Investigating the role of the JAK/STAT and MAPK ... - UCL Discovery

develop systolic dysfunction eventually resulting in congestive heart failure which can lead to
further hospitalisation or mortality.
1.2 Ischaemia/Reperfusion Injury
Following MI, interventions are aimed at restoring blood flow to the previously ischaemic
vascular bed. In a seemingly contradictory process however, restoration of blood flow, while
obviously being essential to restore cardiac function, can actually result in enhanced levels of
myocardial damage and increased infarct size (Eefting, 2004). This phenomenon of
reperfusion-induced damage, known as ischaemia/reperfusion (I/R) injury was first described
in 1960 and is caused by exacerbated death of cardiac myocytes which were viable until
immediately before reperfusion (Jennings et al., 1960). Despite successful medical
reperfusion following ischaemia, the incidence of cardiac failure after reperfusion stands at
25% and mortality rates at almost 10% which can be attributed to I/R injury (Keeley et al.,
2003) and myocardial I/R thus represents an important target for therapeutic intervention.
The publication of the AMISTAD (Acute Myocardial Infarction Study of Adenosine) study,
demonstrated for the first time that a drug could reduce infarct size in a multi-centre trial
(Mahaffey et al., 1999), however translation of positive pre-clinical results from other
potential therapies has been disappointing (Bolli et al., 2004).
I/R injury encompasses several types of myocardial dysfunction, including myocardial
stunning, no-reflow ischaemia, reperfusion induced arrhythmias and lethal reperfusion injury
(Yellon and Hausenloy, 2007). Myocardial stunning, also called post-ischaemic leftventricular
dysfunction, is manifested by mechanical dysfunction after ischaemia, even
though blood flow has been restored and there is no evidence of cellular necrosis
(Heyndrickx et al., 1975). The time taken to recover contractile performance varies but
damage to the heart is reversible and patients usually recover after several weeks (Barnes and
Khan, 2003). No-reflow ischaemia occurs when the microvasculature is obstructed after
ischaemia, pathologically this manifests as tissue compression, endothelial swelling, myocyte
oedema and neutrophil infiltration, all resulting in an inability to fully perfuse a previously
ischaemic area (Kloner et al., 1980). No-reflow occurs after the myocytes are already dead
and is associated with reduced left ventricular function, ventricular arrhythmia and cardiac
rupture; patients diagnosed with no-reflow therefore have a poor prognosis (Ito et al., 1996).
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