcome of patients with
coronary artery disease (for details, see Reference 14).
Questions that could be of interest about this particular
issue are: damage of coronary vasculature and of
cardiomyocytes develops in parallel during ischemia-
reperfusion? Damage of coronary vasculature and of
cardiomyocytes influences each other during this
condition?
In relation to the effects of ischemia and reperfusion
on the heart, there are recent excellent revisions (9, 13,
14, 111-114), and these effects are summarized below.
3.1. Effects of ischemia
Coronary occlusion results in abrupt deprivation of
oxygen supply to the myocardium, which induces
26
Godofredo Diéguez Castrillo
ischemia and, it left uncorrected, death of myocytes by
necrosis. Cessation of oxygen supply disrupts aerobic
metabolism and oxidative phosphorylation with the
consequent depletion of ATP and other energy
compounds, and increased concentration of lactate and
acidosis in cardiomyocytes. Depletion of energy
compounds rapidly causes myocardial dysfunction and
detrimental effects on biochemistry and metabolism of
cardiomyocytes. These effects of oxygen deprivation,
however, can be reversed if the duration of ischemia lasts
<20 min. But if ischemia continues, irreversible injury
develops, which is characterized by disruption of
plasmatic, sarcolemmal and lisosomal membranes of the
cardiomyocytes. This induces loss of osmotic balance,
alteration of ions exchange through membranes and
leakage of cellular metabolites into the extracellular
space, with increased concentration and overload of
calcium inside of cells and remaining closed the
mitochondrial permeability transition pore. Damage of
produce ATP upon reperfusion, as well as the release of
digestive enzymes, culminating in cell necrosis and
apoptosis (13, 111-114).
The consequences of ischemia depend on several
factors, as for example the duration of the occlusion
(115), whether this ischemia is partial or global, and the
presence or not of functional collateral circulation (116).
Shrader et al. observed a reduction of 65% in ATP after
15 minutes ischemia (117), and Jones et al. in a murine
model observed a reduction of 95% in ATP after 40
minutes ischemia (118). At the beginning of ischemia,
the oxidative phosphorylation stops to work, and there is
a transition from aerobic to anaerobic respiration, which
may be detectable by observation of the
electrocardiographic modifications (119) and the
decrease of the myocardial contractility (120). In the
myocardium, the activated glycogenolysis is quickly
slowed down and the intracellular pH may decrease to 6.
2 after 10 min (121). The cause of the decrease in pH
during ischemia is not clear (122, 123).
3.2. Effects of reperfusion
In the 1960s, R. B. Jennings and cols. (12) and R. A.
Krug et al. (124) published that reperfusion by itself can
damage the myocardium previously exposed to ischemia,
and advanced the pioneering concept of “reperfusion
injury” (13). These authors showed that if reperfusion is
applied within 20 min after provoking coronary
occlusion, myocardial affected is recovered and did not
die. When ischemia was prolongedto20-40 min before
institution of reperfusion, subendocardial myocardial
cells underwent necrosis, but midmyocardial and
subepicardial cells were salvaged. When duration of
ischemia extended from 40 min to 3 h, necrosis affected
in ischemic risk zone from the subendocardium to the
subepicardium. During this ischemia, it develops the
phenomenon known as “wave front phenomenon of
ischemic cell death” (13, 111-114, 125, 126). These ideas
@Real Academia Nacional de Farmacia. Spain