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.