Targeting reperfusion injury in patients with ST-segment elevation myocardial infarction: trials and tribulations

Time to Give Up on Cardioprotection?

“…To achieve that in the quartile of patients with the most severe myocardial infarction and an area at risk between 28.5% and 53% of the left ventricle, the cardioprotective intervention would need to reduce infarct size from 75% to <40% of the area at risk. Several subsequent consensus papers 13,19,228 agreed that patients with a large area at risk, notably those with an anterior infarction, would have the greatest benefit from cardioprotection and that trials with clinical outcome as end point should, therefore, focus only on these patients. For effective cardioprotection by ischemic postconditioning to become apparent, the coronary blood flow at admission must be of TIMI (Thrombolysis in Myocardial Infarction) grade 0 to 1, whereas with some spontaneous thrombolysis (TIMI 2-3), no further infarct size reduction is achieved, 192 possibly as a result of preexisting protection by gentle reperfusion in both the placebo and the intervention groups.…”

“…73,110,192 Finally, for effective cardioprotection to become apparent and clinically meaningful, there must be sufficient salvageable myocardium left, and the time from symptom onset to interventional reperfusion should be no longer than 2 to 4 hours. 19,230,231 On the contrary, with a short duration of ischemia, all ischemic myocardium may be rescued by reperfusion per se, and an additional cardioprotection may be difficult to demonstrate. 20,179,231 Also, with a short duration of ischemia, ischemic postconditioning may even add to myocardial injury.…”

“…[10][11][12] Therefore, additional interventions and treatments on top of timely reperfusion are still needed to reduce infarct size and improve the clinical outcome of patients with AMI. [13][14][15][16][17][18][19][20] Apart from acute STEMI (type 1 myocardial infarction), additional cardioprotection is also sought in elective PCI with the aim to reduce periprocedural myocardial infarction (type 4a) and in surgical coronary revascularization with the aim to reduce perioperative myocardial infarction (type 5) 21 ; in some studies, cardioprotection was also sought in major cardiovascular surgery other than coronary artery bypass grafting (CABG).…”

“…The translation of cardioprotection by the conditioning phenomena and by drugs that recruit part of their signaling to the clinical arena has been difficult to date. [13][14][15][16][17][18][19] Although there are several positive proof-of-concept studies for each of the conditioning phenomena, no phase III study has yet reported a better clinical outcome as the primary end point. With the neutral results of 2 recent phase III trial in cardiosurgical patients, that is, ERICCA (Effect of Remote Ischemic Preconditioning on Clinical Outcomes in CAGB Surgery) 37 and RIPHeart (Remote Ischemic Preconditioning in Heart Surgery), 38 and also a number of recent neutral trials which used drugs to recruit signaling steps of the conditioning phenomena in patients with AMI, that is, CIRCUS (Does Cyclosporine Improve Clinical Outcome in ST Elevation Myocardial Infarction Patients) 39 and CYCLE (Cyclosporine A in Reperfused Myocardial Infarction), 40 disappointment and frustration prevail.…”

Melatonin as an Agent for Cardioprotection in Patients with ST-Elevation Myocardial Infarction and Short Ischaemic Time

“…While the inhibition of mitochondrial permeability transition by postconditioning may be effective after a prolonged ischemic period, treatments that reduce mitochondrial dysfunction appear to be more effective after shorter ischemic periods [10]. The effect of melatonin in relation to duration of ischemia was not a part of the original statistical analysis plan, but the hypothesis came to our attention after the parent study was published.…”