Myocardial ischemia-reperfusion injury: a neglected therapeutic target (original) (raw)

For patients presenting with a STEMI in whom acute myocardial ischemia has already taken place, the opportunity to intervene is limited to after the onset of myocardial ischemia or at the time of myocardial reperfusion (PPCI). The process of myocardial reperfusion by PPCI continues to be improved with earlier reperfusion, advances in PCI technology, and the introduction of more efficacious antiplatelet and antithrombotic agents for maintaining the patency of the infarct-related coronary artery. However, there remains no effective therapeutic agent for preventing either MVO or lethal myocardial reperfusion injury in patients with STEMI who are undergoing PPCI. Unfortunately, therapeutic targeting of the individual components of lethal myocardial reperfusion injury, including oxidative stress, calcium overload, pH correction, and, more recently, inflammation have produced disappointing results, the reasons for which are discussed below (59, 60).

However, a number of emerging therapeutic strategies for preventing lethal myocardial reperfusion injury have shown promise in small proof-of-concept clinical studies, and multicenter randomized clinical trials are currently underway to investigate the effects of these strategies on clinical outcomes in PPCI patients (Tables 1 And 2).

Table 1

Mechanical therapeutic interventions for preventing myocardial reperfusion injury in patients undergoing PPCI

Table 2

Pharmacologic therapies for preventing myocardial reperfusion injury in PPCI patients

IPost. In contrast to unimpeded reperfusion, IPost is intermittent reperfusion of the acute ischemic myocardium, which has been reported to prevent myocardial reperfusion injury and reduce MI size by 40%–50% (61). It must be appreciated that IPost represents a form of modified reperfusion that was demonstrated in the 1980s to be beneficial in the form of gradual reperfusion (62–65). Staat et al. (66) first applied IPost to the clinical setting of PPCI: immediately after direct stenting, coronary blood reflow was allowed for 60 seconds, following which the angioplasty balloon was inflated upstream of the stent for 60 seconds to occlude coronary blood flow, and this cycle was repeated 4 times in total (Table 1). The results of this study confirmed the existence of lethal myocardial reperfusion injury in humans (67). A number of clinical studies have subsequently confirmed the beneficial effects of IPost, although not all studies have had positive results (Table 1). A large multicenter randomized clinical trial is now underway in Denmark (DANAMI-3) to investigate the effects of IPost on clinical outcomes in PPCI patients (Clinicaltrials.gov identifier NCT01435408).

Remote ischemic conditioning. IPost requires an invasive therapeutic intervention applied directly to the heart. However, the heart can be protected against acute IRI from a distance, by applying one or more cycles of brief, nonlethal ischemia and reperfusion to another organ or tissue, a phenomenon that has been termed remote ischemic conditioning (RIC) (68, 69). In the clinical setting, RIC has been achieved noninvasively by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce three 5-minute cycles of ischemia and reperfusion (70, 71). This therapeutic approach has been reported to be beneficial in patients undergoing cardiac surgery (72–75) and in patients undergoing elective PCI (76). Most recently, Botker et al. (77) demonstrated that RIC applied by a paramedic to patients with STEMI in transit to the PPCI center improved myocardial salvage compared with control patients (Table 1). Again, the patients that benefited most from this therapeutic intervention were those presenting with an anterior STEMI and an occluded coronary artery (77). Whether RIC can actually improve clinical outcomes following PPCI is currently unknown.

Therapeutic hyperoxemia and hypothermia. Two other mechanical interventions that have been reported in animal studies to be beneficial against myocardial reperfusion injury include therapeutic hyperoxemia (78) and hypothermia (79). Hyperbaric oxygen reduces MI size by decreasing tissue edema, reducing formation of lipid peroxide radicals, altering nitric oxide synthase expression, and inhibiting leukocyte adherence and plugging in the microcirculation. Lowering myocardial temperature during ischemia to 32°C–33°C can limit MI size in experimental studies by reducing metabolic demand, reducing the inflammatory response, decreasing platelet aggregation, and increasing myocardial efficiency. Proof-of-concept clinical studies in PPCI patients have demonstrated these therapeutic interventions to be potentially promising (Table 1).

Pharmacologic agents for preventing myocardial reperfusion injury. Elucidation of the mechanistic pathways underlying IPost have resulted in the identification of a number of new targets to prevent myocardial reperfusion injury. These include pharmacologic modulators of the reperfusion injury salvage kinase prosurvival pathway, such as adenosine, atrial natriuretic peptide, atorvastatin, erythropoietin, exenatide, delcasertib, and GIK (Table 2). Other agents are known to preserve mitochondrial function during acute IRI, such as cyclosporin A, sodium nitrite, and TRO40303 (Table 2). However, the results of clinical studies investigating these agents have been mixed, with the most promising pharmacologic agents being cyclosporin A (80) and exenatide (ref. 81 and Table 2).