Update on Cardioprotective Strategies for STEMI

Highlights • Beyond restoring myocardial perfusion, there is an unmet need to further reduce the size of myocardial infarctions; only 1 therapy is FDA-approved to specifically treat ischemic myocardium as an adjunct to reperfusion therapy.• Here, we present the basic science and clinical studies showing that treatment with supersaturated oxygen following mechanical reperfusion therapy in patients with large anterior myocardial infarctions improves myocardial perfusion and reduces infarct size.• Early clinical studies also show that supersaturated oxygen improves left ventricular function and reduces adverse left ventricular remodeling in patients with large anterior myocardial infarctions.

Experimental studies confirmed that early reperfusion reduced infarct size (5), and clinical studies revealed that effectively reperfusing the infarcted artery as soon as possible and preventing reocclusion were the foundations to minimize infarct size and mortality. Stenting plus abciximab was shown to reduce infarct size compared to alteplase alone (6).
However, there is still an unmet need to further reduce the MI size using agents and therapies that directly protect the myocardium while opening the infarcted artery and keeping it patent. Despite reducing mean door-to-balloon times to <90 minutes (w60 minutes at most major U.S. medical centers) and the routine use of optimal pharmacology, 20%-30% of acute MI (AMI) patients still develop heart failure (HF) within 1 year (9), and 30-day mortality rates in AMI patients >65 years of age are approximately 12% (10). Unfortunately, resulting infarct size is often substantial, despite timely myocardial reperfusion (11). Although 85%-90% of STEMI patients experience restored coronary flow (Thrombolysis In Myocardial Infarction [TIMI] flow grade 3) via primary percutaneous coronary intervention (PCI), it has been observed that microcirculatory perfusion and myocardial metabolism are not restored in w50% of cases (12,13).
Salvaging an additional 5% of the LV myocardium can have major beneficial effects on clinical outcomes, including reducing mortality and new-onset HF (11). Therapies beyond timely reperfusion to further reduce infarct size have been studied over several decades. Yet, although many such therapies have shown promise in the experimental laboratory, few have shown benefit in randomized clinical trials (14)(15)(16).
Many therapies that worked in experimental models failed when tested clinically (often referred to as the "graveyard" of therapies) (14)(15)(16). There are potential reasons for these failures as described in previous reviews (14)(15)(16).
One major mechanism of infarct size reduction targeted by many of these therapies is the prevention of reperfusion injury (ie, the mechanisms whereby the reperfusion process itself harms ischemic, but not yet necrosed, cardiomyocytes). Whereas some investigators claim that about one-half of all cell death during an infarct is caused by reperfusion, others are less convinced of the existence of reperfusion injury in humans or its substantial role in myonecrosis (17)(18)(19).

THERAPIES TO REDUCE INFARCT SIZE
Despite a host of negative studies, there are still a few approaches that have shown promise for further reducing MI size beyond epicardial reperfusion alone ( Table 1). Some recent studies have also suggested that a few of these therapies may reduce adverse LV remodeling with or without acutely reducing MI size.
First, in 2 separate multicenter randomized trials prolonged adenosine intravenous infusions resulted in a reduction of MI size in patients with anterior STEMI (20,21). It is important to note that in these studies, adenosine was initiated before reperfusion and included a lengthy (3-hour) infusion. Studies of   LV unloading before reperfusion may reduce infarct size by decreasing oxygen demand, increasing oxygen supply, and activating cardioprotective mechanisms (26), which is being tested in an ongoing pivotal randomized trial (27). Pilot studies have suggested that pressure-controlled intermittent coronary sinus occlusion may reduce infarct size by redistributing coronary flow to watershed ischemic zones (28).
Studies on post-conditioning-a series of brief ischemia-reperfusion cycles induced after achieving patency of the infarct-related coronary artery-have been mixed, with early studies of mechanical or pharmacologic post-conditioning (eg, with cyclosporine A that also blocks opening of the mitochondrial permeability transition pore) showing enhanced myocardial salvage (29,30), but with later larger studies failing to show reduced infarct size (31) or improved clinical outcomes (32). However, 1 study did show that post-conditioning was associated with less adverse LV remodeling than in the placebo group (31), and most recently, a randomized trial in 270 patients reported that remote ischemic conditioning within 48 hours post-PCI reduced adverse LV remodeling (33). Remote ischemic conditioning (inducing ischemia in a remote tissue, such as a limb, before reperfusion) has also shown mixed results on MI size. An early study in 333 patients reported that this therapy reduced infarct size and improved long-term outcomes (34,35). A subsequent randomized trial in 5,401 patients failed to show any benefit (36). However, patients in this trial may have been low risk, because it was noted that the control group had an unusually low rate of adverse cardiovascular events. Other approaches include 1 2006 study reporting that atrial natriuretic peptide may modestly reduce infarct size and increase LV ejection fraction (LVEF) with no effect on mortality (37).
Exenatide is a glucagon-like peptide-1 receptor agonist, which in 1 2014 study (38) increased salvage index in patients with MIs whether they were normoglycemic or hyperglycemic. However, a 2016 study failed to observe any reduction in infarct size with the addition of exenatide (39).
Hyperoxemic infusion of SSO 2 therapy has shown promise as an adjunct to primary PCI. In the AMIHOT (Acute Myocardial Infarction with Hyperoxemia Therapy) I and II trials, patients with anterior wall STEMI who were reperfused within 6 hours had smaller LV infarcts with SSO 2 therapy compared with controls (18.5% vs 25% of the total LV mass) (40).   Control groups received normoxemic reperfusion by The patient is administered a 60-minute infusion of supersaturated oxygenated blood at a flow rate of 100 ml/min with a PO 2 (pO 2 ) of 760-1,000 mm Hg into the left main coronary artery immediately following successful percutaneous coronary intervention. SSO 2 ¼ supersaturated oxygen.       To enhance the safety of SSO 2 therapy, an "opti-     confirming that early SSO 2 therapy reduces adverse LV dilatation (remodeling) during the healing phase of infarction ( Figure 8). These data suggest that infusion of SSO 2 therapy following primary PCI in patients with anterior STEMI is safe and may improve 1-year clinical outcomes (57), although a randomized trial adequately powered for clinical events is required to determine the long-term consequences of this therapy.
Details on how to perform SSO 2 delivery and other practical issues are contained in the Supplemental Appendix.

CONCLUSIONS
The clinical studies completed to date have demonstrated that SSO 2 therapy is a safe and efficacious adjunctive agent to use with reperfusion to reduce infarct size, preserve cardiac function, reduce adverse LV remodeling, and potentially improve clinical outcomes in patients with acute anterior STEMI reperfused within 6 hours of symptoms. A major advantage of this treatment compared with many other investigative therapies to reduce infarct size is that reperfusion is not delayed. Future studies will examine the real-world outcomes of SSO 2 therapy in STEMI and further explore its effect on clinical outcomes following STEMI. KEY WORDS LV function, LV remodeling, myocardial infarct size reduction, STsegment elevation myocardial infarction, supersaturated oxygen APPENDIX For a supplemental methods section, please see the online version of this paper.