A Hidden Pathway to a Major Concern: The Role of Pyroptosis in Inducing Myocardial Infarction Reperfusion Injury and Emerging Therapeutic Targets

Myocardial infarction reperfusion injury (MIRI) is a paradoxical phenomenon. Restoration of blood flow to the heart potentially saves our lives, but at the same time, kills other heart cells. This impact on final infarct size counteracts the advantages of revascularization. While oxidative stress and calcium overload have long been the focus of cell demise, disease pathways that lead to cell death are classic as well, particularly the highly inflammatory pyroptosis. This review will provide a comprehensive discussion on the established pathophysiology of MIRI and its current therapies, followed by an extensive discussion on pyrotosis. It also seeks to examine the therapeutic potential of targeting pyroptosis, evaluating drugs from preclinical development to active clinical trials. The oxidative burst, calcium overload, mPTP (mitochondrial permeability transition pore) opening, and inflammation are all causes of the classical MIRI model. Although investigations have been undertaken for several decades, a therapeutic agent specifically for MIRI has not yet been approved. Trials of agents like cyclosporine A and remote ischemic conditioning have yielded mixed results. About pyroptosis, the pathway gets activated by signals like mtDNA and ROS, hence it triggers the NLRP3 inflammasome, leading to caspase-1 activation and gasdermin D (GSDMD) separation, forming lytic openings in the plasma membrane. It activates the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 that further enhance tissue damage. MCC950, OLT1177, and VX-765 are NLRP3, caspase-1, and GSDMD inhibitors that decrease the infarct size in mice prior to use in humans. The clinical IL-1β antagonist canakinumab was effective in reducing recurrent events in the CANTOS (Cardiovascular Risk Reduction Study (Reduction in Recurrent Major CV Disease Events)) trial. Colchicine is beneficial in chronic coronary disease. A drug called Dapansutrile is undergoing phase II trials for new indications, and it is an NLRP3 inhibitor. Pyroptosis is an important contributor to MIRI, linking cardiomyocyte death to potent inflammation. Focusing on this can help expand our aim to look for more potential therapeutics. The re-purposing of existing drugs, such as colchicine and disulfiram, and the development of new, specific NLRP3 inhibitors represent a promising pipeline toward finally achieving clinically relevant cardioprotection that enhances the prognosis in patients suffering from myocardial infarction.