Long and narrow road to win over myocardial ischemia-reperfusion injury

Michele Samaja – Pasquale Pagliaro

Myocardial infarct (MI) is the world leading cause of morbidity and mortality. The MI severity depends on the extent of the ischemia-reperfusion injury (IRI) that occurs when oxygenated blood returns to tissue after a period of ischemia. A story of success, failure, and hope, the first recognition of IRI as a clinical entity dates back to the 70s [1]. Great hope to treat IRI came in 1986 when ischemic preconditioning (IPC) was discovered [2]. Since then, nearly 35,000 PubMed manuscripts published in the last 10 years met the search for “ischemia reperfusion” (PubMed), 11,300 of which were specifically devoted to IRI in the myocardium. Nevertheless, at present, IRI still remains a vexing, unsolved problem that did not meet a single fully supportive clinical trial [3] despite a plethora of positive results in animal and in vitro models. This clearly urges the need for basic and translational studies aimed at better understanding the multiple mechanisms underlying IRI.

In an excellent review, Algoet et al. [3] focused on two relevant aspects of particular interest to enlighten the long and narrow road to the treatment of myocardial IRI: the emerging role of inflammation, and the development of IPC, which appears today still the most powerful maneuver for protecting the heart and reducing MI – no pharmacological intervention is today superior to the recruitment of myocardial endogenous defense against stress.

Several mechanisms, but especially inflammation, play synergic, self-fueling roles in determining IRI. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome represents the common pathway toward which many pro-inflammatory factors converge. The activation of NLRP3 inflammasome after reperfusion concurs to the progression of IRI, promoting cardiomyocyte loss by inducing pyroptosis, and favoring adverse remodeling by inducing the excessive release of IL-1β and IL-18 [4]. Indeed, deletion or inhibition of NLRP3 ameliorates cardiac remodeling, reducing inflammation and fibrosis [5], [6], [7]. Of note, the activation of the NLRP3 inflammasome and caspase 1 with subsequent pyroptosis occurs especially when the myocardium has previously been “primed” by comorbidities [8]. The NLRP3 pathway can be downregulated by specific inhibitors or by gene silencing [9], with reduced infarct size and improved cardiac function in animals. Remarkably, the ineffectiveness of the IPC maneuvers in NLRP3-KO mice of both sexes suggests a complex role of NLRP3 and the possible presence of compensatory mechanisms [10]. As a matter of fact, however, Algoet et al. [3] in the review by Algoet et al. reports rather disappointing results in clinical trials testing anti-inflammatory therapies, with the only exceptions of trials targeting IL-1RE, IL-1β and microtubule assembly that target the NLRP3 inflammasome.

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