Future Research
Despite advances in methods and mechanisms of myocardial protection,
areas remain that could benefit from further exploration. The
pathological process of ischaemic-reperfusion injury (IRI) is central to
post-operative outcomes and therefore has potential for targeted
therapeutic intervention, to minimise the effects of reperfusion injury
on the heart.
The notion of IRI was first observed in 1960 by Jennings et al. who
discovered extreme acceleration of necrosis in dog hearts following
ischaemia and subsequent reperfusion(51). The process
of IPC, as described above, was the first of its kind that focused on
mediating IRI as a method of cardioprotection, by making the heart
resistant to ischaemia prior to surgery(35). However,
there remains scope to further refine therapeutic interventions that
minimise the effects of IRI. This is possible due to the extensive
research into the mechanism of IRI, which has identified various
contributing pathways, with the long-term prospect to target each.
One such aspect for consideration is targeting the mitochondrial
permeability transition pore (mPTP). The role of mPTP in IRI has been
discussed since its first proposal in 1987 by Crompton et
al.(52). Opening of the mPTP is triggered in the
reperfusion phase of IR by Ca2+ influx, oxidative
stress and reversal of ischaemic induced
acidosis(52,53) . Upon opening of the pore, cell
swelling and apoptosis occurs, resulting in cardiomyocyte cell death.
The mPTP is therefore a candidate for targeting by novel inhibitors.
Cyclosporin A (CsA) and cyclophilin D (CyP-D) are two mPTP related
molecules. CsA is a non-selective inhibitor of mPTP and acts by binding
and inhibiting CyP-D, a mediator that facilitates the opening of the
pore. Research into its cardioprotective use have proven somewhat
beneficial. A study performed in 2015 found CsA reduced IRI in patients
undergoing aortic valve surgery(54).
However, Cyclosporin to Improve Clinical Outcome in STEMI patient
(CIRCUS), a phase III trial in MI patients, failed to show improvement
in all-cause mortality with CsA use(55). The
limitations of CsA lie within its non-specific nature, resulting in
inhibitory effects of other molecules such as cyclophilin A and B. These
unwanted side effects reduce the clinical translatability of CsA into
practice, and further research is needed to overcome these issues.
Identifying more specific inhibitory molecules, or altering the
structure of CsA(56) could prove useful in adapting
its functionality.